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WE WELCOME ALL OUR SPEAKERS AND

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PARTICIPANTS AND WE WOULD ALSO

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LIKE TO WELCOME THE 175

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PARTICIPANTS WHO SIGNED UP TO

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ATTEND ONLINE.

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I'M SURE THEY'RE NOT HERE QUITE

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YET BUT WE DO EXPECT A LARGE

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TURN OUT ONLINE AS WELL.

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WE WILL REMIND ALL ONLINE

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PARTICIPANTS TO REMAIN MUTED

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DURING THE DURATION OF THE

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MEETING.

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SO ANIMAL MODELS PLAY CRUCIAL

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ROLES IN BASIC STUDIES OF

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RESPIRATORY I HAVE USS AIMED AT

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UNDERSTANDING PATHOGENESIS,

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TRANSMISSION AND IMMUNITY.

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--AND AN MOLL MODELS PROVIDED A

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FOUNDATION FOR MANY NEW VACCINE

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APPROACHES.

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HOWEVER TO IMPROVE OUR

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APPROACHES TO VACCINE AND

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THERAPY DEVELOPMENT WE FEEL

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THERE A STRONG NEED TO

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UNDERSTAND DETAILS FOR

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RESPIRATORY PATHOLOGY AND IMMUNE

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RESPONSES.

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SO THIS WORKSHOP WILL BE FOCUSED

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ON ANIMAL MODELS USED TO STUDY

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BASIC ASPECTS OF INFLUENZA AND

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SARS-COV-2 INFECTION IN HUMANS

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AND THIS TEMS FROM THE CAPACITY

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FOR SUBSTANTIAL ANTIGENIC DRIFT

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AND THE PANDEMIC POTENTIAL OF

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BOTH OF THESE VIRUSES, AS WELL

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AS NATURE OF THE RESEARCH BEING 

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PERFORMED IN NIAID PORTFOLIOS.

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ALTHOUGH IT MAY BE ATTEMPTING

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TODAY AND TOMORROW TO DISCUSS

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THE STATUS OF THE H5 N1

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INFLUENZA OUTBREAK IN COW XTION

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OTHER DAIRY ANIMALS WE WANT THIS

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WORKSHOP TO TRY TO REMAIN

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FOCUSED ON BETTER UNDERSTANDING

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THE HUMAN HEALTH OUTCOMES AND

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NOT STRAY TOO FAR INTO ANIMAL

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HEALTH OUTCOMES.

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SO WE ASKED SPEAKERS TO ADDRESS

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THE EXPERIMENT AMILLIO BENEFITS

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OF LIMITATIONS OF THE ANIMAL

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MODELS THEY USE TO STUDY VIRUS

52
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INFECTIONS.

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WE ENCOURAGE RESPECT OF

54
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DISCOURSE ON APPROPRIATE ANIMAL

55
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MODELS FOR STUDYING VIRAL

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PATHOGENESIS AND TRANSMISSION.

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AND PERHAPS IDENT AREAS WHERE

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NOVEL APPROACHES ARE NEEDED TO

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IMPROVE OUR UNDERSTANDING OF

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INFLUENZA AND SARS-COV-2

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INFECTIONS AND VIRUS HOST

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INTERACTIONS.

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THROUGHOUT THE WOWRS OF THE

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WORKSHOP, WE WOULD LIKE ALL

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PARTICIPANTS TO NOT ONLY THINK

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ABOUT THE IMPACT OF WHAT IS

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DISCUSSED ON YOUR OWN RESEARCH

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BUT ALSO TO THE FIELD AS A

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WHOLE.

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AND SO SOME OF THE QUESTIONS WE

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WANT YOU TO THINK ABOUT ARE WHAT

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ARE SOME OF THE REAGENT NEEDS

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THAT ARE NEEDED TO ADVANGS YOUR

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RESEARCH.

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WHAT ARE SOME OF THE MOST

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APPROPRIATE VIRUS STRAINS TO BE

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USING FOR THE STUDIES IN YOUR

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LAB AND IN THE FIELD.

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AND WHAT ANIMAL MODELS ARE MOST

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SUITED TO ANSWER SPECIFIC

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EXPERIMENTAL QUESTIONS.

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AND ARE THERE IMPROVEMENTS TO

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THESE ANIMAL MODELS THAT ARE

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NEEDED SO THAT THEY BETTER

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REFLECT HUMAN PHYSIOLOGY.

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SO TO GUIDE YOU IN THINKING

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ABOUT THESE QUESTIONS AND TO

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00:03:02,503 --> 00:03:04,905
ALLOW YOU TO OFFER CONCRETE

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FEEDBACK TO US WE'VE INCLUDED 3

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00:03:06,907 --> 00:03:07,808
QUESTIONS FOR YOU TO CONSIDER

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DURING THE COURSE OF THIS

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WORKSHOP.

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THESE QUESTIONS ARE POSTED HERE.

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WHAT REAGENTS ARE NEEDED TO

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ADVANCE THE RESEARCH IN YOUR

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FIELD?

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IS THERE A NEED FOR THE

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CONSISTENT, VALIDATED USE OF

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CONSISTENT VALIDATED CHALLENGED

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STRAINS OF VIRUS TO BE ABLE TO

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COMPARE STUDIES IN ANIMAL MODELS

102
00:03:30,631 --> 00:03:32,766
AND IF SO WHAT VIRUS STRAINS

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WORK BROADLY IN DIFFERENT ANIMAL

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MODELS?

105
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AND A BIT CHALLENGING QUESTION

106
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IS WHAT CRITERIA SHOULD BE

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CONSIDERED WHEN COMPARING ANIMAL

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MODELS TO HUMAN DATA TO ENSURE

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THE MODELS ARE CLINICALLY

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RELEVANT?

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00:03:45,245 --> 00:03:46,714
SO THE WAY WE WILL COLLECT

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FEEDBACK IS USING THE

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CONFERENCE'S I. O. APP.

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SO IF YOU WANT TO ENTER THIS WEB

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LINK, IT WILL TAKE YOU THERE OR

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YOU CAN USE THE QR CODE. 

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AND OUR GOAL HERE IS WE WILL

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START TO LOOK AT INITIAL

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RESPONSES AT THE END OF THE

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TODAY BUT WE WILL ALSO

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INCORPORATE THESE RESULTS INTO

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SESSIONS FOR TOMORROW WHEN WE

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DISCUSS SMALL ANIMAL MODEL

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RESOURCES AND DEVELOPMENT AND WE

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WILL ALSO TRY TO POST THIS LINK

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INTO THE ZOOM CHAT AS WELL FOR

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THOSE WHO ARE ONLINE.

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BEFORE WE GET STARTED I HAVE

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JUST A FEW HOUSEKEEPING ITEMS.

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IF YOU WOULD LIKE TO ORDER LUNCH

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FOR TODAY PLEASE USE THE QR CODE

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00:04:30,524 --> 00:04:32,026
OR LINK PROVIDED ON THE

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AYEPPEDDA TO PLACE AN ORDER WITH

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CHOPT.

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THERE ARE FLYERS ON EACH TABLE

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WITH ORDERING INSTRUCTIONS.

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YOU HAVE TO PLACE THESE ORDERS

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BY 9:30 AMIN ORDER FOR THEM TO

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MAKE IT TODAY SO MAKE YOUR LUNCH

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PLANS AS SOON AS POSSIBLE.

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FOR EACH SESSION, WE HAVE AN

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ASSIGNED MODERATOR WHO WILL HAVE

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SOME MAJOR TESTS, FIRST IS

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KEEPING THE TALKS ON TIME

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BECAUSE WE DO HAVE A RELATIVELY

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TIGHT PROGRAM AND THEP MAKING

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SURE THAT THE DISCUSSION STAYS

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ON TOPIC. 

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WE DO HAVE NIAID THROW A

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FOOTBALL MEMBERS WHO WILL HELP

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MONITOR ZOOM QUESTIONS BUT WE

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WILL TRY TO PRIORITIZE THE

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IN-PERSON DISCUSSIONS.

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SO NOW I WOULD LIKE TO INTRODUCE

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DR. MICHAEL ISON, WITH THE NIAID

156
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FOR A WELCOME.

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>> WELL, THANK YOU ALL FOR

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JOINING US TODAY.

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FOR THOSE THAT DON'T KNOW ME,

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I'VE BEEN HERE FOR ABOUT A YEAR

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AND HALF NOW.

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I COME FROM A BACKGROUND OF

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ANTIVIRALS AND ANIMALS, AND I

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MOST REEBTLY WORKED ON THE GSK

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RSV VACCINE, AS YOU ULTIMATELY

166
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KNOW WORKING WITH SMALL ANIMALS,

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NONE OF THE CLINICAL IMPACT OF

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ALL THE MEDICAL MEASURES WE KNOW

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WOULD BE POSSIBLE WITHOUT SMALL

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ANIMAL MODELS.

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I'M REALLY EXCITED TO LISTEN TO

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THE DISCUSSION TODAY AND I WANT

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TO THANK ALL OF YOU FOR COMING

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TO THE MEETING EITHER IN PERSON

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OR VIRTUALLY, CONTRIBUTING TO

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THE DISCUSSION.

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OUR TEAM REALLY IS COMMITTED TO

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TAKING THESE HOME AS LESSONS TO

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SEE HOW WE CAN HELP FACILITATE

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THE WORK OF THE RESEARCH

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COMMUNITY.

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SO PLEASE SHARE YOUR IDEAS, BE

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THOUGHTFUL, IF THINGS COME UP OR

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ISSUES, AN IDEA COMES TO YOU

185
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AFTER YOU LEAVE THE MEETING,

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PLEASE DON'T HESITATE TO REACH

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OUT TO ANY OF US.

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I WANT TO THANK OUR TEAM,

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PARTICULARLY MICHELLE AND STEVEN

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WHO HAVE DONE INCREDIBLE WORK

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AND WHILE IT MAY NOT FEEL LIKE

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IT FOR YOU THIS IS THE SECOND

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MEET THANKSGIVING WEEK THAT

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MICHELLE HAS BEEN HEAVILY

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INVOLVED WITH IT AND THE THIRD

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BIG MEETING IN THE LAST MONTH

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ORIGINAL SO SO SHE'S BEEN

198
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WORKING EXTRA HARD SO

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CONGRATULATIONS MICHELLE AND

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AGAIN, THANKS TO THE ENTIRE

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VIRAL SECTION OF THE RESPIRATORY

202
00:06:55,068 --> 00:06:56,703
DISEASE BRANCH WHO HAD BEEN

203
00:06:56,703 --> 00:06:58,272
DOING INCREDIBLE AMOUNT OF WORK

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BOTH WITH THE H5 RESPONSE, AND

205
00:07:00,140 --> 00:07:02,543
WORK TO HELP SUPPORT YOUR

206
00:07:02,543 --> 00:07:03,310
RESEARCH ENDEAVORS.

207
00:07:03,310 --> 00:07:13,854
THANKS FOR COMING AND WELCOME TO

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NAID.

209
00:07:21,295 --> 00:07:22,129
>> HI, EVERYONE, I AM

210
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DISCIPLINARY 18 POST AND I AM

211
00:07:23,931 --> 00:07:30,270
THE SECTION CHIEF FOR THE NAID,

212
00:07:30,270 --> 00:07:35,108
AND IT IS MY PLEASURE TO

213
00:07:35,108 --> 00:07:38,111
INTRODUCE DR. STACEY CHERRY,

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ST. JUDE CHILDREN'S RESEARCH

215
00:07:39,513 --> 00:07:41,148
HOSPITAL, STUDIESOT ECOLOGY OF

216
00:07:41,148 --> 00:07:43,283
INFLUENZA AND ANIMALS AND BIRDS,

217
00:07:43,283 --> 00:07:45,786
THE SENIOR ASSOCIATE DEAN FOR

218
00:07:45,786 --> 00:07:47,187
ACADEMIC AFFAIRS FOR THE

219
00:07:47,187 --> 00:07:48,722
TBRADUATE SCHOOL OF BIOMEDICAL

220
00:07:48,722 --> 00:07:51,592
SCIENCES AND COPI OF OUR CENTERS

221
00:07:51,592 --> 00:07:52,826
OF EXCELLENCE FOR INFLUENZA

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00:07:52,826 --> 00:07:53,760
RESEARCH AND RESPONSE AS WELL AS

223
00:07:53,760 --> 00:07:55,529
1 OF OUR CIVICS PROGRAMS AND

224
00:07:55,529 --> 00:07:57,264
STACEY HAS A LOT OF EXPERTISE

225
00:07:57,264 --> 00:08:00,534
AND A LOT OF DIFFERENT ANIMAL

226
00:08:00,534 --> 00:08:02,502
MODELS AND WITH MAKING REAGENTS

227
00:08:02,502 --> 00:08:04,605
A LOT OF EXPERTISE IN THAT AREA,

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SO WE'RE VERY HAPPY TO HAVE HER

229
00:08:07,207 --> 00:08:10,777
AS OUR KEY NOTE SPEAKER TODAY. 

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00:08:10,777 --> 00:08:19,953
SO WELCOME, STACEY.

231
00:08:19,953 --> 00:08:20,387
>> GOOD MORNING.

232
00:08:20,387 --> 00:08:21,555
THANK YOU FOR THAT INTRODUCTION.

233
00:08:21,555 --> 00:08:22,923
THIS IS NICE TALKING TO A

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00:08:22,923 --> 00:08:25,325
SMALLER GROUP, I FEEL LIKE I'M A

235
00:08:25,325 --> 00:08:28,395
LAB MEETING OR DEPARTMENT, SO

236
00:08:28,395 --> 00:08:29,363
IT'S A LITTLE LESS DOWN THING

237
00:08:29,363 --> 00:08:31,131
WHEN I AM PREACHING TO THE CHOIR

238
00:08:31,131 --> 00:08:32,566
INSTEAD OF THE EXPERTS.

239
00:08:32,566 --> 00:08:33,600
SO MICHELLE SAID WHEN SHE

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00:08:33,600 --> 00:08:35,102
SEPTORS OUT THE SCHEDULE I'M

241
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LIKE OH MY GOD.

242
00:08:37,504 --> 00:08:39,606
OKAY, SO, WHAT I'M HOPING WE CAN

243
00:08:39,606 --> 00:08:42,609
DO IS HAVE A CONVERSATION, MAYBE

244
00:08:42,609 --> 00:08:44,578
THE ONLINE PEOPLE, MOSTLY US AND

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00:08:44,578 --> 00:08:46,213
I'M LOOKING AT YOU BECAUSE I

246
00:08:46,213 --> 00:08:49,082
THINK THERE ARE AREAS WHERE WE

247
00:08:49,082 --> 00:08:50,217
NEED TO DISCUSS HOW TO MOVE

248
00:08:50,217 --> 00:08:54,221
FORWARD AND TO MOVE FORWARD IN

249
00:08:54,221 --> 00:08:54,655
THE RIGHT WAY.

250
00:08:54,655 --> 00:08:59,192
SO LET ME GO AHEAD AND GET

251
00:08:59,192 --> 00:08:59,426
STARTED.

252
00:08:59,426 --> 00:09:09,970
I DON'T THINK THERE'S A POINTER.

253
00:09:10,704 --> 00:09:10,971
THERE'S THAT.

254
00:09:10,971 --> 00:09:13,740
SO AS WE KNOW THERE WHEN WE'RE

255
00:09:13,740 --> 00:09:16,343
EXPOSED TO A RESPIRATORY

256
00:09:16,343 --> 00:09:17,477
INFECTION, THERE'S A SERIES OF

257
00:09:17,477 --> 00:09:19,079
EVENTS THAT NEED TO HAPPEN

258
00:09:19,079 --> 00:09:21,715
STARTING WITH THE MUCOSAL RATE

259
00:09:21,715 --> 00:09:23,583
DEALING WITH THE IMMUNE RESPONSE

260
00:09:23,583 --> 00:09:25,218
AND THE MICROBIAL DEPARTMENT

261
00:09:25,218 --> 00:09:26,653
PLAYS A BIG ROLE IN WHAT'S

262
00:09:26,653 --> 00:09:28,922
HAPPENING AND WHAT HAPPENS THEN

263
00:09:28,922 --> 00:09:29,923
IS YOU ILLICIT THAT SYSTEM

264
00:09:29,923 --> 00:09:31,958
TEMMIC INNATE IN THE ADAPTIVE

265
00:09:31,958 --> 00:09:33,860
IMMUNE RESPONSES AND IN MOST

266
00:09:33,860 --> 00:09:38,498
PEOPLE, IT WORKS BEAUTIFULLY.

267
00:09:38,498 --> 00:09:39,800
BUT WE KNOW IT DOES NOT WORK THE

268
00:09:39,800 --> 00:09:41,668
SAME WAY IN ALL PEOPLE AND THIS

269
00:09:41,668 --> 00:09:43,603
STARTS TO BECOME SOMETHING WE

270
00:09:43,603 --> 00:09:45,005
HAVE TO THINK ABOUT WHEN WE ARE

271
00:09:45,005 --> 00:09:46,606
TRYING TO PLAN WHAT ANIMAL

272
00:09:46,606 --> 00:09:47,908
MODELS ARE WE GOING TO USE, WHO

273
00:09:47,908 --> 00:09:49,876
ARE WE TRYING TO MODEL BECAUSE

274
00:09:49,876 --> 00:09:51,845
IT'S VERY COMPLEX AND IT DEPENDS

275
00:09:51,845 --> 00:09:54,247
ON WHAT THE QUESTION IS YOU'RE

276
00:09:54,247 --> 00:09:56,983
ASKING AND WHO YOU'RE ASKING IT

277
00:09:56,983 --> 00:09:57,150
IN.

278
00:09:57,150 --> 00:10:00,787
WE ALSO HAVE TO THINK ABOUT WHAT

279
00:10:00,787 --> 00:10:01,955
VIRUSES WE'RE WORKING WITH AND

280
00:10:01,955 --> 00:10:05,992
MOST OF US THINK ABOUT

281
00:10:05,992 --> 00:10:06,893
MONOINFECTIONS, BUT IN REALITY

282
00:10:06,893 --> 00:10:10,163
IS THAT TRULY WHAT'S  HAPPENING?

283
00:10:10,163 --> 00:10:12,499
OR ARE THERE A LOT MORE

284
00:10:12,499 --> 00:10:13,533
CO-INFECTIONS, AND HERE WE'RE

285
00:10:13,533 --> 00:10:15,502
JUST FOCUSING ON THE BACTERIA

286
00:10:15,502 --> 00:10:17,104
BECAUSE THE BACTERIA ARE WELL,

287
00:10:17,104 --> 00:10:19,172
THE BACTERIA BUT THEY PLAY AN

288
00:10:19,172 --> 00:10:21,074
IMPORTANT ROLE, THE UNDERLYING

289
00:10:21,074 --> 00:10:23,343
COMMENSAL OR MIKE ROY BIOME AS

290
00:10:23,343 --> 00:10:25,946
WELL AS THOSE MORE OPPORTUNISTIC

291
00:10:25,946 --> 00:10:26,213
BACTERIA.

292
00:10:26,213 --> 00:10:27,581
AND WE ALSO HAVE TO THINK ABOUT

293
00:10:27,581 --> 00:10:28,882
WHEN WE'RE LOOKING AT ANIMAL

294
00:10:28,882 --> 00:10:33,420
MODELS HOW EACH OF RESPIRATORY

295
00:10:33,420 --> 00:10:34,788
VIRUSES MAY BEHAVIOR DIFFERENTLY

296
00:10:34,788 --> 00:10:36,423
AND DIFFERENT MODELS MIGHT BE

297
00:10:36,423 --> 00:10:36,690
IMPORTANT.

298
00:10:36,690 --> 00:10:37,758
SO WHAT WE WANT TO TALK ABOUT OR

299
00:10:37,758 --> 00:10:39,192
WHAT I WANT TO TALK ABOUT TODAY

300
00:10:39,192 --> 00:10:42,429
ARE A COUPLE OF THINGS.

301
00:10:42,429 --> 00:10:43,830
THIS IS--I TYPICALLY DON'T DO AN

302
00:10:43,830 --> 00:10:45,031
OUTLINE BUT THIS WAS HELPFUL FOR

303
00:10:45,031 --> 00:10:47,367
ME TO THINK ABOUT THE BIG TOPICS

304
00:10:47,367 --> 00:10:48,702
I THOUGHT WE MAYBE NEEDED TO

305
00:10:48,702 --> 00:10:48,935
DISCUSS.

306
00:10:48,935 --> 00:10:50,570
ONE IS YOU HAVE TO TART WITH

307
00:10:50,570 --> 00:10:52,038
JUST COMPARING AND CONTRASTING

308
00:10:52,038 --> 00:10:53,306
THE DIFFERENT MODELS AND THIS IS

309
00:10:53,306 --> 00:10:55,208
WHERE YOU GUYS ARE THE EXPERTS

310
00:10:55,208 --> 00:10:56,376
SO I'M HOPING YOU WILL YUSM IN

311
00:10:56,376 --> 00:10:58,044
AND TELL ME WHERE I GOT THINGS

312
00:10:58,044 --> 00:11:00,414
WRONG OR WHERE WE NEED TO THINK

313
00:11:00,414 --> 00:11:02,182
MORE ABOUT IT.

314
00:11:02,182 --> 00:11:03,917
AND THEN, WHAT QUESTION FOR YOU

315
00:11:03,917 --> 00:11:04,518
GETTING AT?

316
00:11:04,518 --> 00:11:06,653
WHAT ARE YOU ACTUALLY TRYING TO

317
00:11:06,653 --> 00:11:09,289
MODEL IN THE ANIMAL AND WHO ARE

318
00:11:09,289 --> 00:11:11,658
YOU TRYING TO MODEL IT?

319
00:11:11,658 --> 00:11:14,561
IF IT'S AN INFANT USING NAIVE

320
00:11:14,561 --> 00:11:16,663
MICE, PERFECT, IF IT'S AN ADULT,

321
00:11:16,663 --> 00:11:18,632
MAYBE YOU NEED TO USE IMMUNE

322
00:11:18,632 --> 00:11:20,634
HISTORY OR DIRTY MICE LIKE WE'LL

323
00:11:20,634 --> 00:11:22,202
HEAR ABOUT FROM RYAN.

324
00:11:22,202 --> 00:11:23,804
CAN WE IMPROVE THESE MODELS AND

325
00:11:23,804 --> 00:11:26,807
IF SO, HOW DO WE DO HA AND WHAT

326
00:11:26,807 --> 00:11:28,175
ARE THE WAYS FORWARD FOR THE

327
00:11:28,175 --> 00:11:28,642
FIELD.

328
00:11:28,642 --> 00:11:33,346
SO THESE ARE THE TOPICS I WILL

329
00:11:33,346 --> 00:11:34,981
TRY AND HINT ON AND AGAIN I'M

330
00:11:34,981 --> 00:11:36,616
HOPING IT'S MORE OF A DISCUSSION

331
00:11:36,616 --> 00:11:39,319
SO FEEL FREE TO JUMP IN.

332
00:11:39,319 --> 00:11:43,223
SO THERE'S A LOT OF GREAT LARGER

333
00:11:43,223 --> 00:11:46,193
ANIMAL MODELS, YOU KNOW,

334
00:11:46,193 --> 00:11:48,728
NONHUMAN PRIMATES FOR BASICALLY

335
00:11:48,728 --> 00:11:55,001
ALL THE VIRUSES, FOR FLU,

336
00:11:55,001 --> 00:11:56,403
CHICKENS, PIGS, [INDISCERNIBLE]

337
00:11:56,403 --> 00:11:58,605
VIRUS, SHEEP, ALL FANTASTIC

338
00:11:58,605 --> 00:11:59,973
MODELS, OF COURSE THOSE OF US

339
00:11:59,973 --> 00:12:02,309
DOING FLU ARE NOW THINKING ABOUT

340
00:12:02,309 --> 00:12:03,944
COWS IN PARTICULAR, IN

341
00:12:03,944 --> 00:12:06,480
PARTICULAR COW UTTERS AND

342
00:12:06,480 --> 00:12:07,647
MAMMARY EPITHELIUM BUT WE WILL

343
00:12:07,647 --> 00:12:09,282
NOT FOCUS ON ANY OF THAT TODAY

344
00:12:09,282 --> 00:12:10,717
AS MICHELLE SAID, WE ARE REALLY

345
00:12:10,717 --> 00:12:12,352
GOING TO FOCUS ON THE SMALL

346
00:12:12,352 --> 00:12:14,321
ANIMAL MODELS OR THE 1 WE'RE

347
00:12:14,321 --> 00:12:17,557
MORE USE THE TO WORKING WITH THE

348
00:12:17,557 --> 00:12:18,925
IN THE LABORATORY PRIMARILY

349
00:12:18,925 --> 00:12:19,759
RODENTS AND FERRETS.

350
00:12:19,759 --> 00:12:20,927
I DIDN'T INCLUDE ANYTHING WITH

351
00:12:20,927 --> 00:12:22,162
RABBITS AND I DON'T KNOW OF

352
00:12:22,162 --> 00:12:25,365
ANYBODY OTHER THAN THE PEOPLE

353
00:12:25,365 --> 00:12:27,801
DOING PNEUMOCOCCUS AND EAR

354
00:12:27,801 --> 00:12:31,137
INFECTIONS THAT ACTUALLY USE

355
00:12:31,137 --> 00:12:31,505
CHINCHILLA.

356
00:12:31,505 --> 00:12:33,340
DOES ANYBODY ELSE KNOW OF

357
00:12:33,340 --> 00:12:37,310
ANYBODY WHO WORKS IN VIRUSES IN

358
00:12:37,310 --> 00:12:37,611
CHINCHILLA.

359
00:12:37,611 --> 00:12:37,911
THAT'S GOOD.

360
00:12:37,911 --> 00:12:42,249
THEY'RE HARD TO FINE EMPLOY

361
00:12:42,249 --> 00:12:42,983
LTD.'S JUST START.

362
00:12:42,983 --> 00:12:44,351
WE WILL HIT THIS ON THE HEAD.

363
00:12:44,351 --> 00:12:46,586
IF WE WERE TALKING ABOUT LARGER

364
00:12:46,586 --> 00:12:48,889
REMODELS, WE WOULD HAVE

365
00:12:48,889 --> 00:12:50,790
FANTASTIC REAGENTS, THERE ARE

366
00:12:50,790 --> 00:12:53,226
FANTASTIC REAGENTS FOR PIGS,

367
00:12:53,226 --> 00:12:55,295
COWS, NONHUMAN PRIMATES LESS SO

368
00:12:55,295 --> 00:12:57,697
FOR SMALL ANIMAL MODELS, MICE

369
00:12:57,697 --> 00:12:58,899
FANTASTIC BUT WE NEED TO GET

370
00:12:58,899 --> 00:13:00,100
THAT OUT THERE, THEY ARE

371
00:13:00,100 --> 00:13:00,934
IMPROVING AND IT'S SOMETHING WE

372
00:13:00,934 --> 00:13:06,907
MEDE TO TALK ABOUT IN THE WAYS

373
00:13:06,907 --> 00:13:08,775
FORWARD IS WHAT KIND OF TOOL

374
00:13:08,775 --> 00:13:11,511
BOXES DO WE HAVE FOR THIS

375
00:13:11,511 --> 00:13:14,214
SPECIES, HOW DO WE PRIORITIZE

376
00:13:14,214 --> 00:13:16,783
AND HOW DO WE GET OUT THAT THESE

377
00:13:16,783 --> 00:13:17,484
ARE AVAILABLE.

378
00:13:17,484 --> 00:13:19,252
SO FIRST COMPARE XG CONTRASTING,

379
00:13:19,252 --> 00:13:21,121
LET'S THINK ABOUT THE DIFFERENT

380
00:13:21,121 --> 00:13:22,122
SMALL ANIMAL MODELS, AGAIN, THIS

381
00:13:22,122 --> 00:13:23,557
IS WHAT I'VE SEEN IN THE

382
00:13:23,557 --> 00:13:26,726
LITERATURE FOR THE NONINFLUENZA

383
00:13:26,726 --> 00:13:27,627
VIRUSES SO EXPERTS PLEASE

384
00:13:27,627 --> 00:13:30,230
CORRECT ME WHERE IT'S WRONG.

385
00:13:30,230 --> 00:13:32,332
MICE, WE ALL USE MICE.

386
00:13:32,332 --> 00:13:40,740
WE SAVE MILLIONS OF MICE EACH

387
00:13:40,740 --> 00:13:41,775
YEAR FROM RESPIRATORY INFECTION,

388
00:13:41,775 --> 00:13:43,176
AND THEY ARE FANTASTIC.

389
00:13:43,176 --> 00:13:44,711
THEY CAN HAVE ANYTHING FROM

390
00:13:44,711 --> 00:13:46,212
SUBCLINICAL INFECTION TO DEATH.

391
00:13:46,212 --> 00:13:47,948
CAN YOU MAKE GREAT SCORING

392
00:13:47,948 --> 00:13:49,849
CHARTS, YOU CAN MONITOR THINGS,

393
00:13:49,849 --> 00:13:54,387
THERE'S A PROBLEM, THEY'RE NOT

394
00:13:54,387 --> 00:13:56,823
REALLY SUSCEPTIBLE TO MOST OF

395
00:13:56,823 --> 00:13:58,091
THE RESPIRATORY VIRUSES WE LIKE

396
00:13:58,091 --> 00:13:58,925
TO USE.

397
00:13:58,925 --> 00:14:01,595
THIS BECOMES AN ISSUE RIGHT?

398
00:14:01,595 --> 00:14:04,664
FOR THINGS LIKE STUDY SECTION, I

399
00:14:04,664 --> 00:14:09,669
WILL BE THE FIRST TO ADMIT FOR

400
00:14:09,669 --> 00:14:11,571
BLASTING PEOPLE FOR SAYING THEY

401
00:14:11,571 --> 00:14:13,440
USE PR8, BUT PR8 IS THE BEST

402
00:14:13,440 --> 00:14:17,777
VIRUS TO LOOK AT WHAT YOU'RE

403
00:14:17,777 --> 00:14:18,678
MODELING.

404
00:14:18,678 --> 00:14:20,413
SHOULD IT BE OKAY?

405
00:14:20,413 --> 00:14:21,615
RSV, LOTS OF WORK IN MICE BUT

406
00:14:21,615 --> 00:14:23,683
YOU WILL SEE A STUDY SECTION,

407
00:14:23,683 --> 00:14:25,552
YOU SHOULDN'T USE MICE FOR RSV,

408
00:14:25,552 --> 00:14:27,220
SO THESE ARE JUST THINGS AS A

409
00:14:27,220 --> 00:14:28,989
FIELD WE NEED TO THINK ABOUT,

410
00:14:28,989 --> 00:14:32,459
YOU KNOW THE AIRWAY ANATOMY HOW

411
00:14:32,459 --> 00:14:34,728
MUCH IS IT LIKE HUMAN?

412
00:14:34,728 --> 00:14:36,029
IT'S OKAY.

413
00:14:36,029 --> 00:14:37,397
SITES OF REPLICATION, TALKING

414
00:14:37,397 --> 00:14:39,899
ABOUT A PNEUMONIA MODEL WHILE

415
00:14:39,899 --> 00:14:41,768
YOU WILL GET SOME RESPIRATORY

416
00:14:41,768 --> 00:14:44,070
TRACT, IT IS LOWER, TRANSMISSION

417
00:14:44,070 --> 00:14:46,139
AT LEAST FOR FLU, SARS, SOME OF

418
00:14:46,139 --> 00:14:47,774
THOSE WILL TRANSMIT IN A MOUSE.

419
00:14:47,774 --> 00:14:50,977
I HAVE SEEN REPORTS IN INFANT

420
00:14:50,977 --> 00:14:54,147
MICE THAT FLU WILL TRANSMIT.

421
00:14:54,147 --> 00:14:55,115
REPEATED SAMPLING, NOT SO MUCH.

422
00:14:55,115 --> 00:14:56,182
THERE ARE THINGS THAT ARE EASY

423
00:14:56,182 --> 00:14:58,685
TO GET FROM THE SAME MOUSE OVER

424
00:14:58,685 --> 00:15:01,087
AND OVER, BUT YOU'RE NOT GOING

425
00:15:01,087 --> 00:15:03,723
TO GET A LUNG.

426
00:15:03,723 --> 00:15:05,125
LOTS OF REAGENTS, RIGHT?

427
00:15:05,125 --> 00:15:06,459
COSTS ARE REASONABLE BUT THEY

428
00:15:06,459 --> 00:15:08,461
ARE INCREASING, I DON'T KNOW IF

429
00:15:08,461 --> 00:15:10,563
ANYBODY ELSE HAD PROBLEMS

430
00:15:10,563 --> 00:15:13,099
GETTING MICE RECENTLY FROM JACKS

431
00:15:13,099 --> 00:15:13,400
LABS.

432
00:15:13,400 --> 00:15:15,235
THAT'S A REAL THING WHETHER

433
00:15:15,235 --> 00:15:16,469
THEY'RE BACK ORDERED OR THEY'RE

434
00:15:16,469 --> 00:15:17,637
JUST GETTING SORT OF PRICED UP.

435
00:15:17,637 --> 00:15:21,541
WHEN YOU GO TO PUBLISH, WHEN YOU

436
00:15:21,541 --> 00:15:23,209
GO TO STUDY SECTION, THE

437
00:15:23,209 --> 00:15:24,944
EXPECTATIONS, YOU WILL BE ABLE

438
00:15:24,944 --> 00:15:26,813
TO DO STATISTICALLY POWERED

439
00:15:26,813 --> 00:15:27,781
STUDIES, YOU WILL ADDRESS

440
00:15:27,781 --> 00:15:29,215
BIOLOGICAL SEX, YOU'RE GOING TO

441
00:15:29,215 --> 00:15:31,084
DO FANCY KNOCK OUTS, YOU KNOW

442
00:15:31,084 --> 00:15:33,153
THE EXPECTATIONS ARE VERY HIGH

443
00:15:33,153 --> 00:15:35,822
WHEN YOU'RE USING MOUSE MODELS

444
00:15:35,822 --> 00:15:40,560
BECAUSE THE REAGENTS ARE THERE.

445
00:15:40,560 --> 00:15:41,661
IT STARTS GETTING A LITTLE BIT

446
00:15:41,661 --> 00:15:43,863
DIFFERENT WHEN YOU LOOK AT OTHER

447
00:15:43,863 --> 00:15:44,764
MODELS.

448
00:15:44,764 --> 00:15:45,899
FOR EXAMPLE, HAMSTERS, NEVER

449
00:15:45,899 --> 00:15:47,767
THOUGHT ABOUT A HAMSTER BEFORE

450
00:15:47,767 --> 00:15:49,202
ALTHOUGH THAT WAS SOMETHING THAT

451
00:15:49,202 --> 00:15:50,370
[INDISCERNIBLE]'S GROUP HAS BEEN

452
00:15:50,370 --> 00:15:52,806
PUSHING FOR YEARS FOR FLU, BUT

453
00:15:52,806 --> 00:15:54,441
AGAIN ASYMPTOMATIC TO DEATH AND

454
00:15:54,441 --> 00:15:56,309
DISEASE, SUSCEPTIBILITY IS

455
00:15:56,309 --> 00:15:56,876
BETTER.

456
00:15:56,876 --> 00:15:58,044
SARS-COV-2 WAS THE FIRST TIME

457
00:15:58,044 --> 00:16:05,018
WE'VE EVER HAD TO WORK WITH A

458
00:16:05,018 --> 00:16:06,286
HAMSTER, BUT RSV WILL AFFECT

459
00:16:06,286 --> 00:16:08,188
THEM AND THEIR AIRWAY ANATOMY IS

460
00:16:08,188 --> 00:16:09,956
CLOSER TO A HUMAN.

461
00:16:09,956 --> 00:16:11,491
SITES OF REPLICATION, YOU CAN

462
00:16:11,491 --> 00:16:13,626
GET UPPER AND LOWER RESPIRATORY

463
00:16:13,626 --> 00:16:15,295
TRACT AND THAT IS SOMETHING WE

464
00:16:15,295 --> 00:16:16,129
NEED TO CONSIDER MOVING FORWARD

465
00:16:16,129 --> 00:16:18,164
IS THAT MORE AND MORE PEOPLE ARE

466
00:16:18,164 --> 00:16:19,899
LOOKING AT MUCOSAL IMMUNITY AND

467
00:16:19,899 --> 00:16:21,801
WILL THEY BE THE ANIMAL MODELS

468
00:16:21,801 --> 00:16:22,602
TO APPROPRIATELY DO THOSE

469
00:16:22,602 --> 00:16:27,273
STUDIES AND COMPARE THEM TO

470
00:16:27,273 --> 00:16:27,507
HUMANS.

471
00:16:27,507 --> 00:16:28,708
TRANSMISSION, YES.

472
00:16:28,708 --> 00:16:30,009
AGAIN REPEATED SAMPLING, IT

473
00:16:30,009 --> 00:16:32,512
DEPENDS ON THE SAMPLE THAT

474
00:16:32,512 --> 00:16:33,913
YOU'RE COLLECTING.

475
00:16:33,913 --> 00:16:36,316
THE REAGENTS ARE UNLIMITED BUT

476
00:16:36,316 --> 00:16:37,484
THEY ARE IMPROVING.

477
00:16:37,484 --> 00:16:38,818
COSTS ARE TILL REASONABLE, AND I

478
00:16:38,818 --> 00:16:41,221
DON'T KNOW FOR THE PEOPLE THAT

479
00:16:41,221 --> 00:16:43,189
DO HAMSTER MODELS, YOU KNOW, CAN

480
00:16:43,189 --> 00:16:46,259
YOU DO A LOT OF MODELS, ARE YOU

481
00:16:46,259 --> 00:16:49,462
EXPECTED TO DO MALE AND FEMALE,

482
00:16:49,462 --> 00:16:50,997
THERE'S REALLY NO FANCY MODELS I

483
00:16:50,997 --> 00:16:51,965
COULD FIND ALTHOUGH I DO THINK

484
00:16:51,965 --> 00:16:55,101
WE HAVE A TALK ON GENERATION OF

485
00:16:55,101 --> 00:16:55,769
MAKING TRANSGENIC HAMSTERS WHICH

486
00:16:55,769 --> 00:17:03,676
I THINK WILL BE REALLY EXCITING.

487
00:17:03,676 --> 00:17:08,148
RAT, HMM, OKAY, SO, AGAIN, FOR

488
00:17:08,148 --> 00:17:11,384
SOME RESPIRATORY PATHOGENS

489
00:17:11,384 --> 00:17:14,154
THEY'RE FANTASTIC.

490
00:17:14,154 --> 00:17:15,622
RSV, THOSE [INDISCERNIBLE] ARE

491
00:17:15,622 --> 00:17:18,091
THE GOLD STANDARD IN THE FIELD.

492
00:17:18,091 --> 00:17:18,992
THEY'RE ALSO TERRIFYING AND AS

493
00:17:18,992 --> 00:17:20,593
WE'RE GETTING MODEL CITIZENNER

494
00:17:20,593 --> 00:17:21,995
INTO RSV, THAT IS 1 I WOULD

495
00:17:21,995 --> 00:17:23,863
RATHER DO A PIG IN HIGH

496
00:17:23,863 --> 00:17:28,268
CONTAINMENT THAN A COTTON RAT IN

497
00:17:28,268 --> 00:17:28,434
BL2.

498
00:17:28,434 --> 00:17:31,571
SARS, FLU, THERE ARE A NUMBER OF

499
00:17:31,571 --> 00:17:34,774
RESPIRATORY THAT WILL REPLICATE

500
00:17:34,774 --> 00:17:37,343
IN THE RAT, GOT A BETTER AIRWAY

501
00:17:37,343 --> 00:17:40,413
ANATOMY AND AGAIN YOU CAN GET

502
00:17:40,413 --> 00:17:41,748
UPPER AND LOWER RESPIRATORY

503
00:17:41,748 --> 00:17:43,983
TRACT AND FOR RSV, THIS IS THE

504
00:17:43,983 --> 00:17:45,652
MODEL WHERE PEOPLE DO A LOT WITH

505
00:17:45,652 --> 00:17:47,453
ASTHMA AND LOOK AT A LOT OF

506
00:17:47,453 --> 00:17:48,021
THERAPEUTICS.

507
00:17:48,021 --> 00:17:49,589
YOU CAN GET TRANSMISSION, YEAH,

508
00:17:49,589 --> 00:17:51,825
WE'RE LIMITED WITH THE REAGENTS,

509
00:17:51,825 --> 00:17:52,025
RIGHT?

510
00:17:52,025 --> 00:17:54,327
THE COSTS ARE REASONABLE, BUT

511
00:17:54,327 --> 00:17:55,862
THE EXPECTATIONS ARE NOT AS FAR

512
00:17:55,862 --> 00:17:58,164
AS I KNOW QUITE WHAT THEY ARE

513
00:17:58,164 --> 00:17:59,833
WITH THE MOUSE WHERE YOU HAVE TO

514
00:17:59,833 --> 00:18:01,568
HAVE 20 MICE PER GROUP.

515
00:18:01,568 --> 00:18:02,502
THINGS LIKE THAT.

516
00:18:02,502 --> 00:18:05,972
I PUT TERRIFYING BECAUSE I FIND

517
00:18:05,972 --> 00:18:09,676
THE COTTON RATS SCARY.

518
00:18:09,676 --> 00:18:11,811
GINNY PIGS, THIS HAS BEEN AN

519
00:18:11,811 --> 00:18:15,582
EXCITING MODEL TO WATCH DEVELOP.

520
00:18:15,582 --> 00:18:18,218
DENEEZ LOHAN REALLY PIONEERED

521
00:18:18,218 --> 00:18:19,752
THIS SEVERAL YEARS AGO NOW FOR

522
00:18:19,752 --> 00:18:22,322
LOOKING AT TRANSMISSION WITH

523
00:18:22,322 --> 00:18:23,923
INFLUENZA VIRUS AND DISEASE

524
00:18:23,923 --> 00:18:25,758
VARY, FOR FLEW WE THINK ABOUT

525
00:18:25,758 --> 00:18:28,294
THEM BEING SUBCLINICAL BUT WITH

526
00:18:28,294 --> 00:18:30,663
OTHER RESPIRATORY VIRUSES YOU DO

527
00:18:30,663 --> 00:18:32,765
GET CLINICAL DEC.

528
00:18:32,765 --> 00:18:34,634
AIRWAY ANATOMY, AGAIN CLOSER TO

529
00:18:34,634 --> 00:18:37,971
HUMAN ANDS YOU DO GET BOTH UPPER

530
00:18:37,971 --> 00:18:39,572
AND LOWER RESPIRATORY TRACT.

531
00:18:39,572 --> 00:18:43,576
REAGENTS ARE JUST AS LIMITED,

532
00:18:43,576 --> 00:18:45,879
BUT WE'RE DOING MORE AND MORE

533
00:18:45,879 --> 00:18:46,479
STUDIES ESPECIALLY FOR

534
00:18:46,479 --> 00:18:47,547
TRANSMISSION BECAUSE THEY ARE

535
00:18:47,547 --> 00:18:50,183
SOMEWHAT EASIER TO WORK WITH

536
00:18:50,183 --> 00:18:52,418
THAN A FERRET AND AGAIN, WE WILL

537
00:18:52,418 --> 00:18:54,287
TALK LATER ABOUT FANCY NEW GINNY

538
00:18:54,287 --> 00:19:04,731
PIG MODELS THAT ARE BEING

539
00:19:07,467 --> 00:19:07,901
DEVELOPED.

540
00:19:07,901 --> 00:19:10,837
FERRETS, THESE ARE GREAT.

541
00:19:10,837 --> 00:19:12,639
A LOT DEPENDS ON HOW YOU

542
00:19:12,639 --> 00:19:15,141
MANIPULATED THAT MODEL, SO WITH

543
00:19:15,141 --> 00:19:17,243
A HUMAN SEASONAL INFLUENZA

544
00:19:17,243 --> 00:19:24,384
STRAIN FOR THIS PART, WE GET A

545
00:19:24,384 --> 00:19:25,318
LOT OF DISEASE--IT DEPENDS ON

546
00:19:25,318 --> 00:19:27,186
THE STRAIN, IF YOU PUT H5 IN

547
00:19:27,186 --> 00:19:28,621
THERE,  YOU MAY NOT GET LUNG

548
00:19:28,621 --> 00:19:30,523
DISEASE, IT'S GOING IT GO

549
00:19:30,523 --> 00:19:33,126
NEUROTROAPIC AND IT'S GOING TO

550
00:19:33,126 --> 00:19:37,797
BE FATAL. 

551
00:19:37,797 --> 00:19:39,232
SARS WOULD INFECT, TRANSMIT

552
00:19:39,232 --> 00:19:41,000
BEAUTIFULLY, SO THESE ARE GOOD

553
00:19:41,000 --> 00:19:44,437
MODELS, YOU DO HAVE THAT NICE

554
00:19:44,437 --> 00:19:45,638
AIRWAY ANATOMY MORE SIMILAR TO A

555
00:19:45,638 --> 00:19:48,041
HUMAN AND AGAIN YOU WILL GET

556
00:19:48,041 --> 00:19:52,745
UPPER AND LOWER RESPIRATORY

557
00:19:52,745 --> 00:19:55,515
TRACT REPLICATION.

558
00:19:55,515 --> 00:19:57,150
REPEATED SAMPLING, THEY GET

559
00:19:57,150 --> 00:19:59,953
EASIER AS THEY GET LARGER, CAN

560
00:19:59,953 --> 00:20:02,155
YOU GET SALIVA, NAISAL SWABS,

561
00:20:02,155 --> 00:20:04,724
NAISAL WASHES, WHATEVER YOU WANT

562
00:20:04,724 --> 00:20:07,193
AND LIKE THE OTHERS REAGENTS ARE

563
00:20:07,193 --> 00:20:08,528
LIMITED BUT THEY ARE IMPROVING.

564
00:20:08,528 --> 00:20:09,729
WE WILL TALK ABOUT THAT AT THE

565
00:20:09,729 --> 00:20:10,029
END.

566
00:20:10,029 --> 00:20:11,764
WITH ALL OF THESE WITH MORE

567
00:20:11,764 --> 00:20:12,832
PEOPLE USING THESE MODELS, THERE

568
00:20:12,832 --> 00:20:14,267
IS MORE OF A CONCERTED EFFORT TO

569
00:20:14,267 --> 00:20:16,235
MAKE THE TOOLS THAT WE NEED TO

570
00:20:16,235 --> 00:20:18,137
BASICALLY MAKE THESE MODELS

571
00:20:18,137 --> 00:20:21,107
LARGE MICE IS THE HOPE.

572
00:20:21,107 --> 00:20:25,011
THEIR EXPENSIVE, THESE ARE NOT

573
00:20:25,011 --> 00:20:26,179
INEXPENSIVE ANIMALS, HOUSING IS

574
00:20:26,179 --> 00:20:28,581
MORE EXPENSIVE AND THEY CAN BE

575
00:20:28,581 --> 00:20:31,417
DIFFICULT TO WORK WITH.

576
00:20:31,417 --> 00:20:35,054
WHEN YOU GO TO PUBLISH, IT'S A

577
00:20:35,054 --> 00:20:37,056
LITTLE BIT EASIER TO--I WON'T

578
00:20:37,056 --> 00:20:38,691
SAY GET AWAY WITH BUT IT'S

579
00:20:38,691 --> 00:20:41,227
EASIER TO JUSTIFY NOT DOING 20

580
00:20:41,227 --> 00:20:43,863
FERRETS PER GROUP AND 5 TIME

581
00:20:43,863 --> 00:20:44,197
POINTS.

582
00:20:44,197 --> 00:20:44,797
BIOLOGICAL SEX, YOU HAVE TO

583
00:20:44,797 --> 00:20:46,399
ADDRESS IT BUT WORKING WITH

584
00:20:46,399 --> 00:20:48,101
FEMALE FERRETS CAN BE DIFFICULT,

585
00:20:48,101 --> 00:20:48,501
RIGHT?

586
00:20:48,501 --> 00:20:50,269
ESPECIALLY WHEN THEY HIT SEXUAL

587
00:20:50,269 --> 00:20:52,438
MATURITY, IT CAN BE TRICKY.

588
00:20:52,438 --> 00:20:55,675
FANCY MODELS, THERE ARE ACTUALLY

589
00:20:55,675 --> 00:20:56,609
TRANSGENIC FERRETS.

590
00:20:56,609 --> 00:20:58,978
THERE'S A GROUP IN IOWA THAT

591
00:20:58,978 --> 00:21:01,381
SPENDS A LOT OF TIME

592
00:21:01,381 --> 00:21:02,415
PARTICULARLY FOR CYSTIC FIBROSIS

593
00:21:02,415 --> 00:21:04,617
AND OTHER LUNG DISEASE IS MAKING

594
00:21:04,617 --> 00:21:06,719
VERY MUCH CELL BIOLOGY BASED

595
00:21:06,719 --> 00:21:08,354
REAGENTS LOOKING AT LUNG REPAIR,

596
00:21:08,354 --> 00:21:11,891
LUNG INJURY AND HE HAS THE

597
00:21:11,891 --> 00:21:13,526
CAPABILITIES OF MAKING

598
00:21:13,526 --> 00:21:15,361
TRANSGENIC FERRETS FOR PEOPLE

599
00:21:15,361 --> 00:21:19,332
AND WILL HOUSE THEM THERE.

600
00:21:19,332 --> 00:21:22,635
AND THEN WE HAVE THE PEN

601
00:21:22,635 --> 00:21:23,936
ULTIMATE ANIMAL MODEL WHICH IS

602
00:21:23,936 --> 00:21:27,073
HUMANS WHICH IS HUMANS RIGHT.

603
00:21:27,073 --> 00:21:30,376
SO THERE, DEC, ASYMPTOMATIC TO

604
00:21:30,376 --> 00:21:32,145
DEATH, JUST LIKE AN ANIMAL

605
00:21:32,145 --> 00:21:33,946
MODEL, YOU CAN DO GOOD SCORING

606
00:21:33,946 --> 00:21:35,415
CHARTS IN PEOPLE, THEY CAN EVEN

607
00:21:35,415 --> 00:21:37,984
HELP YOU.

608
00:21:37,984 --> 00:21:38,751
SUSCEPTIBILITY, GOOD, DEPENDING

609
00:21:38,751 --> 00:21:40,353
ON THE PERSON, DEPENDING ON THE

610
00:21:40,353 --> 00:21:41,921
STRAIN, YOU HAVE AIRWAY ANATOMY

611
00:21:41,921 --> 00:21:44,791
THAT LOOKS LIKE A HUMAN AND YOU

612
00:21:44,791 --> 00:21:48,995
HAVE SITES OF VIRAL REPLICATION,

613
00:21:48,995 --> 00:21:50,163
UPPER, LOWER AND WE'RE ALL

614
00:21:50,163 --> 00:21:51,864
GIGGLING BUT THERE ARE PEOPLE

615
00:21:51,864 --> 00:21:54,300
THAT ARE PUSHING TO GET AWAY

616
00:21:54,300 --> 00:21:56,135
FROM ANIMAL MODELS AND IF YOU

617
00:21:56,135 --> 00:21:57,703
WANT TO STUDY INFECTION IN A

618
00:21:57,703 --> 00:21:59,005
HUMAN, YOU STUDY IT IN A HUMAN

619
00:21:59,005 --> 00:22:02,775
SO I THINK IT NEEDS TO BE HERE

620
00:22:02,775 --> 00:22:04,077
BECAUSE WE NEED TO THINK ABOUT

621
00:22:04,077 --> 00:22:06,179
HOW CAN WE DO THIS AND CAN IT

622
00:22:06,179 --> 00:22:07,580
CAN BE DONE AND CAN IT BE DONE

623
00:22:07,580 --> 00:22:09,649
IN SUCH A WAY YOU CAN BRING THAT

624
00:22:09,649 --> 00:22:11,217
INFORMATION BACK TO IMPROVE OUR

625
00:22:11,217 --> 00:22:14,220
ANIMAL MODELS AS WELL.

626
00:22:14,220 --> 00:22:15,721
WILL YOU GET TRANSMISSION IN

627
00:22:15,721 --> 00:22:18,124
ABSOLUTELY GIVEN THE RIGHT

628
00:22:18,124 --> 00:22:18,491
PEOPLE.

629
00:22:18,491 --> 00:22:20,093
REPEATED SAMPLING, YEAH, IF THAT

630
00:22:20,093 --> 00:22:21,694
PERSON WILL LET YOU DO IT, YOU

631
00:22:21,694 --> 00:22:22,995
CAN GET LOTS OF DIFFERENT

632
00:22:22,995 --> 00:22:23,229
THINGS.

633
00:22:23,229 --> 00:22:25,164
AGAIN, YOU'RE NOT GOING TO GET A

634
00:22:25,164 --> 00:22:26,899
LUNG SAM SAMPLE FROM THEM BUT

635
00:22:26,899 --> 00:22:29,735
MAYBE THEY'LL LET YOU DO 1

636
00:22:29,735 --> 00:22:30,303
BOWEL.

637
00:22:30,303 --> 00:22:31,771
REAGENTS, LOTS OF REAGENTS FOR

638
00:22:31,771 --> 00:22:32,338
HUMANS, RIGHT?

639
00:22:32,338 --> 00:22:37,110
NOW THEY'RE GOING TO BE PRICEY

640
00:22:37,110 --> 00:22:38,644
AND DIFFICULT TO DO, AND THEN

641
00:22:38,644 --> 00:22:40,379
YOU'RE REALLY GETTING INTO THE

642
00:22:40,379 --> 00:22:41,781
COMPLEXITY THAT I THINK ISN'T

643
00:22:41,781 --> 00:22:43,649
PRESENT IN MOST FOR ANIMAL

644
00:22:43,649 --> 00:22:47,987
MODELS THAT ALLOWS US TO BETTER

645
00:22:47,987 --> 00:22:48,454
UNDERSTAND THINGS

646
00:22:48,454 --> 00:22:50,923
MECHANISTICALLY WITHOUT THE

647
00:22:50,923 --> 00:22:53,759
COMPLICATIONS OF HOST GENETICS

648
00:22:53,759 --> 00:22:54,727
AND UNDERLYING INFECTIONS, BUT

649
00:22:54,727 --> 00:22:56,996
THAT'S ALSO I THINK WHAT THE

650
00:22:56,996 --> 00:22:59,499
ARGUMENT IS ABOUT WHY THE ANIMAL

651
00:22:59,499 --> 00:23:01,834
MODELS WILL NEVER COMPLETELY

652
00:23:01,834 --> 00:23:03,269
RECAPITULATE WHAT WE SEE IN

653
00:23:03,269 --> 00:23:04,403
HUMAN, SO IS IT REALITY TO THINK

654
00:23:04,403 --> 00:23:06,272
THAT WE WOULD MOVE TOWARDS JUST

655
00:23:06,272 --> 00:23:07,773
DOING EVERYTHING IN AWE HUMAN.

656
00:23:07,773 --> 00:23:10,009
I DON'T THINK SO, BUT THERE ARE

657
00:23:10,009 --> 00:23:12,578
PLENTY OF PEOPLE THAT DO THINK

658
00:23:12,578 --> 00:23:14,614
THIS IS POSSIBLE ESPECIALLY WITH

659
00:23:14,614 --> 00:23:16,516
THE NEW HUMAN CHALLENGE VIRUSES

660
00:23:16,516 --> 00:23:23,723
IN HUMAN CHALLENGE MODELS.

661
00:23:23,723 --> 00:23:26,259
SO WE HAVE A LOT OF DIFFERENT

662
00:23:26,259 --> 00:23:27,293
ANIMAL MODELS, WE POTENTIALLY

663
00:23:27,293 --> 00:23:28,194
HAVE PEOPLE, BUT THE FIRST THING

664
00:23:28,194 --> 00:23:29,629
WE HAVE TO THINK ABOUT IS WHAT

665
00:23:29,629 --> 00:23:32,131
ARE THE QUESTIONS THAT YOU'RE

666
00:23:32,131 --> 00:23:34,834
ASKING, WHAT ARE YOU TRYING TO

667
00:23:34,834 --> 00:23:36,002
MODEL AND THAT WILL HELP YOU

668
00:23:36,002 --> 00:23:39,739
THINK ABOUT WHAT'S THE BEST WAY

669
00:23:39,739 --> 00:23:40,273
TO DO THIS.

670
00:23:40,273 --> 00:23:42,975
SO IF YOU'RE DOING DISEASE

671
00:23:42,975 --> 00:23:45,645
SEVERITY, REALLY LOOKING AT

672
00:23:45,645 --> 00:23:46,512
PNEUMONIA, LUNG, YOU KNOW, YOU

673
00:23:46,512 --> 00:23:48,014
KNOW THAT YOU CAN DO THESE

674
00:23:48,014 --> 00:23:49,482
STUDIES IN MICE, BUT THERE ARE

675
00:23:49,482 --> 00:23:50,983
OTHER MODELS THAT WILL ALLOW YOU

676
00:23:50,983 --> 00:23:54,353
TO DO THIS, DEPENDING ON THE

677
00:23:54,353 --> 00:23:55,354
VIRAL STRAIN AND DEPENDING ON

678
00:23:55,354 --> 00:23:56,822
WHAT YOU'VE DONE TO THAT HOST,

679
00:23:56,822 --> 00:23:58,558
IF YOU MADE THAT HOST IMMUNO

680
00:23:58,558 --> 00:24:02,228
COMPROMISED IN SOME WAY,

681
00:24:02,228 --> 00:24:03,129
MALNOURISHED, PREGNANT.

682
00:24:03,129 --> 00:24:04,664
IF YOU'RE USING MALE VERSUS

683
00:24:04,664 --> 00:24:06,098
FEMALE, THERE ARE ALL THINGS CAN

684
00:24:06,098 --> 00:24:07,867
YOU DO TO MODULATE THAT SO THAT

685
00:24:07,867 --> 00:24:10,136
YOU DO GET MORE OF A SEVERE

686
00:24:10,136 --> 00:24:10,369
DISEASE.

687
00:24:10,369 --> 00:24:13,806
IF YOU'RE TRYING TO MODEL WHAT

688
00:24:13,806 --> 00:24:17,076
HAPPENS MUCOSAL AT THE UPPER

689
00:24:17,076 --> 00:24:19,145
RESPIRATORY TRACT, THIS GETS

690
00:24:19,145 --> 00:24:20,379
TRICKIER, SPECIALLY IN A MOUSE,

691
00:24:20,379 --> 00:24:22,715
WHERE IT MAY BE HARDER TO DO,

692
00:24:22,715 --> 00:24:24,317
SOMETHING WITH AN INFLUENZA

693
00:24:24,317 --> 00:24:26,919
VIRUS WHERE IT WAS SET UP TO BE

694
00:24:26,919 --> 00:24:27,987
THE PNEUMONIA MODEL, IT CAN BE

695
00:24:27,987 --> 00:24:29,088
DONE BUT YOU'RE HAVING TO THINK

696
00:24:29,088 --> 00:24:31,190
ABOUT WHAT YOU'RE TRYING TO

697
00:24:31,190 --> 00:24:32,558
MODEL AND HOW YOU'RE GOING TO DO

698
00:24:32,558 --> 00:24:33,759
IT, WHAT STRAIN OF VIRUSES ARE

699
00:24:33,759 --> 00:24:35,094
YOU GOING TO USE, AND THEN YOU

700
00:24:35,094 --> 00:24:36,862
HAVE TO THINK ABOUT THOSE

701
00:24:36,862 --> 00:24:38,030
CO-INFECTIONS, I DON'T KNOW IF

702
00:24:38,030 --> 00:24:39,432
ANYBODY ELSE HAS HAD SOMETHING

703
00:24:39,432 --> 00:24:41,200
RUN THROUGH THEIR ANIMAL

704
00:24:41,200 --> 00:24:45,738
FACILITY THAT ALL OF A SUDDEN,

705
00:24:45,738 --> 00:24:47,273
YOUR WANING STRAIN OF VIRUS IS

706
00:24:47,273 --> 00:24:48,474
KILLING ALL OF YOUR ANIMALS

707
00:24:48,474 --> 00:24:50,977
BECAUSE SOMETHING HAS GONE

708
00:24:50,977 --> 00:24:53,212
THROUGH THE FACILITY, NORO

709
00:24:53,212 --> 00:24:54,614
VIRUS, ASTRO VIRUS, PIN WORMS,

710
00:24:54,614 --> 00:24:57,617
WHATEVER SO WE KNOW THESE CAN

711
00:24:57,617 --> 00:25:01,821
INFLUENCE THE MODELS THAT WE'RE

712
00:25:01,821 --> 00:25:02,388
USING.

713
00:25:02,388 --> 00:25:03,589
IF YOU'RE DOING VACCINE STUDIES,

714
00:25:03,589 --> 00:25:06,926
I THINK THIS IS WHERE IT ALSO

715
00:25:06,926 --> 00:25:07,460
BECOMES REALLY IMPORTANT.

716
00:25:07,460 --> 00:25:09,629
AGAIN, WE DO A LOT OF VACCINE

717
00:25:09,629 --> 00:25:12,031
WORK IN MICE AND WHAT WE'RE

718
00:25:12,031 --> 00:25:15,801
LOOKING AT IS A BABY RIGHT?

719
00:25:15,801 --> 00:25:17,770
IF YOU'RE USING THIS NAIVE MOUSE

720
00:25:17,770 --> 00:25:20,206
THAT HAS NO IMMUNE HISTORY,

721
00:25:20,206 --> 00:25:21,207
YOU'RE BASICALLY MODELING WHAT

722
00:25:21,207 --> 00:25:23,309
WOULD HAPPEN IN AN INFANT.

723
00:25:23,309 --> 00:25:24,744
IS THAT WHAT YOU'RE TRYING TO

724
00:25:24,744 --> 00:25:24,944
MODEL?

725
00:25:24,944 --> 00:25:27,079
BECAUSE IF YOU GO INTO A HUMAN

726
00:25:27,079 --> 00:25:29,215
TRIAL, THAT'S THOT WHERE IT'S

727
00:25:29,215 --> 00:25:29,515
GOING TO GO.

728
00:25:29,515 --> 00:25:31,217
IT'S GOING TO GO IN AN ADULT.

729
00:25:31,217 --> 00:25:35,388
SO DO YOU NEED TO USE AN ANIMAL,

730
00:25:35,388 --> 00:25:36,155
FERRET HAMSTER, WHATEVER YOU

731
00:25:36,155 --> 00:25:39,292
WANT THAT HAS MORE OF AN ADULT

732
00:25:39,292 --> 00:25:42,328
IMMUNOLOGICAL RESPONSE OR HAS

733
00:25:42,328 --> 00:25:43,296
THAT IMMUNE HISTORY AND I THINK

734
00:25:43,296 --> 00:25:45,464
MOST OF US ARE GOING TOWARDS

735
00:25:45,464 --> 00:25:46,766
THAT IMMUNE HISTORY, IT'S

736
00:25:46,766 --> 00:25:47,967
IMPORTANT FOR FLU, IT'S NOW

737
00:25:47,967 --> 00:25:51,203
IMPORTANT FOR SARS THAT YOU HAVE

738
00:25:51,203 --> 00:25:52,238
A COMPLEX SARS-COV-2 IMMUNE

739
00:25:52,238 --> 00:25:54,373
HISTORY AND IT'S GETTING THAT

740
00:25:54,373 --> 00:25:56,208
WAY FOR RSV AS WELL.

741
00:25:56,208 --> 00:26:01,447
AND I CAN SAY FOR THE PAST 12,

742
00:26:01,447 --> 00:26:03,482
15 YEARS BEFORE WE WOULD ORDER

743
00:26:03,482 --> 00:26:05,651
FERRETS, WE WOULD PUT A LOT OF

744
00:26:05,651 --> 00:26:10,222
TIME AND EXPENSE INTO SCREENING

745
00:26:10,222 --> 00:26:11,757
EVERY FERRET.

746
00:26:11,757 --> 00:26:13,192
WE ORDER SERIES POINTSA FROM

747
00:26:13,192 --> 00:26:15,194
THESE FERRETS, HERE'S THE 1S WE

748
00:26:15,194 --> 00:26:16,829
WILL CHOOSE, WE WILL CHOOSE 20%

749
00:26:16,829 --> 00:26:18,798
MORE THAN WHAT WE NEED, WE WILL

750
00:26:18,798 --> 00:26:22,268
SCREEN THEM AND FIEBD  FIND THET

751
00:26:22,268 --> 00:26:23,536
ARE NAIVE, I DON'T KNOW IF

752
00:26:23,536 --> 00:26:24,737
ANYBODY ELSE DOES THAT BUT THAT

753
00:26:24,737 --> 00:26:27,406
IS WHAT WE WOULD DO, WE DO

754
00:26:27,406 --> 00:26:29,041
HHIs, AND I THINK THAT WAS

755
00:26:29,041 --> 00:26:30,476
COMPLETELY THE WRONG WAY TO GO.

756
00:26:30,476 --> 00:26:33,612
BECAUSE NOW WE'RE GETTING THESE

757
00:26:33,612 --> 00:26:35,581
FERRETS AND HAVING TO GIVE THEM

758
00:26:35,581 --> 00:26:36,682
AN IMMUNE HISTORY WHERE WE COULD

759
00:26:36,682 --> 00:26:38,551
HAVE HAD THEM RIGHT FROM THE

760
00:26:38,551 --> 00:26:38,818
BEGINNING.

761
00:26:38,818 --> 00:26:40,686
SO AGAIN, WE HAVE TO THINK ABOUT

762
00:26:40,686 --> 00:26:41,821
THAT IMMUNE RESPONSE, WHAT ARE

763
00:26:41,821 --> 00:26:43,956
YOU TRYING TO LOOK AT AND IS IT

764
00:26:43,956 --> 00:26:46,258
THE RIGHT MODEL AND THEN WHAT I

765
00:26:46,258 --> 00:26:48,027
MEAN IS THEY'RE CLEAN, RIGHT?

766
00:26:48,027 --> 00:26:49,362
THEY'RE GETTING A MONOINFECTION,

767
00:26:49,362 --> 00:26:51,030
THEY HAVE UNDERLYING THINGS BUT

768
00:26:51,030 --> 00:26:52,498
NOT--WE KNOW THEY DON'T HAVE

769
00:26:52,498 --> 00:26:53,833
THINGS THAT WE DON'T WANT THEM

770
00:26:53,833 --> 00:26:55,468
TO HAVE, THEY DON'T HAVE FLU,

771
00:26:55,468 --> 00:26:58,904
THEY DON'T HAVE RSV, THEY DON'T

772
00:26:58,904 --> 00:26:59,572
HAVE SARS-COV-2.

773
00:26:59,572 --> 00:27:04,043
DOES THAT MAKE A DIFFERENCE?

774
00:27:04,043 --> 00:27:04,243
YEAH.

775
00:27:04,243 --> 00:27:08,247
SO, THIS IS SOME OF MY

776
00:27:08,247 --> 00:27:10,149
INDIGENOUS PEOPLE ENROLLED IN

777
00:27:10,149 --> 00:27:12,518
OUR STUDIES IN COLUMBIA AND WHAT

778
00:27:12,518 --> 00:27:14,653
WE DID IS WE WENT IN AND JUST

779
00:27:14,653 --> 00:27:15,688
OFFERED THE GOVERNMENT FLU

780
00:27:15,688 --> 00:27:17,323
VACCINE BECAUSE THEY DIDN'T TAKE

781
00:27:17,323 --> 00:27:18,724
IT BECAUSE THEY DIDN'T HAVE

782
00:27:18,724 --> 00:27:19,558
ACCESS TO IT.

783
00:27:19,558 --> 00:27:20,826
SO NOT A CLINICAL TRIAL, JUST

784
00:27:20,826 --> 00:27:22,595
BRING IT TO THE COMMUNITIES IF

785
00:27:22,595 --> 00:27:24,263
THEY WANT TO TAKE IT, THEY CAN,

786
00:27:24,263 --> 00:27:27,967
SO HERE YOU HAVE THESE PEOPLE,

787
00:27:27,967 --> 00:27:29,034
REALLY COMPLICATED IMMUNE

788
00:27:29,034 --> 00:27:36,842
HISTORIES, RIGHT, ALL FROM

789
00:27:36,842 --> 00:27:37,910
NATURAL INFECKIONS, THEY HAVE

790
00:27:37,910 --> 00:27:39,712
WORMS, THEY HAVE PARASITES, THEY

791
00:27:39,712 --> 00:27:43,048
HAVE A LOT OF ZOANNOTTIC

792
00:27:43,048 --> 00:27:43,516
DISEASES.

793
00:27:43,516 --> 00:27:45,384
WHAT WE DIDN'T EXPECT IS THIS IS

794
00:27:45,384 --> 00:27:46,819
JUST A SAMPLE IS A NUMBER OF

795
00:27:46,819 --> 00:27:48,654
THESE PEOPLE, I WOULD SAY ABOUT

796
00:27:48,654 --> 00:27:50,423
HALF OF THEM IN THIS FIRST PHASE

797
00:27:50,423 --> 00:27:53,125
OF STUDY WHEN THEY CAME IN, AT

798
00:27:53,125 --> 00:27:56,095
DAY 0 TO GET THEIR FLU SHOT,

799
00:27:56,095 --> 00:27:57,630
THEY HAD SARS AND YOU CAN SEE

800
00:27:57,630 --> 00:28:02,902
WHAT THE CT VALUES LOOK LIKE.

801
00:28:02,902 --> 00:28:05,304
I MEAN 18.

802
00:28:05,304 --> 00:28:07,640
THAT'S NOT NOTHING.

803
00:28:07,640 --> 00:28:09,508
NO CLINICAL DISEASE WHATSOEVER,

804
00:28:09,508 --> 00:28:10,910
THAT'S VERY TYPICAL, IT'S

805
00:28:10,910 --> 00:28:12,611
COMPLETELY THE OPPOSITE OF WHAT

806
00:28:12,611 --> 00:28:13,646
WE HAD HYPOTHESIZED WHEN WE

807
00:28:13,646 --> 00:28:14,580
START DOG THESE STUDY SYSTEM

808
00:28:14,580 --> 00:28:16,115
THEY'RE GOING TO GET REALLY

809
00:28:16,115 --> 00:28:17,383
SEVERE DISEASE.

810
00:28:17,383 --> 00:28:20,786
THESE GUYS DON'T GET SICK FROM

811
00:28:20,786 --> 00:28:22,321
RESPIRATORY VIRUSES AND THEN 28

812
00:28:22,321 --> 00:28:24,323
DAYS LATER WE GET INTO, WE ARE

813
00:28:24,323 --> 00:28:25,524
STARTING TO SEE FLU BUT NOT

814
00:28:25,524 --> 00:28:27,927
SOMETHING WE THOUGHT ABOUT FOR A

815
00:28:27,927 --> 00:28:29,528
VACCINE STUDY IN A MOUSE OR

816
00:28:29,528 --> 00:28:30,729
FERRET IS THAT OOH, WHAT

817
00:28:30,729 --> 00:28:32,832
HAPPENED TO THIS PERSON ACTUALLY

818
00:28:32,832 --> 00:28:36,602
HAS SARS-COV-2 AT THE SAME TIME

819
00:28:36,602 --> 00:28:38,270
SO THIS IS THE REAL WORLD AND

820
00:28:38,270 --> 00:28:40,739
THIS IS 1 GROUP YOU CAN SAY IT'S

821
00:28:40,739 --> 00:28:42,074
INDIGENOUS, I DON'T THINK SO,

822
00:28:42,074 --> 00:28:49,748
IT'S JUST DO WE EVER LOOK,

823
00:28:49,748 --> 00:28:50,082
RIGHT?

824
00:28:50,082 --> 00:28:50,449
TRANSMISSION.

825
00:28:50,449 --> 00:28:52,017
THIS IS FUN AND SUSCEPTIBILITY

826
00:28:52,017 --> 00:28:54,220
TO TRANSMISSION, THIS IS WHERE

827
00:28:54,220 --> 00:28:56,522
HAVING REALLY CLEAN ANIMALS

828
00:28:56,522 --> 00:28:59,959
COULD CHANGE WHAT YOU'RE SEEING

829
00:28:59,959 --> 00:29:00,493
RIGHT?

830
00:29:00,493 --> 00:29:02,061
YOU'RE USED TO WORKING WITH

831
00:29:02,061 --> 00:29:04,530
CLEAN ANIMALS BUT IF THEY HAVE

832
00:29:04,530 --> 00:29:06,065
UPDATER LYING BACTERIA INFECS,

833
00:29:06,065 --> 00:29:09,835
WE KNOW CERTAIN THINGS LIKE

834
00:29:09,835 --> 00:29:10,769
STREPT O COCCUS PNEUMONIA, IF

835
00:29:10,769 --> 00:29:12,972
THEY GET FLU, IT CAN HELP IT

836
00:29:12,972 --> 00:29:13,572
TRANSMIT.

837
00:29:13,572 --> 00:29:15,541
IT CAN HELP IT BIND TO CELLS, WE

838
00:29:15,541 --> 00:29:21,046
KNOW IF IT HAS RSV, THAT CAN

839
00:29:21,046 --> 00:29:22,515
COMPLETELY CHANGE SO THAT

840
00:29:22,515 --> 00:29:25,084
INFECTION HISTORY ESPECIALLY AT

841
00:29:25,084 --> 00:29:26,385
THE MUCOSAL SURFACE, HOW WILL

842
00:29:26,385 --> 00:29:28,521
THAT CHANGE THAT SUSCEPTIBILITY

843
00:29:28,521 --> 00:29:29,755
TOO AND TRANSMISSION FROM THE

844
00:29:29,755 --> 00:29:30,789
ANIMAL AND THERE'S DIFFERENT

845
00:29:30,789 --> 00:29:32,091
TYPES OF CONTACT AND WE WILL

846
00:29:32,091 --> 00:29:33,392
HEAR MORE ABOUT THAT BECAUSE I

847
00:29:33,392 --> 00:29:35,494
THINK THAT'S SOME OF THE REALLY

848
00:29:35,494 --> 00:29:38,764
EXCITING STUDIES COMING OUT.

849
00:29:38,764 --> 00:29:40,766
SEEMA'S GROUP IS DOING A LOT BUT

850
00:29:40,766 --> 00:29:41,700
ALSO THE MECHANICS OF

851
00:29:41,700 --> 00:29:43,102
TRANSMISSION, BEING IN A CAGE

852
00:29:43,102 --> 00:29:45,204
TOGETHER, DOES THAT REALLY

853
00:29:45,204 --> 00:29:46,005
MIMIC, ALTHOUGH TIMES YOU FEEL

854
00:29:46,005 --> 00:29:47,873
LIKE THAT AT HOME WITH YOUR KIDS

855
00:29:47,873 --> 00:29:51,777
BUT IT DOES REALLY MIMIC HOW WE

856
00:29:51,777 --> 00:29:54,346
WOULD GET EXPOSED IN NATURE?

857
00:29:54,346 --> 00:29:55,614
THE OTHER THING WE HAVE TO THINK

858
00:29:55,614 --> 00:29:57,917
ABOUT, WHEN YOU'RE DOING

859
00:29:57,917 --> 00:30:02,087
AN ANIMAL MODEL IS WHAT ARE YOUR

860
00:30:02,087 --> 00:30:02,821
DOWN STREAM APPLICATIONS?

861
00:30:02,821 --> 00:30:04,523
WHAT ARE YOU GOING TO DO WITH

862
00:30:04,523 --> 00:30:06,859
THOSE TISSUES, IF YOU ARE GOING

863
00:30:06,859 --> 00:30:11,497
TO DO TYPOLOGY, VIRAL

864
00:30:11,497 --> 00:30:13,098
EMONSTRATIONS AND CYTOKINE ANDS

865
00:30:13,098 --> 00:30:13,832
CHEMOKINES, ANY MODEL WILL DO,

866
00:30:13,832 --> 00:30:17,403
IF YOU WANT TO GET FANCY AND YOU

867
00:30:17,403 --> 00:30:20,072
WANT TO DO TRANSCRIPTOMICS OR

868
00:30:20,072 --> 00:30:21,674
SINGLE CELL SEQUENCING IT GETS

869
00:30:21,674 --> 00:30:23,375
TRICKIER IF THE ANIMAL IS LARGE,

870
00:30:23,375 --> 00:30:26,245
SO THIS IS 1 EXAMPLE, THIS IS

871
00:30:26,245 --> 00:30:29,415
ACTUALLY TAKING A MOUSE LUNG, 3

872
00:30:29,415 --> 00:30:32,117
DAYS POST INFLUENZA INFECTION

873
00:30:32,117 --> 00:30:36,221
AND DOING THIS TISSUE CLEARING

874
00:30:36,221 --> 00:30:37,289
LIGHT PHASE MICROSCOPY AND ALL

875
00:30:37,289 --> 00:30:40,159
THE FLU IS INFLUENZA VIRUS

876
00:30:40,159 --> 00:30:41,827
NUCLEIC PROTEIN SO THIS IS SUPER

877
00:30:41,827 --> 00:30:43,896
ARE EASY TO DO WITH THE MOUSE.

878
00:30:43,896 --> 00:30:45,431
THE MOUSE LUNG, THE BRAIN, THE

879
00:30:45,431 --> 00:30:50,002
HEART, WE'VE DONE THEM ALL NOW,

880
00:30:50,002 --> 00:30:51,370
WE'VE DONE UPPER RESPIRATORY

881
00:30:51,370 --> 00:30:53,105
TRACT, A LITTLE BIT TRICKIER IN

882
00:30:53,105 --> 00:30:54,640
THE A FERRET BECAUSE THE TISSUE

883
00:30:54,640 --> 00:30:55,741
IS SO MUCH BIGGER BECAUSE YOU

884
00:30:55,741 --> 00:30:57,276
DON'T REALLY GET TO MODEL IT THE

885
00:30:57,276 --> 00:30:58,711
SAME WAY AND THAT'S SOMETHING

886
00:30:58,711 --> 00:31:03,782
WE'VE HAD TO THINK ABOUT DOING

887
00:31:03,782 --> 00:31:05,184
THIS SPATIAL IS WE DON'T WANT TO

888
00:31:05,184 --> 00:31:07,386
DO IT IN MICE BUT CAN WE DO IT

889
00:31:07,386 --> 00:31:08,253
IN ANOTHER MODEL BECAUSE THE

890
00:31:08,253 --> 00:31:11,991
TISSUE IS SO BIG.

891
00:31:11,991 --> 00:31:12,391
WHO'S YOUR TARGET?

892
00:31:12,391 --> 00:31:14,994
WHAT IS YOUR TARGET AUDIENCE,

893
00:31:14,994 --> 00:31:15,995
RIGHT?

894
00:31:15,995 --> 00:31:17,663
IS IT ADULTS, IS IT HEALTHY

895
00:31:17,663 --> 00:31:19,698
ADULTS, IS IT THE ELDERLY?

896
00:31:19,698 --> 00:31:24,703
DOES IT MAKE A DIFFERENCE?

897
00:31:24,703 --> 00:31:26,405
ABSOLUTELY I MEAN WE KNOW WHEN

898
00:31:26,405 --> 00:31:27,906
YOU THINK ABOUT VIRULENCE, WHEN

899
00:31:27,906 --> 00:31:29,108
YOU THINK ABOUT TRANSMISSION,

900
00:31:29,108 --> 00:31:31,076
WHEN YOU THINK ABOUT

901
00:31:31,076 --> 00:31:32,011
THERAPEUTICS, IT'S REALLY DEPEND

902
00:31:32,011 --> 00:31:33,646
EPT ON THE STRAIN, THE HOST AND

903
00:31:33,646 --> 00:31:34,747
AGAIN WHAT THEY'VE SEEN IN TERMS

904
00:31:34,747 --> 00:31:41,286
OF BEING ABLE TO PREVENT AND

905
00:31:41,286 --> 00:31:42,955
CONTROL AND WHEN IT COMES TO THE

906
00:31:42,955 --> 00:31:45,724
ANIMAL MODEL, WHEN WE KNOW IS IT

907
00:31:45,724 --> 00:31:48,627
HAPPENS IN AN ANIMAL MODEL.

908
00:31:48,627 --> 00:31:49,194
ABSOLUTELY.

909
00:31:49,194 --> 00:31:50,863
CYBER KLEIN GROUPS HAS SHOWN THE

910
00:31:50,863 --> 00:31:52,498
IMPORTANCE OF BIOLOGICAL SEX, WE

911
00:31:52,498 --> 00:31:56,101
ALL DO A STUDY NOW AND WE HEAR

912
00:31:56,101 --> 00:31:57,536
SABRA, IN OUR HEAD WHAT HAPPENS

913
00:31:57,536 --> 00:31:58,737
TO THE FEMALES AND YOU DO IT

914
00:31:58,737 --> 00:32:00,773
BECAUSE IT CAN BE VERY, VERY

915
00:32:00,773 --> 00:32:01,306
DIFFERENT.

916
00:32:01,306 --> 00:32:04,276
SARS IN INFANTS, WE WILL HEAR A

917
00:32:04,276 --> 00:32:09,481
TALK ABOUT THAT AND STANLEY

918
00:32:09,481 --> 00:32:11,250
PERLMAN'S WORK WITH SARS AND

919
00:32:11,250 --> 00:32:12,751
AGED, SHOWING IN THE AGED MICE,

920
00:32:12,751 --> 00:32:13,952
THATTA WHERE YOU CAN GET

921
00:32:13,952 --> 00:32:16,388
DISEASE, YOU KNOW WE HAVE MATT

922
00:32:16,388 --> 00:32:18,957
FRIEMAN WHO WORKED A LOT WITH

923
00:32:18,957 --> 00:32:19,992
DIABETES AND OTHER UNDERLYING

924
00:32:19,992 --> 00:32:22,161
CONDITIONS AND MIKE WILLA

925
00:32:22,161 --> 00:32:23,696
WORKING WITH OBESITY IN SARS,

926
00:32:23,696 --> 00:32:24,997
ALL OF THESE MAKE A DIFFERENCE

927
00:32:24,997 --> 00:32:27,032
IN PEOPLE AND NOT PRIZINGLY IT

928
00:32:27,032 --> 00:32:29,234
DOES MAKE A DIFFERENCE IN YOUR

929
00:32:29,234 --> 00:32:33,338
ANIMAL MODEL, EVEN USING THE

930
00:32:33,338 --> 00:32:34,073
SAME STRAIN OF VIRUS.

931
00:32:34,073 --> 00:32:36,275
IT CAN BE A GAME CHANGER IN WHAT

932
00:32:36,275 --> 00:32:38,143
YOU'RE ACTUALLY MODELING AND

933
00:32:38,143 --> 00:32:42,247
WE'VE SPENT A LOT OF TIME FOR

934
00:32:42,247 --> 00:32:46,085
FLU WORKING OUT NEW MODELS,

935
00:32:46,085 --> 00:32:47,019
PARTICULARLY AROUND OBESITY

936
00:32:47,019 --> 00:32:50,789
WHERE IN MICE, WE HAVE LOTS OF

937
00:32:50,789 --> 00:32:52,391
DIFFERENT MODELS, DIET INDUCED

938
00:32:52,391 --> 00:32:53,759
OBESITY, I WILL SHOW YOU A BIT

939
00:32:53,759 --> 00:32:55,627
ABOUT A NEW CHILDHOOD OBESITY

940
00:32:55,627 --> 00:33:00,165
MODEL THAT WE'RE WORKING ON,

941
00:33:00,165 --> 00:33:01,433
PREGNANCY, TIME PREGNANCY,

942
00:33:01,433 --> 00:33:02,935
MALNOURISHED, SO GOING THE OTHER

943
00:33:02,935 --> 00:33:04,570
DIRECTION BECAUSE WE KNOW IT'S

944
00:33:04,570 --> 00:33:07,039
NOT THAT OBESITY PER SE BUT MORE

945
00:33:07,039 --> 00:33:08,407
THE METABOLIC SYNDROME.

946
00:33:08,407 --> 00:33:14,713
WE'RE CALLING IT OZEMPIC, BUT

947
00:33:14,713 --> 00:33:18,951
ACTUALLY OZEMPIC VERUS METFORMIN

948
00:33:18,951 --> 00:33:21,653
VERSUS DIET AND EXERCISE.

949
00:33:21,653 --> 00:33:22,354
EFFICACY RESPONSES, DONE THE

950
00:33:22,354 --> 00:33:24,456
SAME THING IN FERRETS TO BE ABLE

951
00:33:24,456 --> 00:33:27,459
TO UNDERSTAND HOW THESE USHED

952
00:33:27,459 --> 00:33:29,428
LYING CONDITIONS OR

953
00:33:29,428 --> 00:33:30,028
CO-MORBIDITIES IMPACT

954
00:33:30,028 --> 00:33:31,430
TRANSMISSION OF THE VIRUS AS

955
00:33:31,430 --> 00:33:33,932
WELL AS SUSCEPTIBILITY TO

956
00:33:33,932 --> 00:33:34,666
GETTING INFECTED.

957
00:33:34,666 --> 00:33:36,235
AND THEN, YOU KNOW TRYING TO

958
00:33:36,235 --> 00:33:37,436
TRANSLATE WHAT WE'RE FINDING,

959
00:33:37,436 --> 00:33:39,505
THERE'S GREAT NEW WAYS TO DO

960
00:33:39,505 --> 00:33:41,640
THAT, EVEN EXVIVO.

961
00:33:41,640 --> 00:33:47,613
USING PRIMARY RESPIRATORY CELLS,

962
00:33:47,613 --> 00:33:49,381
USING THINGS LIKE THE

963
00:33:49,381 --> 00:33:50,382
ORGANELLESOT CHIP MODEL SYSTEMS

964
00:33:50,382 --> 00:33:51,450
WHICH ARE GETTING RETINAL

965
00:33:51,450 --> 00:33:52,384
LOCATION REALLY GOOD AND

966
00:33:52,384 --> 00:33:53,919
ULTIMATELY BEING ABLE TO DO

967
00:33:53,919 --> 00:33:55,320
HUMAN CORHOTTERS AND THEN

968
00:33:55,320 --> 00:33:56,488
PULLING THAT DATA TOGETHER.

969
00:33:56,488 --> 00:33:58,857
SO WE THINK ABOUT GOING 1 WAY,

970
00:33:58,857 --> 00:34:00,526
TAKING OUR ANIMALS, TRANSLATING

971
00:34:00,526 --> 00:34:01,860
IT TO HUMANS BUT I THINK WE

972
00:34:01,860 --> 00:34:02,795
SHOULD ALSO BE GOING THE OTHER

973
00:34:02,795 --> 00:34:04,429
WAY AND THINK ABOUT WHAT WE SEE

974
00:34:04,429 --> 00:34:06,398
IN HUMANS AND CAN WE

975
00:34:06,398 --> 00:34:07,900
RECAPITULATE THAT IN THE ANIMAL

976
00:34:07,900 --> 00:34:08,133
MODELS.

977
00:34:08,133 --> 00:34:10,302
SO JUST TO SHOW YOU SOME.

978
00:34:10,302 --> 00:34:11,203
DOES IT MATTER?

979
00:34:11,203 --> 00:34:13,505
SO THESE ARE OUR DIET INDUCED

980
00:34:13,505 --> 00:34:18,010
OBESE FERRETS, OR FURY

981
00:34:18,010 --> 00:34:20,779
FOOTBALLS, THEY WEIGH ABOUT 1.5

982
00:34:20,779 --> 00:34:22,981
KILOGRAMS SORE THEY'RE HONKING

983
00:34:22,981 --> 00:34:24,483
HUGE BEASTYS, SO WE GET THEM IN,

984
00:34:24,483 --> 00:34:28,821
WE PUT THEM ON A HIGH FAT DIET

985
00:34:28,821 --> 00:34:30,689
FOR UP TO 12 WEEKS.

986
00:34:30,689 --> 00:34:32,991
YOU HAVE TO MAKE IT BACKON

987
00:34:32,991 --> 00:34:34,426
FLAVORED OR THEY WON'T EAT IT,

988
00:34:34,426 --> 00:34:36,962
YOU HAVE TO GIVE THEM WET CAT

989
00:34:36,962 --> 00:34:38,297
FOOD, SO THERE ARE THESE LITTLE

990
00:34:38,297 --> 00:34:40,399
TRICKS YOU HAVE TO PLAY AND IF

991
00:34:40,399 --> 00:34:43,635
WE GIVE THEM SEASONAL INFLUENZA

992
00:34:43,635 --> 00:34:45,304
VIRUS INCLUDING FLEW B IT'S A

993
00:34:45,304 --> 00:34:46,705
MUCH MORE SEVERE DISEASE.

994
00:34:46,705 --> 00:34:50,943
SO IF YOU ARE USE A REPORTER

995
00:34:50,943 --> 00:34:51,910
VIRUS, WE'VE USED

996
00:34:51,910 --> 00:34:52,878
[INDISCERNIBLE], IF I CAN GET

997
00:34:52,878 --> 00:34:58,517
THIS TO WORK, MAYBE NOT, WE'VE

998
00:34:58,517 --> 00:34:59,785
USED [INDISCERNIBLE] AND

999
00:34:59,785 --> 00:35:00,719
[INDISCERNIBLE], WHAT YOU CAN

1000
00:35:00,719 --> 00:35:03,822
SEE HERE IS THAT THE OBESE YOU

1001
00:35:03,822 --> 00:35:05,991
HAVE MORE VIRUS IN THE LUNG.

1002
00:35:05,991 --> 00:35:09,394
SO IT DOESN'T STAY AN UPPER

1003
00:35:09,394 --> 00:35:10,462
RESPIRATORY TRACT INFECTION NOW.

1004
00:35:10,462 --> 00:35:12,531
YOU'VE LOST THE BARRIER AND IT'S

1005
00:35:12,531 --> 00:35:15,834
GETTING DEEPER INTO THE LUNGS OF

1006
00:35:15,834 --> 00:35:16,268
THESE ANIMALS.

1007
00:35:16,268 --> 00:35:19,471
AND WHEN YOU LOOK AT YOUR TCID50

1008
00:35:19,471 --> 00:35:21,240
OR TISSUE INFECT CULTURE DOSE 50

1009
00:35:21,240 --> 00:35:22,541
AND YOU LOOK AT THE DIFFERENT

1010
00:35:22,541 --> 00:35:23,942
LOBES OF THE LUNG, CAN YOU SEE

1011
00:35:23,942 --> 00:35:26,311
CLEARLY WE WE HAVE A LOT MORE

1012
00:35:26,311 --> 00:35:31,884
VIRUS IN NEEZ OBESE ANIMALS.

1013
00:35:31,884 --> 00:35:33,151
THE OTHER THING THAT WILL HAPPEN

1014
00:35:33,151 --> 00:35:34,920
IS WE WILL TRULY DEPENDOT STRAIN

1015
00:35:34,920 --> 00:35:38,657
AND HOW BIG THESE ANIMALS ARE

1016
00:35:38,657 --> 00:35:41,393
GET INTO ACUTE RESPIRATORY

1017
00:35:41,393 --> 00:35:42,961
DISTRESS SYNDROME, AGAIN THIS,

1018
00:35:42,961 --> 00:35:44,963
IS ABOUT THESE ANIMALS HAVING

1019
00:35:44,963 --> 00:35:46,431
METABOLIC SYNDROME.

1020
00:35:46,431 --> 00:35:49,902
ANYBODY WHO ORDERS ANIMALS FROM

1021
00:35:49,902 --> 00:35:53,639
TRIPLE F, PRE AND POST PANDEMIC

1022
00:35:53,639 --> 00:35:54,973
YOU'RE GETTING THESE FERITS AND

1023
00:35:54,973 --> 00:35:57,910
THEY'RE A LOT BIGGER THAN THEY

1024
00:35:57,910 --> 00:36:00,145
WERE PREVIOUSLY BUT THEY'RE

1025
00:36:00,145 --> 00:36:00,879
STILL METABOLICALLY HEALTHY.

1026
00:36:00,879 --> 00:36:03,582
SO THAT'S THE KEY OBESITY STARTS

1027
00:36:03,582 --> 00:36:05,117
SEEING VIRUS IN THE HEART.

1028
00:36:05,117 --> 00:36:07,986
IT'S TRULY REPLICATING IN THE

1029
00:36:07,986 --> 00:36:08,220
HEART.

1030
00:36:08,220 --> 00:36:09,521
THIS IS WHAT THE LUNGS LOOK LIKE

1031
00:36:09,521 --> 00:36:12,090
WHERE YOU CAN SEE IN THE TOP AT

1032
00:36:12,090 --> 00:36:15,661
3 DAYS POST INFECTION, THE

1033
00:36:15,661 --> 00:36:17,162
PATHOLOGY THAT'S HAPPENING THAT

1034
00:36:17,162 --> 00:36:18,964
EXPLAINS THE INCREASED CLINICAL

1035
00:36:18,964 --> 00:36:19,598
DISEASE, INCREASE INFLAMMATORY

1036
00:36:19,598 --> 00:36:20,866
RESPONSE AND THAT'S WHAT THE

1037
00:36:20,866 --> 00:36:25,037
LUNGS END UP LOOKING LIKE.

1038
00:36:25,037 --> 00:36:26,371
AND WE DEVELOPED, I THINK WE'RE

1039
00:36:26,371 --> 00:36:28,206
OVER A HUNDRED NOW, VALIDATED

1040
00:36:28,206 --> 00:36:35,580
PRIMER PROBES TO LOOK AT LUNG

1041
00:36:35,580 --> 00:36:36,949
REPAIR INJURY, INFLAMMATORY

1042
00:36:36,949 --> 00:36:38,183
RESPONSES, SO IF ANYBODY WANTS

1043
00:36:38,183 --> 00:36:39,017
THOSE, THOSE ARE AVAILABLE TO

1044
00:36:39,017 --> 00:36:42,421
YOU EMPLOY DOES IT MATTER BEYOND

1045
00:36:42,421 --> 00:36:43,221
DISEASE SEVERITY?

1046
00:36:43,221 --> 00:36:45,557
ABSOLUTELY, WHEN YOU LOOK AT

1047
00:36:45,557 --> 00:36:47,225
TRANSMISSION OR SUSCEPTIBILITY,

1048
00:36:47,225 --> 00:36:48,460
TOO, THOSE METABOLICALLY

1049
00:36:48,460 --> 00:36:49,728
UNHEALTHY FERRETS ARE MORE

1050
00:36:49,728 --> 00:36:52,497
LIKELY TO GET INFECTED EVEN WITH

1051
00:36:52,497 --> 00:36:54,967
ZOANNOTTIC STRAINS OF VIRUS,

1052
00:36:54,967 --> 00:36:56,601
THEY SPREAD MORE.

1053
00:36:56,601 --> 00:37:04,042
THEY SHRED MORE  MORE VIRUS, SHS

1054
00:37:04,042 --> 00:37:06,011
LONGER, AND IT'S IT DOESN'T

1055
00:37:06,011 --> 00:37:07,479
MATTER THE STRAIN OR FLU.

1056
00:37:07,479 --> 00:37:09,548
YOU ALSO GET CHANGES TO THE

1057
00:37:09,548 --> 00:37:10,849
VIRUS ITSELF, WHICH MAKES SENSE.

1058
00:37:10,849 --> 00:37:13,285
HAVE YOU A LOT MORE VIRUS

1059
00:37:13,285 --> 00:37:14,319
REPLICATING LONGER IN NISSAN

1060
00:37:14,319 --> 00:37:18,090
MALS AND WHAT IT LEADS TO IS A

1061
00:37:18,090 --> 00:37:21,526
CHANGE INLET VIRAL QUASI

1062
00:37:21,526 --> 00:37:22,227
SPECIES.

1063
00:37:22,227 --> 00:37:23,996
THERE'S FEWER DEFECTIVE

1064
00:37:23,996 --> 00:37:24,663
PARTICLES, THERE'S ACTUALLY MORE

1065
00:37:24,663 --> 00:37:28,233
CHANGES WHEN YOU LOOK AT SINGLE

1066
00:37:28,233 --> 00:37:28,967
NUCLEOTIDE VARIANTS INCLUDING IN

1067
00:37:28,967 --> 00:37:30,736
AREAS OF THE GENOME THAT WE KNOW

1068
00:37:30,736 --> 00:37:32,704
ARE IMPORTANT FOR ANTIGENIC

1069
00:37:32,704 --> 00:37:35,674
DRIFT. 

1070
00:37:35,674 --> 00:37:39,177
WE ALSO SEE MORE RESORT ANTS

1071
00:37:39,177 --> 00:37:41,747
HAPPEN IN THESE ANIMALS AND THIS

1072
00:37:41,747 --> 00:37:43,348
IS NOT FERRET SPECIFIC, IT

1073
00:37:43,348 --> 00:37:44,316
HAPPENS ALSO IN MICE.

1074
00:37:44,316 --> 00:37:48,020
WE KNOW THE SAME WAS TRUE WITH

1075
00:37:48,020 --> 00:37:48,220
SARS.

1076
00:37:48,220 --> 00:37:49,688
MICHAEL HAD DONE SARS AND

1077
00:37:49,688 --> 00:37:53,725
OBESITY IN MICE, SHOWED IT'S

1078
00:37:53,725 --> 00:37:54,026
WORSE.

1079
00:37:54,026 --> 00:37:55,560
WE REPEATED IT AND SAW EXACTLY

1080
00:37:55,560 --> 00:37:57,129
THE SAME THING INCLUDE NOTHING

1081
00:37:57,129 --> 00:37:58,296
OUR OBESE FERRETS, THEN WE

1082
00:37:58,296 --> 00:38:00,532
DECIDED TO DO RSV, FIGURED THIS

1083
00:38:00,532 --> 00:38:01,800
HAS TO BE THE SAME THING, THIS

1084
00:38:01,800 --> 00:38:04,569
IS GOING TO BE A GENERAL

1085
00:38:04,569 --> 00:38:06,471
PRINCIPAL OF OBESITY AND AT

1086
00:38:06,471 --> 00:38:07,539
LEAST PREEMILYINARLY THAT IS NOT

1087
00:38:07,539 --> 00:38:09,408
WHAT WE'RE SEEING, WHAT WE'RE

1088
00:38:09,408 --> 00:38:13,211
ACTUALLY SEE SUGGEST RSV IN THE

1089
00:38:13,211 --> 00:38:16,014
FERRET, THERE'S ACTUALLY--AND

1090
00:38:16,014 --> 00:38:17,082
THIS IS PRELIMINARY--BUT APPEARS

1091
00:38:17,082 --> 00:38:18,383
TO BE LESS VIRUS GETTING TO THE

1092
00:38:18,383 --> 00:38:21,386
LUNGS OF THESE ANIMALS.

1093
00:38:21,386 --> 00:38:24,322
AND MORE VIRUS STAYING IN THE

1094
00:38:24,322 --> 00:38:25,891
UPPER RESPIRATORY TRACT AND

1095
00:38:25,891 --> 00:38:33,899
ACTUALLY  SHEDDING IT A BIT

1096
00:38:33,899 --> 00:38:34,099
LATER.

1097
00:38:34,099 --> 00:38:36,001
SO WE'RE NOT DOING COTTON RATS

1098
00:38:36,001 --> 00:38:39,905
THERE, 'S NO WAY IN--BUT WE WILL

1099
00:38:39,905 --> 00:38:42,974
DO OBESE MICE, AND WE DID THOSE

1100
00:38:42,974 --> 00:38:44,309
THINKING OKAY, THIS IS WHERE

1101
00:38:44,309 --> 00:38:47,045
RUBBER HITS THE ROAD, THESE GUYS

1102
00:38:47,045 --> 00:38:50,348
WILL DROP DEAD, NOT SO MUCH.

1103
00:38:50,348 --> 00:38:52,818
ACTUALLY IN OBESE MICE, RSV IS

1104
00:38:52,818 --> 00:38:53,151
BETTER.

1105
00:38:53,151 --> 00:38:58,356
SO IF YOU LOOK AT THE PERCENT

1106
00:38:58,356 --> 00:38:59,991
WEIGHT CHANGE, DAYS POST

1107
00:38:59,991 --> 00:39:00,926
INFECTION, HERE'S YOUR LEAN

1108
00:39:00,926 --> 00:39:04,029
ANIMALS WHERE WE'RE USING 10 TO

1109
00:39:04,029 --> 00:39:05,831
THE SEVENTH RSV WHERE WE CAN GET

1110
00:39:05,831 --> 00:39:08,500
DISEASE AND THIS HAS BEEN

1111
00:39:08,500 --> 00:39:10,135
REPRODUCIBLE IS THE DIET INDUCED

1112
00:39:10,135 --> 00:39:14,272
OBESE ARE NOT AS SICK AND WE SEE

1113
00:39:14,272 --> 00:39:18,510
THIS, THERE'S LESS VIRUS IN THE

1114
00:39:18,510 --> 00:39:20,912
LUNGS, IT'S LOW BUT WE'RE

1115
00:39:20,912 --> 00:39:21,947
REPEATING THIS LOOKING AT

1116
00:39:21,947 --> 00:39:23,482
DIFFERENT TIME POINTS AND THE

1117
00:39:23,482 --> 00:39:25,217
SPREAD, BECAUSE THAT'S THE KEY

1118
00:39:25,217 --> 00:39:27,385
IS GETTING WITH RSV IS GETTING

1119
00:39:27,385 --> 00:39:29,254
DOWN TO THE ALVEOLAR SPACES AND

1120
00:39:29,254 --> 00:39:32,257
LISTING THAT IMMUNO PATHOLOGY

1121
00:39:32,257 --> 00:39:33,725
AND WE'RE LOOKING AT SPREAD BUT

1122
00:39:33,725 --> 00:39:35,994
WE KNOW FROM FLOW CYTOMETRY

1123
00:39:35,994 --> 00:39:37,062
WE'RE SEEING LESS IMMUNO

1124
00:39:37,062 --> 00:39:38,363
PATHOLOGY IN THESE MICE BECAUSE

1125
00:39:38,363 --> 00:39:39,931
IT'S DELAYED AND FOR FLU THAT'S

1126
00:39:39,931 --> 00:39:43,635
BAD, FOR SARS THAT'S BAD, FOR

1127
00:39:43,635 --> 00:39:44,369
RSV IT'S ACTUALLY GOOD.

1128
00:39:44,369 --> 00:39:45,871
SO THIS MAKE ITS REALLY

1129
00:39:45,871 --> 00:39:47,706
INTERESTING THAT IT MAY NOT JUST

1130
00:39:47,706 --> 00:39:48,673
BE THE BROAD STROKE.

1131
00:39:48,673 --> 00:39:49,474
SO IT'S SOMETHING WE'RE HAVING

1132
00:39:49,474 --> 00:39:50,675
TO LOOK AT AND THINK ABOUT.

1133
00:39:50,675 --> 00:39:53,311
AND THIS IS JUST SHOWING YOU IN

1134
00:39:53,311 --> 00:39:56,414
THE MICE, YOU CAN SEE JUST A LOT

1135
00:39:56,414 --> 00:39:57,816
LESS PATHOLOGY, AND AGAIN IT'S

1136
00:39:57,816 --> 00:39:59,818
BECAUSE WE'RE GETTING LESS OF

1137
00:39:59,818 --> 00:40:02,387
THOSE IMMUNE CELL INFILTRATES,

1138
00:40:02,387 --> 00:40:03,955
PARTICULARLY NUTRIFILLS, MA

1139
00:40:03,955 --> 00:40:07,092
ROUGH ATOM PHAGES AND T-CELLS.

1140
00:40:07,092 --> 00:40:09,728
SO, THIS HAS BEEN A LITTLE BIT

1141
00:40:09,728 --> 00:40:13,098
SURPRISING AND WE DON'T KNOW

1142
00:40:13,098 --> 00:40:14,633
ANYTHING, AT LEAST I HAVEN'T

1143
00:40:14,633 --> 00:40:16,735
SEEN ANYTHING ABOUT OBESITY AND

1144
00:40:16,735 --> 00:40:18,904
RSV, BUT WE'RE DIGGING THROUGH

1145
00:40:18,904 --> 00:40:29,414
ACTUALLY CLINICAL INFORMATION

1146
00:40:29,814 --> 00:40:30,148
AND METADATA.

1147
00:40:30,148 --> 00:40:31,550
SO ALSO WHEN YOU THINK ABOUT

1148
00:40:31,550 --> 00:40:33,518
INFECTION, DO YOU HAVE ANOTHER

1149
00:40:33,518 --> 00:40:34,119
VIRUS IN THERE?

1150
00:40:34,119 --> 00:40:35,487
AND THE ANSWER IS ABSOLUTELY.

1151
00:40:35,487 --> 00:40:37,989
WE KNOW IN OUR FERRETS IF THEY

1152
00:40:37,989 --> 00:40:40,759
HAVE RSV, THEY CAN STILL GET FLU

1153
00:40:40,759 --> 00:40:42,427
AND BOY IS IT BAD.

1154
00:40:42,427 --> 00:40:42,861
IT'S BAD, BAD.

1155
00:40:42,861 --> 00:40:45,463
EVEN IF THE RSV ARE 3 OR 4

1156
00:40:45,463 --> 00:40:46,965
MONTHS BEFORE, IT REALLY MAKES A

1157
00:40:46,965 --> 00:40:49,434
BIG DIFFERENCE.

1158
00:40:49,434 --> 00:40:52,204
CONTRAST IF THE FERRETS HAVE FLU

1159
00:40:52,204 --> 00:40:56,675
OR HAD FLU, THEY DON'T GET RSV. 

1160
00:40:56,675 --> 00:40:58,310
IT'S ALMOST BLOCKED AND WE KNOW

1161
00:40:58,310 --> 00:40:59,411
THAT THERE'S INTERACTION BETWEEN

1162
00:40:59,411 --> 00:41:01,279
RSV AND SARS, AND WE NOW HAVE

1163
00:41:01,279 --> 00:41:04,282
DATA ON SOME OF THESE OTHER

1164
00:41:04,282 --> 00:41:05,617
RESPIRATORY VIRUSES, BUT ALSO

1165
00:41:05,617 --> 00:41:09,154
BACTERIA, WE'VE DONE WORK WITH

1166
00:41:09,154 --> 00:41:11,489
SEEMA, ON BACTERIA AND WE HAVE A

1167
00:41:11,489 --> 00:41:13,391
GROUP AT ST. JUDE THAT WILL HELP

1168
00:41:13,391 --> 00:41:15,126
US LOOK AT FUNGUS, SO WHATEVER

1169
00:41:15,126 --> 00:41:18,597
YOU SEE IN HUMAN IN THOSE

1170
00:41:18,597 --> 00:41:19,197
HOUSEHOLD TRANSMISSION MODELS,

1171
00:41:19,197 --> 00:41:23,735
CAN YOU THEORETICALLY MODEL THIS

1172
00:41:23,735 --> 00:41:24,903
IN THE FERRETS.

1173
00:41:24,903 --> 00:41:25,837
PREGNANCY IS ANOTHER 1 AND WE

1174
00:41:25,837 --> 00:41:28,773
THINK THIS IS REALLY

1175
00:41:28,773 --> 00:41:30,108
INTERESTING, IS, YOU KNOW

1176
00:41:30,108 --> 00:41:31,943
PREGNANT WOMEN, HIGH, HIGH, RISK

1177
00:41:31,943 --> 00:41:39,417
FOR FLU, HIGH RISK FOR

1178
00:41:39,417 --> 00:41:39,784
SARS-COV-2.

1179
00:41:39,784 --> 00:41:41,119
ENCOURAGE THEM TO GET VACCINATED

1180
00:41:41,119 --> 00:41:42,854
AND WHEN WE VACCINATE WE HAVE

1181
00:41:42,854 --> 00:41:44,522
LOTS OF DIFFERENT FLU VACCINES,

1182
00:41:44,522 --> 00:41:48,893
WE HAVE LIVE VIRUS, THE

1183
00:41:48,893 --> 00:41:49,961
ENACTIVATED FLU MIST,

1184
00:41:49,961 --> 00:41:52,330
RECOMBUPENORPHINE ANT HA BASED

1185
00:41:52,330 --> 00:41:54,266
AND WHEN YOU TAKE A PREGNANT

1186
00:41:54,266 --> 00:41:56,468
MOUSE AND YOU VACCINATE IT, LET

1187
00:41:56,468 --> 00:41:58,670
THAT MOM GIVE BIRTH AND THEN YOU

1188
00:41:58,670 --> 00:41:59,871
CHALERG HER, YOU THINK THEY'RE

1189
00:41:59,871 --> 00:42:01,640
ALL GOING TO BE PROTECTED

1190
00:42:01,640 --> 00:42:03,208
BECAUSE IF IT'S NOT A PREGNANT

1191
00:42:03,208 --> 00:42:05,477
MOUSE, JUST A FEMALE, CAN YOU

1192
00:42:05,477 --> 00:42:07,145
PROTECT THEM WITH ALL THESE

1193
00:42:07,145 --> 00:42:09,314
VACCINES, NOT THE CASE IF THAT

1194
00:42:09,314 --> 00:42:13,952
MOM IS PREGNANT WHEN SHE GETS

1195
00:42:13,952 --> 00:42:14,252
VACCINATED.

1196
00:42:14,252 --> 00:42:15,320
OUR ENACTIVATED VACCINE DOES NOT

1197
00:42:15,320 --> 00:42:16,721
WORK WELL AT ALL.

1198
00:42:16,721 --> 00:42:18,456
WHERE THE OTHER 1S, AND YOU HAVE

1199
00:42:18,456 --> 00:42:21,493
TO USE A REALLY LOW DOSE OF

1200
00:42:21,493 --> 00:42:22,661
FLEW, WHEN YOU CHALLENGE THEM,

1201
00:42:22,661 --> 00:42:25,964
IT DOESN'T WORK WELL, SO THERE'S

1202
00:42:25,964 --> 00:42:27,932
SOMETHING VERY DIFFERENT ABOUT

1203
00:42:27,932 --> 00:42:29,200
THAT PREGNANCY STATE THAT

1204
00:42:29,200 --> 00:42:33,972
CHANGES HOW YOUR VACCINE

1205
00:42:33,972 --> 00:42:34,939
PLATFORMS BEHAVE AND THAT HOLES

1206
00:42:34,939 --> 00:42:36,675
TRUE THEN WHEN YOU LOOK AT HOW

1207
00:42:36,675 --> 00:42:38,677
DO THOSE PUPS BORN TO THAT

1208
00:42:38,677 --> 00:42:42,347
VACCINATED MOM, HOW DO THEY

1209
00:42:42,347 --> 00:42:43,581
SURVIVE THAT CHALLENGE.

1210
00:42:43,581 --> 00:42:45,216
THAT PLATFORM MAKES A DIFFERENCE

1211
00:42:45,216 --> 00:42:46,384
IN HOW THAT MOM RESPONDS AND

1212
00:42:46,384 --> 00:42:48,019
THIS WAS SOMETHING WE HADN'T

1213
00:42:48,019 --> 00:42:49,087
REALLY EXPECTED TO SEE, WE KNEW

1214
00:42:49,087 --> 00:42:52,090
THERE WOULD BE MORE SUSCEPTIBLE

1215
00:42:52,090 --> 00:42:52,924
TO INFECTION BUTEE DIDN'T EXPECT

1216
00:42:52,924 --> 00:42:54,693
TO SEE THAT THE VACCINE PLATFORM

1217
00:42:54,693 --> 00:42:58,129
WAS MAKE SUCH A BIG DIFFERENCE

1218
00:42:58,129 --> 00:43:00,665
IN A VACCINATED--IN A PREGNANT

1219
00:43:00,665 --> 00:43:03,735
VERSUS A NONPREGNANT FEMALE

1220
00:43:03,735 --> 00:43:03,968
MOUSE.

1221
00:43:03,968 --> 00:43:06,404
SO I THINK THE NEXT QUESTION IS,

1222
00:43:06,404 --> 00:43:10,508
CAN WE IMPROVE, OR WHAT CAN WE

1223
00:43:10,508 --> 00:43:11,242
DO TO IMPROVE?

1224
00:43:11,242 --> 00:43:13,511
AND THERE'S A LOT OF THINGS WE

1225
00:43:13,511 --> 00:43:14,479
CAN DO.

1226
00:43:14,479 --> 00:43:16,848
THERE'S MANY, MANY NEW FUN

1227
00:43:16,848 --> 00:43:17,515
MODELS COMING OUT.

1228
00:43:17,515 --> 00:43:18,950
RYAN'S GOING TO TALK ABOUT HIS

1229
00:43:18,950 --> 00:43:24,389
DIRTY  MICE, WHICH I THINK HAVE

1230
00:43:24,389 --> 00:43:26,324
BEEN A GAME CHANGER IN A LOT OF

1231
00:43:26,324 --> 00:43:26,891
WAYS FOR UNDERSTANDING MAYBE

1232
00:43:26,891 --> 00:43:28,193
SOME OF THE ISSUES WE NEED TO

1233
00:43:28,193 --> 00:43:30,962
CONSIDER IF YOU'RE USING SPF

1234
00:43:30,962 --> 00:43:32,630
MOUSE AND WHAT YOU'RE REALLY

1235
00:43:32,630 --> 00:43:35,066
MODELING IN TERMS OF THE

1236
00:43:35,066 --> 00:43:35,333
IMMUNITY.

1237
00:43:35,333 --> 00:43:36,468
AND OF COURSE I LIKE IT BECAUSE

1238
00:43:36,468 --> 00:43:40,405
SHE'S SHOWN THAT A LOT OF THOSE

1239
00:43:40,405 --> 00:43:43,141
SORT OF INDEMMIC MOUSE ENTERIC

1240
00:43:43,141 --> 00:43:45,944
PATHOIENS END UP BEING REALLY

1241
00:43:45,944 --> 00:43:47,512
IMPORTANT WITH THE RESPIRATORY

1242
00:43:47,512 --> 00:43:48,747
VIRUS INFECTIONS.

1243
00:43:48,747 --> 00:43:50,915
WE CAN MANIPULATE OUR

1244
00:43:50,915 --> 00:43:53,084
TRANSMISSION MODELS, AND SEEMA

1245
00:43:53,084 --> 00:43:54,886
WILL TALK ABOUT, I ASSUME YOUR

1246
00:43:54,886 --> 00:43:55,687
DAY CARE TRANSMISSION MODEL

1247
00:43:55,687 --> 00:43:56,888
WHICH IS REALLY COOL AND FORCES

1248
00:43:56,888 --> 00:44:00,291
YOU TO THINK ABOUT HOW WE'RE

1249
00:44:00,291 --> 00:44:01,559
DOING THIS BECAUSE HISTORICALLY

1250
00:44:01,559 --> 00:44:03,962
WITH FLU THE WAY WE'VE DONE

1251
00:44:03,962 --> 00:44:06,131
TRANSMISSION, DIRECT CONTACT OR

1252
00:44:06,131 --> 00:44:07,999
RESPIRATORY, IS YOU INFECT THAT

1253
00:44:07,999 --> 00:44:10,101
INDEX, 24 HOURS LATER, YOU PUT

1254
00:44:10,101 --> 00:44:11,970
THE OTHER, THE NAIVE FERRET IN

1255
00:44:11,970 --> 00:44:13,605
CONTACT AND THEY JUST SIT THERE

1256
00:44:13,605 --> 00:44:14,439
FOR OVER LONG THAT YOU ARE GOING

1257
00:44:14,439 --> 00:44:15,974
TO BE THERE, WHICH I GUESS IT

1258
00:44:15,974 --> 00:44:19,711
COULD BE A HOUSEHOLD MODEL, BUT

1259
00:44:19,711 --> 00:44:21,679
YOU ARE IN CLOSE INTIMATE

1260
00:44:21,679 --> 00:44:25,784
CONTACT WITH THAT OTHER FERRET

1261
00:44:25,784 --> 00:44:27,385
FOR 14 DAYS.

1262
00:44:27,385 --> 00:44:29,154
AND THEN ZONDA WANG WILL TELL US

1263
00:44:29,154 --> 00:44:36,127
MORE ABOUT THE FANCY GINY PIGS

1264
00:44:36,127 --> 00:44:38,329
AND AN INTERESTING MOUSE MODEL

1265
00:44:38,329 --> 00:44:38,863
SHE'S MAKING.

1266
00:44:38,863 --> 00:44:41,766
WE'VE ALSO WORKED ON A NUMBER OF

1267
00:44:41,766 --> 00:44:42,400
IMPROVED TRANSMISSION MODELS,

1268
00:44:42,400 --> 00:44:43,201
FIRST WE'RE CALLING THE SLEEP

1269
00:44:43,201 --> 00:44:49,007
OVER WHICH IS BASIC  BASIC LYE E

1270
00:44:49,007 --> 00:44:50,308
THAT INFECTED INDEX AND WE DO IT

1271
00:44:50,308 --> 00:44:52,510
FOR FLU AND RSV.

1272
00:44:52,510 --> 00:44:54,946
ALTHOUGH RSV IS A VERY DIFFERENT

1273
00:44:54,946 --> 00:44:56,681
TRANSMISSION TIMING, MAKING IT A

1274
00:44:56,681 --> 00:44:57,749
BIT MORE CHALLENGING, MAKE IT 1

1275
00:44:57,749 --> 00:44:59,551
DAY YOU HAVE TO WAIT 3 OR 4 DAYS

1276
00:44:59,551 --> 00:45:01,853
BEFORE YOU PUT THAT CONTACT IN,

1277
00:45:01,853 --> 00:45:03,655
BUT THE SLEEP OVER IS YOU HAVE

1278
00:45:03,655 --> 00:45:04,989
YOUR INFECTED INDEX YOU PUT YOUR

1279
00:45:04,989 --> 00:45:06,291
CONTACT IN, YOU LET THEM SPEND

1280
00:45:06,291 --> 00:45:08,460
THE NIGHT TOGETHER AND YOU PULL

1281
00:45:08,460 --> 00:45:09,327
THEM OUT.

1282
00:45:09,327 --> 00:45:10,128
SO SLEEP OVER.

1283
00:45:10,128 --> 00:45:12,363
WE ALSO HAVE 1 WE CALL IT

1284
00:45:12,363 --> 00:45:15,500
KROGER, BECAUSE THAT'S OUR

1285
00:45:15,500 --> 00:45:18,937
FAVORITE GROCERY STORE, CAN YOU

1286
00:45:18,937 --> 00:45:20,772
CALL IT PUBLIC, WHEREVER YOU

1287
00:45:20,772 --> 00:45:22,373
ARE, PIGGLY WIGGLY, THAT'S A

1288
00:45:22,373 --> 00:45:23,441
SHORTER TRANSMISSION PERIOD,

1289
00:45:23,441 --> 00:45:25,343
THAT'S REALLY FORCING THE ISSUE

1290
00:45:25,343 --> 00:45:26,544
WHETHER IT'S DIRECT OR

1291
00:45:26,544 --> 00:45:27,679
RESPIRATORY CONTACT, YOU'RE

1292
00:45:27,679 --> 00:45:30,782
TALKING ABOUT A LESS THAN 4 HOUR

1293
00:45:30,782 --> 00:45:32,750
EXPOSURE TIME SO YOUR REALLY

1294
00:45:32,750 --> 00:45:35,687
FORCING THAT VIRUS OR THAT HOST

1295
00:45:35,687 --> 00:45:37,922
TO TRANSMIT ASK TELL YOU IT

1296
00:45:37,922 --> 00:45:39,557
WORKS BEAUTIFULLY WITH THE OBESE

1297
00:45:39,557 --> 00:45:41,459
FERRETS WITH ALL THE STRAINS

1298
00:45:41,459 --> 00:45:41,793
WE'VE TESTED.

1299
00:45:41,793 --> 00:45:44,529
AND THEN WE HAVE 1 THAT WE

1300
00:45:44,529 --> 00:45:45,763
AFFECTATELY IN THE LAB CALL

1301
00:45:45,763 --> 00:45:50,668
THIS, WHICH I WON'T SAY.

1302
00:45:50,668 --> 00:45:52,504
IT'S BASICALLY IF YOU ARE OUT IN

1303
00:45:52,504 --> 00:45:53,671
PUBLIC AND YOU'VE BEEN

1304
00:45:53,671 --> 00:45:57,041
VACCINATED OR YOU'RE ON TAMIVIR,

1305
00:45:57,041 --> 00:45:59,677
OR--YOU KNOW, WHATEVER YOU WANT,

1306
00:45:59,677 --> 00:46:01,346
AND YOU WERE EXPOSED TO SOMEBODY

1307
00:46:01,346 --> 00:46:07,652
WHETHER AT A SLEEP OVER OR AT

1308
00:46:07,652 --> 00:46:09,487
YOUR LOCAL GROCE REAR STORE THAT

1309
00:46:09,487 --> 00:46:10,822
HAS NOT BEEN VACCINATED OR

1310
00:46:10,822 --> 00:46:12,023
TREATED OR WEARING A MASK, ARE

1311
00:46:12,023 --> 00:46:14,392
YOU GOING TO BE PROTECTED WITH

1312
00:46:14,392 --> 00:46:19,731
THAT THERAPEUTIC IF THAT PERSON

1313
00:46:19,731 --> 00:46:21,165
IS SHEDDING SOMETHING?

1314
00:46:21,165 --> 00:46:21,833
AND THAT'S REALLY INTERESTING

1315
00:46:21,833 --> 00:46:23,301
BECAUSE YOU WOULD ASSUME, YES,

1316
00:46:23,301 --> 00:46:24,936
IF THINGS ARE WORKING RIGHT BUT

1317
00:46:24,936 --> 00:46:26,337
SURPRISINGLY IT'S NOT QUITE THE

1318
00:46:26,337 --> 00:46:32,977
CASE AT LEAST IN THE ANIMAL

1319
00:46:32,977 --> 00:46:33,545
MODELS.

1320
00:46:33,545 --> 00:46:35,313
THE OTHER THINGS WE'VE BEEN

1321
00:46:35,313 --> 00:46:37,215
WORKING ON ARE REALLY AROUND

1322
00:46:37,215 --> 00:46:40,552
OBESITY AND THAT HAS BEEN MAKING

1323
00:46:40,552 --> 00:46:41,419
A METABOLICALLY HEALTHY OBESE

1324
00:46:41,419 --> 00:46:44,088
MOUSE AND A METABOLICALLY

1325
00:46:44,088 --> 00:46:45,723
UNHEALTHY LEAN MOUSE, THE

1326
00:46:45,723 --> 00:46:47,425
UNHEALTHY LEAN A LITTLE BIT

1327
00:46:47,425 --> 00:46:51,262
EASIER, YOU CAN BASICALLY DO

1328
00:46:51,262 --> 00:46:55,133
FOOD WITHDRAW FOR ABOUT 24-48

1329
00:46:55,133 --> 00:46:56,234
HOURS IF YOUR [INDISCERNIBLE]

1330
00:46:56,234 --> 00:47:01,139
WILL LET YOU AND YOU GET INTO A

1331
00:47:01,139 --> 00:47:02,540
MALNOURISHED STATE PRETTY

1332
00:47:02,540 --> 00:47:02,774
QUICKLY.

1333
00:47:02,774 --> 00:47:09,113
THIS IS INTERESTING, THIS IS

1334
00:47:09,113 --> 00:47:11,215
DBA, BALB-C, WE'VE DONE 6 J AND

1335
00:47:11,215 --> 00:47:12,817
6 N, MALE ANDS FEMALES YOU CAN

1336
00:47:12,817 --> 00:47:15,720
SEE ON A HIGH FAT DIET THEY ALL

1337
00:47:15,720 --> 00:47:18,756
GAIP WEIGHT, IN FACT THE DBAs

1338
00:47:18,756 --> 00:47:19,791
ARE REALLY FAST, THEY TRIP

1339
00:47:19,791 --> 00:47:21,960
NELSON CEASAR SIZE WITHIN ABOUT

1340
00:47:21,960 --> 00:47:23,227
A MONTH.

1341
00:47:23,227 --> 00:47:26,965
BUT UNLIKE THE 6 J AND UNLIKE

1342
00:47:26,965 --> 00:47:30,668
THE C57 BLACK 6 J, I DON'T CARE

1343
00:47:30,668 --> 00:47:35,807
HOW BIG WE MAKE THESE GUYS, AND

1344
00:47:35,807 --> 00:47:37,542
THEY'RE LIKE 80 GRAPS THEY'RE

1345
00:47:37,542 --> 00:47:39,877
LIKE WATER BUFFALO, THEY'RE

1346
00:47:39,877 --> 00:47:41,479
HEALTHY, THEY CONTROL THEIR

1347
00:47:41,479 --> 00:47:43,114
GLUCOSE, AND IF YOU WERE TO GO

1348
00:47:43,114 --> 00:47:45,383
IN AND INFECT THEM YOU SAW NO

1349
00:47:45,383 --> 00:47:46,851
DIFFERENCE IN DISEASE SEVERITY,

1350
00:47:46,851 --> 00:47:48,720
IF YOU VACCINATE THEM, THE

1351
00:47:48,720 --> 00:47:50,188
VACCINES STILL WORK BEAUTIFULLY,

1352
00:47:50,188 --> 00:47:57,629
WHICH IS NOT TRUE IN THE

1353
00:47:57,629 --> 00:47:59,330
METABOLICALLY UNHEALTHY ANIMAL.

1354
00:47:59,330 --> 00:48:01,332
WE--PEOPLE IN THE LAB, THEY WANT

1355
00:48:01,332 --> 00:48:03,034
TO DO JAMBA JUICE DIETS, THEY

1356
00:48:03,034 --> 00:48:05,036
WANT TO DO ATKINS DIETS, THEY

1357
00:48:05,036 --> 00:48:07,038
WANT TO DO LIPO SECTION, WHICH,

1358
00:48:07,038 --> 00:48:08,806
NO, WE'RE NOT DOING THAT BUT WE

1359
00:48:08,806 --> 00:48:13,811
HAVE GOTTEN INTO HOW DOES DIET

1360
00:48:13,811 --> 00:48:15,813
OR OZEMPIC, OR AND METFORMIN,

1361
00:48:15,813 --> 00:48:17,548
YOU CAN HAVE THE BIGGEST

1362
00:48:17,548 --> 00:48:19,751
HEAVIEST MOUSE ON THERE AND YOU

1363
00:48:19,751 --> 00:48:22,520
PUT THEM ON METFORMIN, AND IT

1364
00:48:22,520 --> 00:48:23,121
WORKS BEAUTIFULLY.

1365
00:48:23,121 --> 00:48:24,122
SO JUST WORKING OUT THE NEW

1366
00:48:24,122 --> 00:48:25,556
MODELS AND THIS IS THE 1 WE'VE

1367
00:48:25,556 --> 00:48:27,458
BEEN THINKING ABOUT A LOT IS

1368
00:48:27,458 --> 00:48:28,593
THIS CHILDHOOD OBESITY BECAUSE

1369
00:48:28,593 --> 00:48:31,229
THIS IS THE GROUP THAT YOU'RE

1370
00:48:31,229 --> 00:48:32,430
SEEING THE MOST DRAMATIC

1371
00:48:32,430 --> 00:48:36,167
INCREASE IN OBESITY AND THERE'S

1372
00:48:36,167 --> 00:48:38,636
DEFINITELY HEALTH DISPARITY

1373
00:48:38,636 --> 00:48:39,971
ASPECTS TO THIS, SOCIOECONOMIC

1374
00:48:39,971 --> 00:48:41,506
ISSUES, BUT THIS IS THE GROUP

1375
00:48:41,506 --> 00:48:42,940
THAT REALLY IS, BUT HOW DO YOU

1376
00:48:42,940 --> 00:48:44,709
MODEL THAT IN A MOUSE, RIGHT?

1377
00:48:44,709 --> 00:48:48,646
OR IN A FERRET BECAUSE IN ALL OF

1378
00:48:48,646 --> 00:48:50,648
THESE YOU'RE STARTING WITH 3-6

1379
00:48:50,648 --> 00:48:52,650
WEEK OLD, PUTTING THEM ON DIETS

1380
00:48:52,650 --> 00:48:54,118
FOR 12 + WEEKS SO YOU'RE GETTING

1381
00:48:54,118 --> 00:48:56,454
INTO ADULT OR YOUNG ADULT.

1382
00:48:56,454 --> 00:48:59,090
SO WHAT WE'VE DECIDED TO DO IS

1383
00:48:59,090 --> 00:49:02,093
LET'S HAVE THEM BE BORN TO

1384
00:49:02,093 --> 00:49:04,295
PARENTS OF DIFFERENT AND AGAIN

1385
00:49:04,295 --> 00:49:06,431
IT'S METABOLIC STATE, SO

1386
00:49:06,431 --> 00:49:08,633
TYPICALLY YOU HAVE A

1387
00:49:08,633 --> 00:49:09,600
METABOLICALLY HEALTHIER LEAN MOM

1388
00:49:09,600 --> 00:49:12,870
AND DAD, WHAT HAPPENS IN BOTH OF

1389
00:49:12,870 --> 00:49:13,471
THEM ARE METABOLICALLY

1390
00:49:13,471 --> 00:49:17,575
UNHEALTHY, OR 1 OR THE OTHER

1391
00:49:17,575 --> 00:49:20,078
PARENT HAS AN ISSUE.

1392
00:49:20,078 --> 00:49:24,148
AND THESE PUPS AT BIRTH, EVEN AT

1393
00:49:24,148 --> 00:49:25,383
WEANING, THERE ARE DRAMATIC

1394
00:49:25,383 --> 00:49:27,919
DIFFERENCES IN THESE ANIMALS.

1395
00:49:27,919 --> 00:49:31,456
SO MOST--AND WE'RE DOING IT IN

1396
00:49:31,456 --> 00:49:34,225
C57 BLACK 6, MOST WEANLINGS ARE

1397
00:49:34,225 --> 00:49:35,860
14, 15, CANE GRAMS, SOME OF

1398
00:49:35,860 --> 00:49:40,364
THESE ESPECIALLY IF THE MOM IS

1399
00:49:40,364 --> 00:49:41,199
METABOLICALLY UNHEALTHY, AT THAT

1400
00:49:41,199 --> 00:49:44,869
3 WEEKS OF AGE, THEY CAN BE

1401
00:49:44,869 --> 00:49:46,170
30-GRAMS AND METABOLICALLY

1402
00:49:46,170 --> 00:49:46,437
UNHEALTHY.

1403
00:49:46,437 --> 00:49:47,505
AND SO WE THINK WE WILL ARE A

1404
00:49:47,505 --> 00:49:48,940
MODEL WHERE WE WILL BE ABLE TO

1405
00:49:48,940 --> 00:49:52,477
WORK WITH THEM RIGHT AWAY AND

1406
00:49:52,477 --> 00:49:53,778
THERE IS FOR--THERE IS HUGE SEX

1407
00:49:53,778 --> 00:49:55,113
BIAS WHEN YOU TART LOOKING AT

1408
00:49:55,113 --> 00:49:56,380
THIS.

1409
00:49:56,380 --> 00:49:58,249
I MEAN IT'S REALLY DRAMATIC HOW

1410
00:49:58,249 --> 00:49:59,984
THE FEMALE OFFSPRING BEHAVE

1411
00:49:59,984 --> 00:50:01,886
COMPARED TO THE MALES, AND

1412
00:50:01,886 --> 00:50:08,793
REALLY TRACKS BACK TO WHAT THAT

1413
00:50:08,793 --> 00:50:09,961
MOM'S METABOLICITATE WAS.

1414
00:50:09,961 --> 00:50:11,963
FUN NEW MODELS, HUMANS, RIGHT?

1415
00:50:11,963 --> 00:50:15,399
WE HAVE A LOT OF COLLEAGUES

1416
00:50:15,399 --> 00:50:19,237
DOING HUMAN COHORTS, WE HAVE

1417
00:50:19,237 --> 00:50:22,540
HIP-C CENTERS, THAT'S ALL THEY

1418
00:50:22,540 --> 00:50:23,307
DO IS HUMAN IMMUNOLOGY.

1419
00:50:23,307 --> 00:50:25,109
AND THE QUESTION BECOMES CAN WE

1420
00:50:25,109 --> 00:50:26,277
PARTNER UP WITH THEM AND LEARN

1421
00:50:26,277 --> 00:50:28,746
MORE ABOUT WHAT THEY'RE SEEING

1422
00:50:28,746 --> 00:50:30,281
ESPECIALLY UPPER MUCOSAL, YOU

1423
00:50:30,281 --> 00:50:32,683
KNOW MUCOSAL, AND CAN WE TAKE

1424
00:50:32,683 --> 00:50:34,152
THAT INFORMATION BACK AND TRY

1425
00:50:34,152 --> 00:50:37,421
AND MODEL IT IN THE ANIMALS TO

1426
00:50:37,421 --> 00:50:39,724
REALLY UNDERSTAND WHICH ANIMAL

1427
00:50:39,724 --> 00:50:41,359
OR ANIMALS WILL BE THE BEST

1428
00:50:41,359 --> 00:50:43,995
MODEL TO ACTUALLY TRY AND

1429
00:50:43,995 --> 00:50:46,164
RECAPITULATE WITH WHAT THEY'RE

1430
00:50:46,164 --> 00:50:47,498
SEEING, EVEN IN THE COMPLEXITY

1431
00:50:47,498 --> 00:50:51,135
OF A HUMAN AND I THINK THAT'S

1432
00:50:51,135 --> 00:50:54,005
SOMETHING THAT MAY BE

1433
00:50:54,005 --> 00:50:55,139
COMMUNICATIONS BETWEEN THESE

1434
00:50:55,139 --> 00:50:56,574
DIFFERENT GROUPS, PEOPLE FOCUS

1435
00:50:56,574 --> 00:50:57,508
SOLELY ON HUMAN IMMUNITY AND

1436
00:50:57,508 --> 00:51:00,211
THOSE OF US DOING MUCH MORE OF

1437
00:51:00,211 --> 00:51:01,646
THE ANIMAL MODELS, GETTING US

1438
00:51:01,646 --> 00:51:02,713
TOGETHER GETTING IN THE SAME

1439
00:51:02,713 --> 00:51:05,149
ROOM TO SAY, HOW DO WE PULL THIS

1440
00:51:05,149 --> 00:51:05,983
TOGETHER BECAUSE AGAIN, RATHER

1441
00:51:05,983 --> 00:51:08,753
THAN JUST GOING FORWARD, IS THIS

1442
00:51:08,753 --> 00:51:10,388
TRANSLATABLE OR HOW CLOSE ARE WE

1443
00:51:10,388 --> 00:51:15,827
TO CLINIC, CAN WE BRING THAT

1444
00:51:15,827 --> 00:51:16,060
BACK?

1445
00:51:16,060 --> 00:51:17,361
AND THEN I WOULD ARGUE IF YOU

1446
00:51:17,361 --> 00:51:19,530
REALLY WANT TO LOOK AT THE

1447
00:51:19,530 --> 00:51:20,598
COMPLEXITY OF PATHOGENESIS,

1448
00:51:20,598 --> 00:51:21,532
IMMUNE RESPONSE, YOU HAVE TO DO

1449
00:51:21,532 --> 00:51:22,600
IT IN A WHOLE ANIMAL.

1450
00:51:22,600 --> 00:51:26,571
YOU KNOW WE HAVE THESE GREAT

1451
00:51:26,571 --> 00:51:30,174
MORE AND MORE TIPS, 2 Ds, AND

1452
00:51:30,174 --> 00:51:32,143
3D CULTURES.

1453
00:51:32,143 --> 00:51:34,545
LOTS OF COOL ENGINEERING

1454
00:51:34,545 --> 00:51:36,013
ORGANOIDS, ANAROIDS, ORGANS ON A

1455
00:51:36,013 --> 00:51:37,782
CHIP, WHICH WE JUST GOT IN THE

1456
00:51:37,782 --> 00:51:39,417
SYSTEMS AND THEY ARE INCREDIBLE,

1457
00:51:39,417 --> 00:51:41,819
AND YOU CAN MAKE THEM FOR ANY

1458
00:51:41,819 --> 00:51:43,721
ORGAN, YOU CAN MAKE THEM FOR

1459
00:51:43,721 --> 00:51:46,023
HUMANS, YOU CAN MAKE THEM FOR

1460
00:51:46,023 --> 00:51:47,892
ANIMALS, YOU JUST NEED THOSE

1461
00:51:47,892 --> 00:51:50,494
PRIMARY CELLS, CAN YOU FLOW IN

1462
00:51:50,494 --> 00:51:51,362
IMMUNE CELLS BUT IT'S NEVER

1463
00:51:51,362 --> 00:51:53,731
GOING TO BE THE SAME AS A WHOLE

1464
00:51:53,731 --> 00:51:53,965
ANIMAL.

1465
00:51:53,965 --> 00:51:57,068
IT WILL HELP US GET MUCH, MUCH

1466
00:51:57,068 --> 00:51:58,336
MORE MECHANISTIC ESPECIALLY

1467
00:51:58,336 --> 00:52:00,371
ABOUT THOSE NONIMMUNE CELLS AND

1468
00:52:00,371 --> 00:52:02,240
THOU THEY RESPOND TO INFECTION

1469
00:52:02,240 --> 00:52:03,774
EMPLOY SO I THINK THINGS LIKE

1470
00:52:03,774 --> 00:52:06,010
THE HUMAN LUNG ON A CHIP IS

1471
00:52:06,010 --> 00:52:09,313
GOING TO BE GREAT TO SEE HOW

1472
00:52:09,313 --> 00:52:10,314
MIGHT LIVE ATTENUATE VACCINE

1473
00:52:10,314 --> 00:52:12,116
THAT SHOULDN'T GO TO THE LUNG,

1474
00:52:12,116 --> 00:52:13,985
BUT WHAT IF IT DID, WHAT'S IT

1475
00:52:13,985 --> 00:52:16,087
GOING TO DO, HOW ARE SOME OF

1476
00:52:16,087 --> 00:52:17,188
THESE NEW THERAPEUTICS GOING TO

1477
00:52:17,188 --> 00:52:19,357
WORK IN THE HUMAN LUNG BECAUSE

1478
00:52:19,357 --> 00:52:21,659
THESE LUNG ON A CHIP, THEY

1479
00:52:21,659 --> 00:52:23,828
BREATHE, YOU HAVE WHE

1480
00:52:23,828 --> 00:52:24,462
KAN--KANAICAL STRESS, HAVE YOU

1481
00:52:24,462 --> 00:52:26,030
BLOOD GOING THROUGH THEM SO THEY

1482
00:52:26,030 --> 00:52:27,265
WILL BE GOOD FOR THINGS LIKE

1483
00:52:27,265 --> 00:52:32,436
THAT YOU ABOUT WILL THEY

1484
00:52:32,436 --> 00:52:35,673
RECAPITULATE WITH AN ANIMAL

1485
00:52:35,673 --> 00:52:35,973
MODEL?

1486
00:52:35,973 --> 00:52:38,409
MAYBE SOMEDAY BUT NOT THERE YET,

1487
00:52:38,409 --> 00:52:40,811
BUT ALSO HAPPY FOR FRIENDLY

1488
00:52:40,811 --> 00:52:41,078
DISCOURSE.

1489
00:52:41,078 --> 00:52:41,679
WAYS FORWARD.

1490
00:52:41,679 --> 00:52:46,717
THIS IS A BIGGIE, REAGENTS,

1491
00:52:46,717 --> 00:52:46,951
RIGHT?

1492
00:52:46,951 --> 00:52:48,152
WE'RE VERY MUCH LIMITED IN A LOT

1493
00:52:48,152 --> 00:52:50,087
OF WAYS BY THE REAGENTS IF WE

1494
00:52:50,087 --> 00:52:51,088
WANT TO LOOK AT IMMUNE RESPONSE,

1495
00:52:51,088 --> 00:52:57,094
IF YOU WANT TO DO PATHOGENESIS,

1496
00:52:57,094 --> 00:52:58,062
VIRAL TITERS, HISTOPATHOLOGY,

1497
00:52:58,062 --> 00:53:00,531
THEY'RE ALL GREAT BUT IF YOU

1498
00:53:00,531 --> 00:53:02,900
REALLY WANT TO START PULLING

1499
00:53:02,900 --> 00:53:05,636
APART MECHANISM, WE NEED A LOT

1500
00:53:05,636 --> 00:53:07,638
MORE REAGENTS AND THAT CAN

1501
00:53:07,638 --> 00:53:09,740
INCLUDE OBVIOUSLY ANTIBODIES BUT

1502
00:53:09,740 --> 00:53:12,310
PRIMER PROBES, IF WE CAN GET THE

1503
00:53:12,310 --> 00:53:16,213
RIGHT SETS OF REAGENTS, WORKING

1504
00:53:16,213 --> 00:53:18,416
WITH SOMEBODY LIKE MILLI PLEX TO

1505
00:53:18,416 --> 00:53:22,453
MAKE MORE AND MORE OF THESE

1506
00:53:22,453 --> 00:53:24,422
LUNINEX PANELS TO HAVE HIGH

1507
00:53:24,422 --> 00:53:24,755
THROUGH PUT.

1508
00:53:24,755 --> 00:53:25,856
HAVING THESE CELLS FROM

1509
00:53:25,856 --> 00:53:27,124
DIFFERENT SPECIES WILL HELP A

1510
00:53:27,124 --> 00:53:31,028
LOT SO IF ANYBODY WANTS ANY COW,

1511
00:53:31,028 --> 00:53:32,096
RESPIRATORY OR MAMMARY

1512
00:53:32,096 --> 00:53:33,431
EPITHELIAL CELLS, LET US KNOW,

1513
00:53:33,431 --> 00:53:36,701
WE HAVE PLENTY OF THEM AND EVEN

1514
00:53:36,701 --> 00:53:37,234
FROM PEOPLE.

1515
00:53:37,234 --> 00:53:40,338
SO THERE'S A LOT OF PEOPLE

1516
00:53:40,338 --> 00:53:42,073
WORKING ON REAGENTS, SO THIS NOT

1517
00:53:42,073 --> 00:53:43,874
A NEW INITIATIVE, RIGHT?

1518
00:53:43,874 --> 00:53:45,276
WE HAVE DMID, WE HAVE DATE

1519
00:53:45,276 --> 00:53:47,478
PEOPLE, WE HAVE PEOPLE,A ROUND

1520
00:53:47,478 --> 00:53:49,680
THE WORLD WORKING ON REAGENTS,

1521
00:53:49,680 --> 00:53:52,817
BUT WE DON'T HAVE A CONSOLIDATED

1522
00:53:52,817 --> 00:53:57,755
WAY OF KNOWING WHO'S WORKING ON

1523
00:53:57,755 --> 00:53:58,556
WHAT, WHAT REAGENTS ARE ACTUALLY

1524
00:53:58,556 --> 00:53:58,990
AVAILABLE.

1525
00:53:58,990 --> 00:54:01,625
THERE ARE SOME THROUGH BEI,

1526
00:54:01,625 --> 00:54:03,894
THAT'S GREAT BUT HAVE THEY BEEN

1527
00:54:03,894 --> 00:54:05,396
VALIDATED, I CAN TELL YOU IN

1528
00:54:05,396 --> 00:54:09,166
MOST CASES THOSE FERRET REAGENTS

1529
00:54:09,166 --> 00:54:09,734
ARE NOT GREAT.

1530
00:54:09,734 --> 00:54:13,337
YOU KNOW TRYING TO GET REAGENTS

1531
00:54:13,337 --> 00:54:14,238
FROM OTHER PEOPLE, ESPECIALLY

1532
00:54:14,238 --> 00:54:16,807
OTHER PARTS OF THE WORLD, YOU'RE

1533
00:54:16,807 --> 00:54:18,342
REALLY STUCK BY MTAs, LICENSE,

1534
00:54:18,342 --> 00:54:20,111
YOU CAN'T GET A LOT OF THESE

1535
00:54:20,111 --> 00:54:23,848
REAGENTS THAT HAVE BEEN CREATED

1536
00:54:23,848 --> 00:54:25,816
BECAUSE THEY'RE LOCKED UNDER

1537
00:54:25,816 --> 00:54:26,183
TECH TRANSCRIPT.

1538
00:54:26,183 --> 00:54:29,520
SO I THINK WOO WE NEED TO THINK

1539
00:54:29,520 --> 00:54:30,721
ABOUT WHAT NEEDED AND I THINK

1540
00:54:30,721 --> 00:54:31,889
THAT'S SOMETHING I HOPE WE CAN

1541
00:54:31,889 --> 00:54:33,224
GET FROM THIS IS MORE DISCUSSION

1542
00:54:33,224 --> 00:54:34,759
FROM YOU GUYS ABOUT WHAT DO WE

1543
00:54:34,759 --> 00:54:38,529
REALLY NEED AND HOW DO WE FOCUS

1544
00:54:38,529 --> 00:54:39,597
ON THAT?

1545
00:54:39,597 --> 00:54:41,132
WHERE SOME THEY BE STORED?

1546
00:54:41,132 --> 00:54:42,066
THAT'S A HUGE 1.

1547
00:54:42,066 --> 00:54:44,535
I THINK THEY SHOULD ALL BE

1548
00:54:44,535 --> 00:54:46,637
STORED AT BEI, I THINK BEI

1549
00:54:46,637 --> 00:54:47,605
THINKS OTHERWISE, RIGHT IN THIS

1550
00:54:47,605 --> 00:54:47,972
IS A LOT.

1551
00:54:47,972 --> 00:54:49,407
YOU HAVE TO THINK ABOUT WHO'S

1552
00:54:49,407 --> 00:54:51,042
GOING TO HAVE FREEZERS THAT THEY

1553
00:54:51,042 --> 00:54:54,345
CAN STORE ALL OF THESE REAGENTS

1554
00:54:54,345 --> 00:54:55,546
AND BASICALLY BE AMAZON AND

1555
00:54:55,546 --> 00:54:57,081
WE'VE DONE THIS FOR OUR PRIMARY

1556
00:54:57,081 --> 00:54:59,316
CELLS AND IT REALLY IS LIKE

1557
00:54:59,316 --> 00:55:01,318
BEING AMAZON, WE WILL GET

1558
00:55:01,318 --> 00:55:02,353
REQUESTS DAILY AND SO WE'VE

1559
00:55:02,353 --> 00:55:03,988
TALKED TO ERIC AND MICHELLE

1560
00:55:03,988 --> 00:55:05,756
ABOUT CAN WE PLEASE PUT THESE IN

1561
00:55:05,756 --> 00:55:09,727
BEI SO WE DON'T HAVE TO DROP

1562
00:55:09,727 --> 00:55:11,629
EVERYTHING AND SHIP CELLS EVERY

1563
00:55:11,629 --> 00:55:12,296
OTHER DAY.

1564
00:55:12,296 --> 00:55:14,732
AND THAT'S A LOT, JUST THE

1565
00:55:14,732 --> 00:55:15,099
STORAGE.

1566
00:55:15,099 --> 00:55:18,269
HOW SHOULD THE INFORMATION BE

1567
00:55:18,269 --> 00:55:18,602
COMMUNICATED?

1568
00:55:18,602 --> 00:55:19,970
THE ONLY WAY PEOPLE KNEW ABOUT

1569
00:55:19,970 --> 00:55:22,206
OUR PRIMARY CELLS WAS THROUGH

1570
00:55:22,206 --> 00:55:23,707
PUBLICATIONS, RIGHT IN AND THEY

1571
00:55:23,707 --> 00:55:25,109
WERE LOOKING FOR IT, THERE'S GOT

1572
00:55:25,109 --> 00:55:27,478
TO BE A BETTER WAY, IT CAN BE

1573
00:55:27,478 --> 00:55:28,679
THE JUST BE BASED ON

1574
00:55:28,679 --> 00:55:29,513
PUBLICATIONS BECAUSE A LOT OF

1575
00:55:29,513 --> 00:55:31,749
THESE YOU WILL NOT PUBLISH, WHAT

1576
00:55:31,749 --> 00:55:32,950
ABOUTA ALL THE COMMERCIAL

1577
00:55:32,950 --> 00:55:34,051
ANTIBODIES, ALL OF US HAVE

1578
00:55:34,051 --> 00:55:36,887
TESTED THAT DON'T WORK EMPLOY

1579
00:55:36,887 --> 00:55:37,121
RIGHT?

1580
00:55:37,121 --> 00:55:38,756
YOU SAY, OH THEY'RE SUPPOSED TO

1581
00:55:38,756 --> 00:55:40,057
WORK AGAINST EVERY SPECIES, WELL

1582
00:55:40,057 --> 00:55:41,459
THEY DON'T WORK AGAINST MY

1583
00:55:41,459 --> 00:55:45,096
FERRET WHEN YOU DO PBMCs, THAT

1584
00:55:45,096 --> 00:55:46,030
INFORMATION IS CRITICAL AND

1585
00:55:46,030 --> 00:55:48,032
NEEDS TO BE SOMEWHERE SO WE'RE

1586
00:55:48,032 --> 00:55:49,800
NOT ALL CONSTANTLY REINVENTING

1587
00:55:49,800 --> 00:55:50,367
THE WHILE.

1588
00:55:50,367 --> 00:55:51,669
BECAUSE THEN YOU TALK TO

1589
00:55:51,669 --> 00:55:53,838
SOMEBODY AND SAY, OH YEAH, TRIED

1590
00:55:53,838 --> 00:55:56,207
THAT 3 YEARS AGO AND IT DOESN'T

1591
00:55:56,207 --> 00:55:57,842
WORK, SO YOU TYPICALLY DON'T

1592
00:55:57,842 --> 00:56:00,611
PUBLISH THINGS LIKE THAT EITHER.

1593
00:56:00,611 --> 00:56:02,079
ARE REAGENTS BEING VALIDATED?

1594
00:56:02,079 --> 00:56:04,048
AND WHAT DO WE MEAN BY

1595
00:56:04,048 --> 00:56:04,348
VALIDATION?

1596
00:56:04,348 --> 00:56:05,082
WHAT DOES THE COMMUNITY WANT TO

1597
00:56:05,082 --> 00:56:07,084
SEE, WHAT ARE YOU GOING TO BE

1598
00:56:07,084 --> 00:56:10,721
COMFORTABLE WITH IF WE SAY THIS

1599
00:56:10,721 --> 00:56:11,889
IS A VALIDATED REAGENT.

1600
00:56:11,889 --> 00:56:14,625
IS IT SIMPLY THAT FLOW CYTOMETRY

1601
00:56:14,625 --> 00:56:18,729
WORKS WITH PBMCs OR DO YOU

1602
00:56:18,729 --> 00:56:23,701
WANT MASS SPEC OR AMINO ACID

1603
00:56:23,701 --> 00:56:24,735
SEQUENCING, DO YOU WANT TO KNOW

1604
00:56:24,735 --> 00:56:26,804
WHAT THIS THING IS BINDING TOO.

1605
00:56:26,804 --> 00:56:29,440
AND WHAT ARE THE MODELS NEEDED.

1606
00:56:29,440 --> 00:56:31,609
WE WILL HEAR A LOT THAT DURING

1607
00:56:31,609 --> 00:56:33,511
THIS WORKSHOP AND IT'S REALLY

1608
00:56:33,511 --> 00:56:34,578
EXCITING BUT IF WE'RE THINKING

1609
00:56:34,578 --> 00:56:35,779
OUTSIDE OF THE BOX, WHAT ARE THE

1610
00:56:35,779 --> 00:56:39,817
NEW MODELS THAT WE NEED TO BE,

1611
00:56:39,817 --> 00:56:40,818
WORKING ON.

1612
00:56:40,818 --> 00:56:42,319
AND THEN COMING BACK TO THOSE

1613
00:56:42,319 --> 00:56:44,722
VIRAL STRAINS THAT WE ALL GET A

1614
00:56:44,722 --> 00:56:46,223
LITTLE BIT POOPY AT STUDY

1615
00:56:46,223 --> 00:56:47,892
SECTION SAYING I DON'T WANT TO

1616
00:56:47,892 --> 00:56:49,994
SEE PR8, I DON'T WANT TO SEE

1617
00:56:49,994 --> 00:56:52,897
X31, I DON'T WANT TO SEE RSV IN

1618
00:56:52,897 --> 00:56:54,298
A MOUSE, WHAT'S ACCEPTABLE AND

1619
00:56:54,298 --> 00:56:55,833
HOW DO THOSE NEED TO BE VALIDATE

1620
00:56:55,833 --> 00:56:57,568
EXCLUDE IF IT'S ACCEPT TO USE

1621
00:56:57,568 --> 00:56:59,436
PR8, THEN MAYBE WE DON'T NEED TO

1622
00:56:59,436 --> 00:57:02,573
BE POOPY AT STUDY SECTION, WE

1623
00:57:02,573 --> 00:57:03,908
SAY, AH, PR8 IS THE BEST 1 SO I

1624
00:57:03,908 --> 00:57:05,576
THINK THAT ALSO NEEDS TO BE

1625
00:57:05,576 --> 00:57:08,045
SOMETHING WE THINK ABOUT MORE

1626
00:57:08,045 --> 00:57:08,979
FOR THE WHOLE COMMUNITY BECAUSE

1627
00:57:08,979 --> 00:57:10,414
IF IT'S NOT ACCEPT, THEN THERE

1628
00:57:10,414 --> 00:57:13,250
NEEDS TO BE A CLEARER MESSAGE,

1629
00:57:13,250 --> 00:57:14,818
YOU KNOW, THERE IS A TIME AND

1630
00:57:14,818 --> 00:57:16,787
PLACE FOR THIS, BUT WE'VE MOVED

1631
00:57:16,787 --> 00:57:21,025
ON FROM THERE AND DO WE NEED

1632
00:57:21,025 --> 00:57:22,059
VALIDATED MAMMALIAN ADAPTED

1633
00:57:22,059 --> 00:57:25,262
VIRUSES OF SOME KIND.

1634
00:57:25,262 --> 00:57:28,399
SO THE BIG THING IS WE REALLY

1635
00:57:28,399 --> 00:57:32,570
NEED TO WORK TOGETHER AS A

1636
00:57:32,570 --> 00:57:35,539
COMMUNITY TO FIGURE OUT THE WAYS

1637
00:57:35,539 --> 00:57:36,840
FOR IT ESPECIALLY FOR THESE

1638
00:57:36,840 --> 00:57:38,409
REAGENTS AND HOW DO WE, HOW DO

1639
00:57:38,409 --> 00:57:39,710
WE FIGURE OUT WHAT'S NEEDED AND

1640
00:57:39,710 --> 00:57:41,245
GET IT SOME PLACE WHERE PEOPLE

1641
00:57:41,245 --> 00:57:44,315
CAN GET IT AND THAT THEY KNOW

1642
00:57:44,315 --> 00:57:44,682
IT'S AVAILABLE.

1643
00:57:44,682 --> 00:57:47,351
AND THEN OF COURSE, APOLOGIES

1644
00:57:47,351 --> 00:57:49,420
FOR ANYBODY'S STUFF THAT I

1645
00:57:49,420 --> 00:57:52,256
MISSED OR I MISSPOKE, THAT'S ON

1646
00:57:52,256 --> 00:57:54,525
ME. 

1647
00:57:54,525 --> 00:57:56,627
AND WITH THAT, THANK THE LAB AND

1648
00:57:56,627 --> 00:58:01,465
THE FERRETS AND THE MICE AND ALL

1649
00:58:01,465 --> 00:58:03,100
OF YOU GUYS FOR LISTENING TO

1650
00:58:03,100 --> 00:58:03,834
STUFF YOU PROBABLY ALREADY

1651
00:58:03,834 --> 00:58:05,669
ANYHOW AND HAPPY TO ANSWER ANY

1652
00:58:05,669 --> 00:58:16,146
QUESTIONS AND HOPEFULLY HAVE

1653
00:58:21,619 --> 00:58:22,820
SOME DISCUSSION.

1654
00:58:22,820 --> 00:58:23,721
>> THAT WAS REALLY GREAT.

1655
00:58:23,721 --> 00:58:25,589
THANKS IT'S A WONDERFUL OVERVIEW

1656
00:58:25,589 --> 00:58:28,125
AND FUN TO SEE THE NEW STUFF.

1657
00:58:28,125 --> 00:58:29,360
I'M CURIOUS ABOUT SINGLE CELL

1658
00:58:29,360 --> 00:58:31,495
RNA SEQUENCING IN THE LESS

1659
00:58:31,495 --> 00:58:33,230
TRADITIONAL ANIMAL MODELS, THAT

1660
00:58:33,230 --> 00:58:35,466
SHOULD DEMOCRATIZE THE STUDY

1661
00:58:35,466 --> 00:58:36,867
ESPECIALLY FOR IMMUNOLOGY, ARE

1662
00:58:36,867 --> 00:58:39,436
THE GENOMES GOOD ENOUGH FOR

1663
00:58:39,436 --> 00:58:40,771
FERRETS, GINNY PIGS, HAMSTERS TO

1664
00:58:40,771 --> 00:58:43,173
GET HIGH QUALITY ANALYSIS.

1665
00:58:43,173 --> 00:58:46,844
>> YEAH, THAT'S A GREAT

1666
00:58:46,844 --> 00:58:50,047
QUESTION, RYAN, I THINK AND

1667
00:58:50,047 --> 00:58:51,749
STANLEY, OTHER PEOPLE, HAMSTER

1668
00:58:51,749 --> 00:58:56,120
HAS BEEN SEQUENCED BOTH SYRIAN,

1669
00:58:56,120 --> 00:58:56,820
GOLDEN.

1670
00:58:56,820 --> 00:58:58,122
FOR THE FERRET, YEAH, THERE'S

1671
00:58:58,122 --> 00:59:00,691
GENOMES OUT THERE BUT WE STILL

1672
00:59:00,691 --> 00:59:01,992
HAVE AN ANNOTATION PROBLEM.

1673
00:59:01,992 --> 00:59:02,726
IT'S GETTING BETTER, IT'S

1674
00:59:02,726 --> 00:59:04,161
GETTING A LOT BETTER BECAUSE YOU

1675
00:59:04,161 --> 00:59:08,065
HAVE PEOPLE THAT ARE FOCUSED ON

1676
00:59:08,065 --> 00:59:09,366
ANNOTATING IT APPROPRIATELY, SO

1677
00:59:09,366 --> 00:59:11,635
YEAH, WE FEEL MORE COMFORTABLE

1678
00:59:11,635 --> 00:59:13,470
NOW GOING IN AND WE'RE DOING

1679
00:59:13,470 --> 00:59:16,840
SINGLE CELL SEQUENCING ON UPPER

1680
00:59:16,840 --> 00:59:18,575
VERSUS LOWER RESPIRATORY TRACT,

1681
00:59:18,575 --> 00:59:20,077
THE PROBLEM COMES WHEN YOU WANT

1682
00:59:20,077 --> 00:59:21,312
TO VALIDATE ANYTHING SO WE GET A

1683
00:59:21,312 --> 00:59:22,946
LOT OF HITS AND A LOT OF DATA

1684
00:59:22,946 --> 00:59:25,115
BUT THEN YOU HAVE TO DEVELOP THE

1685
00:59:25,115 --> 00:59:27,084
TOOLS TO BE ACTUALLY BE ABLE TO

1686
00:59:27,084 --> 00:59:28,519
VALIDATE WHAT YOU'RE SIGHING BY

1687
00:59:28,519 --> 00:59:31,455
THE SINGLE CELL SEQUENCING

1688
00:59:31,455 --> 00:59:32,289
MAKING PRIMER PROBES EASY BUT

1689
00:59:32,289 --> 00:59:34,358
WHEN YOU GOET INTO PROTEINS OR

1690
00:59:34,358 --> 00:59:36,093
ANTIBODIES IT GETS MUCH, MUCH

1691
00:59:36,093 --> 00:59:37,795
TRICKIER AND THAT'S WHERE YOU

1692
00:59:37,795 --> 00:59:41,965
KIND OF GET STUCK IF YOU GO TO

1693
00:59:41,965 --> 00:59:44,635
PUBLISH THAT, OKAY, WELL WE

1694
00:59:44,635 --> 00:59:45,969
CAN'T VALIDATE THIS.

1695
00:59:45,969 --> 00:59:48,138
SO THE I THINK THE GENOMES ARE

1696
00:59:48,138 --> 00:59:49,406
BETTER--DOES ANYBODY KNOW ABOUT

1697
00:59:49,406 --> 00:59:51,642
THE HAMSTER OR ANY OF THE OTHER

1698
00:59:51,642 --> 00:59:54,978
1S GO,A HEAD?

1699
00:59:54,978 --> 00:59:57,648
YEAH, YOU'RE PRETTY MUCH SPOT ON

1700
00:59:57,648 --> 00:59:59,149
WITH IT, WE'RE WORKING ON OUR

1701
00:59:59,149 --> 01:00:00,250
SECOND ANNOTATION FOR THE

1702
01:00:00,250 --> 01:00:01,085
HAMSTER BUT THEY'RE GETTING

1703
01:00:01,085 --> 01:00:04,822
BETTER ABOUT YOU THERE ARE CHRIS

1704
01:00:04,822 --> 01:00:05,322
CREPANCYS BETWEEN THE 2

1705
01:00:05,322 --> 01:00:07,858
ANNOTATIONS THAT ARE EXISTING

1706
01:00:07,858 --> 01:00:09,460
AND HOPEFULLY SOME MORE DATA

1707
01:00:09,460 --> 01:00:10,761
WILL RESULT IN ANNOTATIONS AND

1708
01:00:10,761 --> 01:00:11,962
IT'S GETTING BETTER AND I THINK

1709
01:00:11,962 --> 01:00:14,965
IN SINGLE CELL HAMSTERS SO FAR,

1710
01:00:14,965 --> 01:00:16,700
YOU CAN IDENTIFY CELL TYPES AND

1711
01:00:16,700 --> 01:00:20,137
GET NICE USEFUL INFORMATION OUT

1712
01:00:20,137 --> 01:00:21,038
OF IT.

1713
01:00:21,038 --> 01:00:22,673
NI'VE NEVER DONE THIS BEFORE, SO

1714
01:00:22,673 --> 01:00:25,809
I WILL MAKE MORE OF A COMMENT

1715
01:00:25,809 --> 01:00:27,611
THAN A QUESTION, I REALLY HATE

1716
01:00:27,611 --> 01:00:29,713
ALL THE PR8 THAT HAPPENS BECAUSE

1717
01:00:29,713 --> 01:00:33,183
THERE ARE NO NATURAL ORTHOTHOUGH

1718
01:00:33,183 --> 01:00:35,886
NECKS O VIRUSES, IN US SO IN MY

1719
01:00:35,886 --> 01:00:37,321
OPINION, CAL9 OR UDON OR

1720
01:00:37,321 --> 01:00:38,922
WHATEVER IS YOUR FAVORITE FLU IS

1721
01:00:38,922 --> 01:00:42,059
NO DIFFERENT THAN PR8, AND PR8

1722
01:00:42,059 --> 01:00:43,594
HAS ADVANTAGES OVER THESE OTHER

1723
01:00:43,594 --> 01:00:48,399
STRAINS SO I REALLY--IT ALWAYS

1724
01:00:48,399 --> 01:00:49,600
MAKES ME CRINGE DEEPLY WHEN

1725
01:00:49,600 --> 01:00:51,769
THOSE CONCERNS COME UP AT STUDY

1726
01:00:51,769 --> 01:00:53,070
SECTION OR REVIEWER CONCERNS THE

1727
01:00:53,070 --> 01:00:53,971
PAPER.

1728
01:00:53,971 --> 01:00:55,372
>> SO NOTE TO EVERYBODY
ONLINE

1729
01:00:55,372 --> 01:00:56,240
MAKE SURE RYAN'S ON STUDY

1730
01:00:56,240 --> 01:01:00,010
SECTION IF YOU'RE GOING TO

1731
01:01:00,010 --> 01:01:00,744
SUBMIT YOUR PR8.

1732
01:01:00,744 --> 01:01:02,346
>> CAN I RESPOND TO THAT.

1733
01:01:02,346 --> 01:01:03,714
>> I CAN COMMENT.

1734
01:01:03,714 --> 01:01:06,650
>> YEAH, NO, I AM A PR8
HATER AS

1735
01:01:06,650 --> 01:01:08,819
WE HAVE HAD MANY DISCUSSIONS ON

1736
01:01:08,819 --> 01:01:11,054
AND I--I WILL SAY WHY I THINK

1737
01:01:11,054 --> 01:01:13,023
PR8, WE NEED TO MOVE ON FROM.

1738
01:01:13,023 --> 01:01:16,827
IT IS NOT BECAUSE IT IS A MOUSE

1739
01:01:16,827 --> 01:01:19,129
ADAPTED VIRUS, IT IS BECAUSE IT

1740
01:01:19,129 --> 01:01:20,063
DOES NOT RECAPITULATE THE THINGS

1741
01:01:20,063 --> 01:01:23,667
THAT WE'RE TRYING TO MODEL IN

1742
01:01:23,667 --> 01:01:24,868
HUMANS, RIGHT, SO IF YOU WANT TO

1743
01:01:24,868 --> 01:01:28,338
USE A MOUSE ADAPTED STRAIN OF

1744
01:01:28,338 --> 01:01:29,840
INFLUENZA, FABULOUS, USE 1 THAT

1745
01:01:29,840 --> 01:01:31,742
IS RELEVANT TO WHAT IS

1746
01:01:31,742 --> 01:01:34,511
CIRCULATING IN HUMANS AND THAT

1747
01:01:34,511 --> 01:01:38,382
HAS A SIMILAR SORT OF PHENOTYPIC

1748
01:01:38,382 --> 01:01:38,749
MANIFESTATION.

1749
01:01:38,749 --> 01:01:41,485
PEOPLE ARE NOT DROPPING DEAD

1750
01:01:41,485 --> 01:01:44,521
FROM 50 PFU OF AN INFLUENZA

1751
01:01:44,521 --> 01:01:45,989
VIRUS, AND AT SOME POINT FORWARD

1752
01:01:45,989 --> 01:01:48,459
THEY MAY BE DEAD NTHEY MAY BE

1753
01:01:48,459 --> 01:01:48,792
DEAD.

1754
01:01:48,792 --> 01:01:50,093
OTHER PEOPLE I'VE INFECTED DO

1755
01:01:50,093 --> 01:01:51,995
NOT DIE SO I WILL SAY IT TAKES A

1756
01:01:51,995 --> 01:01:55,732
LOT MORE THAN THAT BUT--NO, BUT

1757
01:01:55,732 --> 01:01:56,867
THAT'S MY POINT.

1758
01:01:56,867 --> 01:01:58,769
MY POINT IS THAT--WE SHOULDN'T

1759
01:01:58,769 --> 01:02:00,604
USE PR8 BECAUSE OF THE MOUSE

1760
01:02:00,604 --> 01:02:01,972
INFECTED VIRUS BUT THAT SHE

1761
01:02:01,972 --> 01:02:03,740
SHOULD BE MORE THOUGHTFUL ON

1762
01:02:03,740 --> 01:02:05,075
WHAT IS THE QUESTION AND WHAT IS

1763
01:02:05,075 --> 01:02:06,910
THE BEST SYSTEM TO ANSWER THAT

1764
01:02:06,910 --> 01:02:07,311
QUESTION.

1765
01:02:07,311 --> 01:02:09,813
IF YOU'RE USING MICE, LET'S USE

1766
01:02:09,813 --> 01:02:10,747
A MORE RELEVANT STRAIN, WELL

1767
01:02:10,747 --> 01:02:14,651
THE'S THINK ABOUT SOMETHING

1768
01:02:14,651 --> 01:02:14,885
BETTER.

1769
01:02:14,885 --> 01:02:16,653
>> ISICAL 09 A PR8.

1770
01:02:16,653 --> 01:02:17,855
>> SUPER QUICKLY, BUT PR8
CAN

1771
01:02:17,855 --> 01:02:19,323
MODEL A LOT OF THINGS THAT DO

1772
01:02:19,323 --> 01:02:20,724
HAPPEN IN PEOPLE, WE CAN DISCUSS

1773
01:02:20,724 --> 01:02:22,493
THIS OFFLINE BUT I DO THINK

1774
01:02:22,493 --> 01:02:24,394
THERE'S A LOT OF VALUE IN THAT

1775
01:02:24,394 --> 01:02:27,331
MODEL SYSTEM.

1776
01:02:27,331 --> 01:02:28,165
NMORE DISCOURSE.

1777
01:02:28,165 --> 01:02:29,800
>> I SECOND THAT, I THINK
PR8 IS

1778
01:02:29,800 --> 01:02:34,171
GREAT, BUT ALSO IT DEPENDS ON

1779
01:02:34,171 --> 01:02:35,239
THE QUESTION, AND I THINK THE

1780
01:02:35,239 --> 01:02:36,073
QUESTION IS MORE IMPORTANT TO

1781
01:02:36,073 --> 01:02:37,708
FOCUS ON SO IF YOU'RE QUESTION

1782
01:02:37,708 --> 01:02:39,243
IS ABOUT HUMAN STRAINS, CLEARLY

1783
01:02:39,243 --> 01:02:42,012
YOU CAN'T USE A MOUSE TO MODEL

1784
01:02:42,012 --> 01:02:42,446
THOSE.

1785
01:02:42,446 --> 01:02:44,314
BUT IF YOU'RE QUESTION IS ABOUT

1786
01:02:44,314 --> 01:02:46,750
HOST FACTORS AND UNDERSTANDING

1787
01:02:46,750 --> 01:02:49,353
THE CONTRIBUTION TO PATHOGENESIS

1788
01:02:49,353 --> 01:02:51,455
OR TRANSMISSION, AT THIS MOMENT

1789
01:02:51,455 --> 01:02:54,024
WE DON'T HAVE GOOD REAGENTS FOR

1790
01:02:54,024 --> 01:02:56,126
FERRETS OR GINNY PIGS SO WE RELY

1791
01:02:56,126 --> 01:02:58,795
ON MICE TO UNDERSTAND THOSE

1792
01:02:58,795 --> 01:03:00,831
MECHANISMS, AND UNFORTUNATELY WE

1793
01:03:00,831 --> 01:03:02,432
DO HAVE TO USE STRAINS THAT WORK

1794
01:03:02,432 --> 01:03:03,433
IN THAT MODEL.

1795
01:03:03,433 --> 01:03:04,835
SO I THINK FOCUSING ON THE

1796
01:03:04,835 --> 01:03:10,574
QUESTION IS A MORE IMPORTANT

1797
01:03:10,574 --> 01:03:14,144
ASPECT.

1798
01:03:14,144 --> 01:03:15,412
>> GOOD QUESTION.

1799
01:03:15,412 --> 01:03:18,148
I'M STILL SENDING MY GRANTS TO

1800
01:03:18,148 --> 01:03:18,615
YOU THAT INCLUDE PR8.

1801
01:03:18,615 --> 01:03:19,683
>> SO I HAVE A QUESTION,
YOU

1802
01:03:19,683 --> 01:03:22,386
WORK AT A HOSPITAL WITH IMMUNO

1803
01:03:22,386 --> 01:03:23,520
COMPROMISED CHILDREN, DO YOU

1804
01:03:23,520 --> 01:03:25,222
EVER OR LET ME CHANGE THAT--A

1805
01:03:25,222 --> 01:03:26,957
GOOD WAY TO DO THINGS THAT WOULD

1806
01:03:26,957 --> 01:03:31,595
BE TO CORRELATE FINDINGS THAT WE

1807
01:03:31,595 --> 01:03:33,297
FIND IN OUR ANIMAL MODELS THAT

1808
01:03:33,297 --> 01:03:35,365
WE TRY TO MAKE THOSE IMMUNO

1809
01:03:35,365 --> 01:03:36,433
COMPROMISED WITH WHAT YOU'RE

1810
01:03:36,433 --> 01:03:39,303
SEEING IN PATIENT WHO IS HAVE

1811
01:03:39,303 --> 01:03:41,638
DECS WHETHER IT BE SARS 2 OR

1812
01:03:41,638 --> 01:03:42,306
WHATEVER ELSE, INFLUENZA,

1813
01:03:42,306 --> 01:03:45,042
WHATEVER, DO YOU HAVE ANY--DO

1814
01:03:45,042 --> 01:03:47,678
HAVE A WAY TO SET THAT UP AT

1815
01:03:47,678 --> 01:03:49,413
ST. JUDE SO CAN YOU TEST SOME OF

1816
01:03:49,413 --> 01:03:50,614
THE THINGS YOU FIND AND THEN

1817
01:03:50,614 --> 01:03:51,682
INFORM WHAT YOU SHOULD BE

1818
01:03:51,682 --> 01:03:53,750
LOOKING FOR IN YOUR ANIMAL

1819
01:03:53,750 --> 01:03:54,084
MODELS.

1820
01:03:54,084 --> 01:03:55,485
NYEAH, THAT'S A GREAT QUESTION.

1821
01:03:55,485 --> 01:03:58,121
SO I'M AT ST. JUDE'S CHILDREN'S

1822
01:03:58,121 --> 01:04:01,124
RESEARCH HOSPITAL WHICH IS

1823
01:04:01,124 --> 01:04:01,792
CATATROPHIC CHILDHOOD ILLNESS

1824
01:04:01,792 --> 01:04:03,360
ALWAYS BEEN KNOWN FOR CANCER BUT

1825
01:04:03,360 --> 01:04:05,596
NOW THERE'S A LOT OF NEUROLOGIC

1826
01:04:05,596 --> 01:04:09,166
AND SICKLE CELL ANEMIA, THINGS

1827
01:04:09,166 --> 01:04:11,301
LIKE THAT, HIV, SO THE ANSWER IS

1828
01:04:11,301 --> 01:04:12,002
YES, WE DO.

1829
01:04:12,002 --> 01:04:13,971
AND IT'S SORT OF--IT SOUNDS

1830
01:04:13,971 --> 01:04:15,505
WEIRD BUT IT'S SORT OF A

1831
01:04:15,505 --> 01:04:16,440
DISCONNECT FROM MOST OF THE WERE

1832
01:04:16,440 --> 01:04:20,110
WE DO BECAUSE WHAT WE IN

1833
01:04:20,110 --> 01:04:21,845
ST. JUDE KIDS IS SO UNUSUAL

1834
01:04:21,845 --> 01:04:23,614
RIGHT BECAUSE THEY'RE SO IMMUNO

1835
01:04:23,614 --> 01:04:27,384
COMPROMISED THAT YOU WILL GET

1836
01:04:27,384 --> 01:04:28,852
PERSONS WITH INFECTIONS, CAN YOU

1837
01:04:28,852 --> 01:04:30,454
DO A LOT OF REALLY COOL, WELL,

1838
01:04:30,454 --> 01:04:34,491
NOT FOR THE KIDS, VIRAL SHEDDING

1839
01:04:34,491 --> 01:04:35,659
STUDIES BECAUSE THEY'RE SHEDDING

1840
01:04:35,659 --> 01:04:37,260
VIRUS FOR A LONG TIME SO TO BE

1841
01:04:37,260 --> 01:04:39,162
ABLE TO TAKE THOSE AND MOODLE

1842
01:04:39,162 --> 01:04:40,864
THINGS SO THAT WE'RE 1-2 STEPS

1843
01:04:40,864 --> 01:04:45,736
REMOVED FROM THE CLINIC, WE CAN

1844
01:04:45,736 --> 01:04:50,407
AND SO WE HAVE MOUSE MODELS THAT

1845
01:04:50,407 --> 01:04:51,642
ARE IMMUNO COMPROMISED, THEY'RE

1846
01:04:51,642 --> 01:04:53,543
TREATED WITH MEX O TREKSATE,

1847
01:04:53,543 --> 01:04:54,478
WE'RE FOLLOWING THE CHEMO

1848
01:04:54,478 --> 01:04:56,913
THERAPEUTIC THAT THE KIDS ARE ON

1849
01:04:56,913 --> 01:04:58,248
SO THEY'RE IMMUNO COMPROMISED IN

1850
01:04:58,248 --> 01:05:00,117
THE SAME WAY, THEY WILL SEE

1851
01:05:00,117 --> 01:05:02,319
THESE THINGS AND WE CAN DO THE

1852
01:05:02,319 --> 01:05:06,623
SAME THING WITH FERRETS IS YOU

1853
01:05:06,623 --> 01:05:09,993
CAN DO [INDISCERNIBLE] DID THIS

1854
01:05:09,993 --> 01:05:12,462
ORIGINALLY USING MEXA TREKSATE

1855
01:05:12,462 --> 01:05:14,564
TO MAKE IMMUNO COMPROMISED

1856
01:05:14,564 --> 01:05:15,198
FERRETS THAT WILL RECAPITULATE

1857
01:05:15,198 --> 01:05:16,600
THAT WE SEE IN THE KIDS.

1858
01:05:16,600 --> 01:05:18,335
SO YEAH, WE DO THAT FREQUENTLY

1859
01:05:18,335 --> 01:05:25,342
ESPECIALLY WHEN LOOKING AT MOUSE

1860
01:05:25,342 --> 01:05:25,575
MODELS.

1861
01:05:25,575 --> 01:05:27,144
SO THEY'RE AVAILABLE AND THEY'RE

1862
01:05:27,144 --> 01:05:30,947
PRETTY EASY ACTUALLY WHAT WE DID

1863
01:05:30,947 --> 01:05:32,315
FOR THE MICE ADAPTED REALLY WELL

1864
01:05:32,315 --> 01:05:33,984
IN THE FERRETS, I WOULD IMAGINE

1865
01:05:33,984 --> 01:05:36,720
YOU CAN DO THE SAME THING OR

1866
01:05:36,720 --> 01:05:37,621
SOMETHING SIMILAR FOR HASMSTERS

1867
01:05:37,621 --> 01:05:40,824
IF WE WANT TO LOOK AT THEM IN

1868
01:05:40,824 --> 01:05:41,491
SARS AS WELL.

1869
01:05:41,491 --> 01:05:42,492
>> TEEING OFF THAT THOUGH,
I

1870
01:05:42,492 --> 01:05:45,062
THINK THERE'S A LOT OF FOCUS ON

1871
01:05:45,062 --> 01:05:46,830
MEX O TREKSATE OR CYCLOFOSTER

1872
01:05:46,830 --> 01:05:49,533
NURSED MID FOR THE THAT WHICH IS

1873
01:05:49,533 --> 01:05:50,767
GREAT FOR THE CANCER PATIENTS

1874
01:05:50,767 --> 01:05:52,936
BUT DOES FOCUS ON THE REFLECT

1875
01:05:52,936 --> 01:05:54,037
THE SOLID ORGAN DEFECTSAs

1876
01:05:54,037 --> 01:05:55,238
WELL, SO AGAIN SOME OF THE

1877
01:05:55,238 --> 01:05:56,306
LESSONS MAY BE HELPFULFUL BUT

1878
01:05:56,306 --> 01:05:57,340
THERE MAY BE DIFFERENCES

1879
01:05:57,340 --> 01:05:59,910
PARTICULARLY WHEN IT COMINGS TO

1880
01:05:59,910 --> 01:06:00,177
VACCINES.

1881
01:06:00,177 --> 01:06:02,512
>> YEAH XSINGLE CELL WE

1882
01:06:02,512 --> 01:06:03,647
ACTUALLY--OR SICKLE CELL WE

1883
01:06:03,647 --> 01:06:04,781
ACTUALLY HAVE SICKLE CELL MICE,

1884
01:06:04,781 --> 01:06:06,850
SO WE CAN MODEL THAT PRETTY EASY

1885
01:06:06,850 --> 01:06:08,185
LE BUT EVEN DOING THINGS LIKE

1886
01:06:08,185 --> 01:06:09,519
THOO ZETAMIN, YOU KNOW THE

1887
01:06:09,519 --> 01:06:12,656
CANCER PATIENTS ARE ON SO MANYY

1888
01:06:12,656 --> 01:06:13,924
ANTIBIOTICS RIGHT TO PREVENT

1889
01:06:13,924 --> 01:06:15,625
REJECTION, CAN YOU EVEN DO THOSE

1890
01:06:15,625 --> 01:06:17,894
MODELS WHERE YOU TREAT THEM WITH

1891
01:06:17,894 --> 01:06:19,463
ANTIBIOTIC ANDS THAT WILL CHANGE

1892
01:06:19,463 --> 01:06:21,098
THE PATHOGENESIS OF YOUR VIRAL

1893
01:06:21,098 --> 01:06:24,735
INFECTION FOR SURE, JUST BEING

1894
01:06:24,735 --> 01:06:26,336
ON THESE CONSTANT ANTIBIOTICS.

1895
01:06:26,336 --> 01:06:30,440
>> SO DO YOU HAVE
ACCESS-DO THE

1896
01:06:30,440 --> 01:06:31,908
PHYSICIANS TAKING CARE OF THOSE

1897
01:06:31,908 --> 01:06:34,111
KID ANDS DO THE PARENTS CONSENT

1898
01:06:34,111 --> 01:06:36,613
FOR ACTUALLY BEING ABLE TO GET

1899
01:06:36,613 --> 01:06:38,315
SPECIMENS THAT AGAIN CAN CROSS

1900
01:06:38,315 --> 01:06:40,751
VALIDATE WITH YOUR FINDING IN

1901
01:06:40,751 --> 01:06:41,384
ANIMAL MODELS?

1902
01:06:41,384 --> 01:06:43,253
>> YEAH, WE DO AND THEY DO
THAT

1903
01:06:43,253 --> 01:06:45,922
A LOT FOR ACTUALLY LIKE XEIN,

1904
01:06:45,922 --> 01:06:48,391
O-TRANSPLANTS SO THEY CAN GET

1905
01:06:48,391 --> 01:06:50,127
THAT TUMOR FROM THE PATIENT AND

1906
01:06:50,127 --> 01:06:51,895
TRANSPLATE IT INTO A SKID OR NOD

1907
01:06:51,895 --> 01:06:54,531
MOUSE AND BE ABLE TO DO THAT SO

1908
01:06:54,531 --> 01:06:56,166
IT'S EASIER FOR US TO INCREASE

1909
01:06:56,166 --> 01:06:59,269
IN BODY ABLE TO TAKE THE

1910
01:06:59,269 --> 01:07:01,004
INFORMATION WE'RE SEEING, YOU

1911
01:07:01,004 --> 01:07:02,105
KNOW IF THEY'RE LOOKING

1912
01:07:02,105 --> 01:07:03,740
IMMUNOLOGICALLY OR THEY HAVE THE

1913
01:07:03,740 --> 01:07:05,242
RIEROUSS FROM THEM, WE CAN BRING

1914
01:07:05,242 --> 01:07:11,548
THOSE INTO THE ANIMAL MODELS.

1915
01:07:11,548 --> 01:07:13,283
NI JUST WANTED TO KIND OF RAISE

1916
01:07:13,283 --> 01:07:16,353
THIS POINT ABOUT THE UNDERLYING

1917
01:07:16,353 --> 01:07:18,355
GENETICS OF KIND OF THE FINE O

1918
01:07:18,355 --> 01:07:20,123
TYPES WE'RE LOOKING AT IN A LOT

1919
01:07:20,123 --> 01:07:22,893
OF THE ANIMAL MODEL STUFF IS

1920
01:07:22,893 --> 01:07:24,594
PHENOTYPE FOCUSED, RIGHT IN LIKE

1921
01:07:24,594 --> 01:07:28,832
DID MY MOUSE GET SICK, DID MY

1922
01:07:28,832 --> 01:07:31,101
FERRET GET SICK, BUT ALL OF THE

1923
01:07:31,101 --> 01:07:34,204
ANIMAL MODELS ARE TO A LARGE

1924
01:07:34,204 --> 01:07:36,173
EXTENT GENETICALLY SIMILAR, EVEN

1925
01:07:36,173 --> 01:07:37,040
OUTBRED ANIMALLINGS LIKE FERRETS

1926
01:07:37,040 --> 01:07:39,576
ARE COMING FROM A TRIPLE F

1927
01:07:39,576 --> 01:07:40,410
FOUNDER STRAIN OR WHATEVER.

1928
01:07:40,410 --> 01:07:42,179
>> THEY HAVE 8 FOUNDER
STRAINS,

1929
01:07:42,179 --> 01:07:45,448
THAT'S IT, SO YEAH.

1930
01:07:45,448 --> 01:07:47,384
>> BUT I WONDER, HOW OFTEN
ARE

1931
01:07:47,384 --> 01:07:52,255
THE DEC MODELS THAT WE'RE USING

1932
01:07:52,255 --> 01:07:52,889
RECAPITULATING A LARGE MAIORITY

1933
01:07:52,889 --> 01:07:55,826
OF WHAT WE WOULD SEE IN PEOPLE

1934
01:07:55,826 --> 01:07:57,260
VERSUS BEING KIND OF NARROW AND

1935
01:07:57,260 --> 01:07:58,595
WHAT YOUR THOUGHTS ARE, MOVING

1936
01:07:58,595 --> 01:08:00,764
FORWARD, HOW TO MAKE SURE THE

1937
01:08:00,764 --> 01:08:02,332
STUFF THAT WE'RE FINDING IN

1938
01:08:02,332 --> 01:08:03,533
THESE ANIMALS APPLIES TO HUMANS

1939
01:08:03,533 --> 01:08:04,734
AS MUCH AS POSSIBLE.

1940
01:08:04,734 --> 01:08:11,041
NYEAH, I THINK THAT'S A GREAT

1941
01:08:11,041 --> 01:08:12,976
QUESTION.

1942
01:08:12,976 --> 01:08:15,011
CLEARLY THE COLLABORATIVE COST

1943
01:08:15,011 --> 01:08:16,213
THEY HAVE AT UNIVERSITY OF NORTH

1944
01:08:16,213 --> 01:08:18,181
CAROLINA WOULD GO A LONG WAYS

1945
01:08:18,181 --> 01:08:20,851
TOWARDS LOOKING AT WHAT ROLE THE

1946
01:08:20,851 --> 01:08:23,553
GENETICS MIGHT PLAY.

1947
01:08:23,553 --> 01:08:24,855
SO THEY HAVE--AND I THINK THOSE

1948
01:08:24,855 --> 01:08:27,390
ARE NOW AVAILABLE TO PEOPLE.

1949
01:08:27,390 --> 01:08:28,592
>> YEAH, SO CAN YOU GET
THEM

1950
01:08:28,592 --> 01:08:30,927
FROM THE SYSTEMS GENETICS CORE

1951
01:08:30,927 --> 01:08:32,796
FACILITY AT UNC BUT ALSO SOME OF

1952
01:08:32,796 --> 01:08:34,197
THE LINES HAVE BEEN SENT TO

1953
01:08:34,197 --> 01:08:36,766
JACKS AND YOU CAN GET THEM

1954
01:08:36,766 --> 01:08:38,668
THERE, THEY'RE EXPENSIVE BUT--

1955
01:08:38,668 --> 01:08:40,003
>> YEAH AND THERE'S A
GROUP IN

1956
01:08:40,003 --> 01:08:41,571
THE UK THAT'S ALSO MADE

1957
01:08:41,571 --> 01:08:44,040
SOMETHING SIMILAR TO THE

1958
01:08:44,040 --> 01:08:46,943
COLLABORATIVE CROSS, SOMEBODY IN

1959
01:08:46,943 --> 01:08:48,511
GERMANY SO YOU CAN GET THOSE BUT

1960
01:08:48,511 --> 01:08:50,080
THAT WOULD BE LOOKING AT HOST

1961
01:08:50,080 --> 01:08:51,781
GENETICS, YOU VALID TO USE

1962
01:08:51,781 --> 01:08:52,816
SOMETHING LIKE THE COLLABORATIVE

1963
01:08:52,816 --> 01:08:54,517
CROSS AND FROM MARK'S WORK IT

1964
01:08:54,517 --> 01:08:56,052
DOES MAKE A DIG DIFFERENCE IN

1965
01:08:56,052 --> 01:08:57,020
HOW THOSE ANIMALS RESPOND WHEN

1966
01:08:57,020 --> 01:08:59,556
YOU'RE LOOKING FOR THE

1967
01:08:59,556 --> 01:09:00,357
PHENOTYPES.

1968
01:09:00,357 --> 01:09:02,025
HOW DO WE RECAPITULATE SOMETHING

1969
01:09:02,025 --> 01:09:03,326
LIKE THAT IN FERRETS.

1970
01:09:03,326 --> 01:09:08,331
THAT WILL BE A LITTLE BIT

1971
01:09:08,331 --> 01:09:08,932
HARDER, SHORT OF--THAT'S GOING

1972
01:09:08,932 --> 01:09:10,934
TO BE A LITTLE BIT HARDER.

1973
01:09:10,934 --> 01:09:13,370
BUT DEFINITELY AND I DON'T KNOW

1974
01:09:13,370 --> 01:09:15,438
HOW INBRED OUR HAMSTERS AND

1975
01:09:15,438 --> 01:09:18,208
COTTON RATS ARE PRETTY INBRED AS

1976
01:09:18,208 --> 01:09:18,575
WELL.

1977
01:09:18,575 --> 01:09:20,577
>> I THINK THEY'RE
TECHNICAL

1978
01:09:20,577 --> 01:09:28,184
OUTBRED BUT COMING FROM THE SAME

1979
01:09:28,184 --> 01:09:28,919
COLONY, SAME STORY.

1980
01:09:28,919 --> 01:09:31,187
>> SO JUST TO COMPLETE THE
LOOP

1981
01:09:31,187 --> 01:09:35,225
THERE, IS THERE ANY APPETITE FOR

1982
01:09:35,225 --> 01:09:35,959
EVALUATING COLLABORATIVE CROSS

1983
01:09:35,959 --> 01:09:37,127
MICE LIKE THAT AND SWINGING BACK

1984
01:09:37,127 --> 01:09:39,763
AND SAYING AS A FIELD WE DON'T

1985
01:09:39,763 --> 01:09:42,666
LIKE BULB C ANYMORE, OR WE DON'T

1986
01:09:42,666 --> 01:09:44,401
LIKE FERRETS FROM TRIPLE F, WE

1987
01:09:44,401 --> 01:09:45,602
LIKE FERRETS FROM WHEREVER ELSE

1988
01:09:45,602 --> 01:09:47,604
AND SAYING HERE'S WHERE WE THINK

1989
01:09:47,604 --> 01:09:49,472
A BETTER MODEL WITHIN THE MODEL

1990
01:09:49,472 --> 01:09:51,574
ACTUALLY IS, AND MAYBE IT'S

1991
01:09:51,574 --> 01:09:53,109
PHENOTYPE SPECIFIC FOR PREGNANCY

1992
01:09:53,109 --> 01:09:54,544
OR WHATEVER ELSE.

1993
01:09:54,544 --> 01:09:55,845
NI THINK THAT'S A GREAT

1994
01:09:55,845 --> 01:09:59,749
SUGGESTION IS TO ABLE TO GET THE

1995
01:09:59,749 --> 01:10:00,583
WHOLE SPAN OF COLLABORATIVE

1996
01:10:00,583 --> 01:10:03,687
CROPS AND ASK WHAT HAPPENS IN

1997
01:10:03,687 --> 01:10:04,220
ALL OF THESE?

1998
01:10:04,220 --> 01:10:05,455
WHAT DOES IT LOOK LIKE?

1999
01:10:05,455 --> 01:10:09,125
I THINK THAT WOULD BE REALLY

2000
01:10:09,125 --> 01:10:10,527
VALUABLE, I'M THINKING

2001
01:10:10,527 --> 01:10:13,630
ESPECIALLY SOMETHING LIKE, YOU

2002
01:10:13,630 --> 01:10:15,231
KNOW H5 INFLUENZA VIRUS WHERE

2003
01:10:15,231 --> 01:10:16,533
MAYBE THERE'S COLLABORATIVE

2004
01:10:16,533 --> 01:10:18,034
CROSS MICE THAT WON'T DROP DEAD

2005
01:10:18,034 --> 01:10:20,170
IN 4 DAYS WHEN THEY'RE INFECT

2006
01:10:20,170 --> 01:10:20,603
WIDE H5.

2007
01:10:20,603 --> 01:10:22,238
AND SO WE WOULD NEED TO KNOW

2008
01:10:22,238 --> 01:10:23,473
THAT BECAUSE IT WOULD GIVE US

2009
01:10:23,473 --> 01:10:24,541
INDICATION THAT THE HOST

2010
01:10:24,541 --> 01:10:26,710
GENETICS MAY BE REAL--WHICH WE

2011
01:10:26,710 --> 01:10:28,378
THINK IS TRUE ANYWAY WITH H5.

2012
01:10:28,378 --> 01:10:30,914
I THINK THERE WOULD BE A LOT OF

2013
01:10:30,914 --> 01:10:33,083
VALUE TO DOING SORT OF A GROUP

2014
01:10:33,083 --> 01:10:33,350
EFFORT.

2015
01:10:33,350 --> 01:10:36,686
MAYBE THERE CAN BE A NEW CENTER

2016
01:10:36,686 --> 01:10:37,620
FOR FOR SOMETHING LIKE THAT,

2017
01:10:37,620 --> 01:10:39,055
BECAUSE THEN WE CAN EVEN THINK

2018
01:10:39,055 --> 01:10:41,324
ABOUT HOW DO YOU THEN TRANSLATE

2019
01:10:41,324 --> 01:10:48,298
THAT TO NONMOUSE MODELS.

2020
01:10:48,298 --> 01:10:49,966
>> WE DO HAVE A FEW
QUESTIONS

2021
01:10:49,966 --> 01:10:51,368
FROM ONLINE THAT I DON'T WANT TO

2022
01:10:51,368 --> 01:10:53,103
LET GO, THIS WAS FROM THE

2023
01:10:53,103 --> 01:10:57,507
BEGINNING OF YOUR TALK FROM RYAN

2024
01:10:57,507 --> 01:10:58,641
AT CORNELL,   PERSUSCEPTIBILITY,

2025
01:10:58,641 --> 01:11:01,544
DO WE HAVE A STRONG OR SUMMARY

2026
01:11:01,544 --> 01:11:03,413
ANALYST OF EXPWRIEWKS IN

2027
01:11:03,413 --> 01:11:05,615
RESPIRATORY TRACTS FOR EACH

2028
01:11:05,615 --> 01:11:06,950
SMALL ANIMAL MODEL?

2029
01:11:06,950 --> 01:11:08,451
>> THAT'S A GREAT
QUESTION.

2030
01:11:08,451 --> 01:11:14,424
I KNOW WE DO, SO YOSHI'S GROUP,

2031
01:11:14,424 --> 01:11:19,229
PETE'S SMILING, MICE, CATS,

2032
01:11:19,229 --> 01:11:20,663
DOGS, FERRETS, HAMSTERS, DO YOU

2033
01:11:20,663 --> 01:11:22,165
HAVE GINNY PIGS, PIGS, I KNOW

2034
01:11:22,165 --> 01:11:27,570
YOU HAVE PIGS, CHICKENS, WHAT

2035
01:11:27,570 --> 01:11:27,904
ELSE?

2036
01:11:27,904 --> 01:11:28,271
RATS?

2037
01:11:28,271 --> 01:11:33,276
SO THE ANSWER IS YES AT A LEVEL,

2038
01:11:33,276 --> 01:11:35,345
SO THIS IS SIELIC ACID

2039
01:11:35,345 --> 01:11:36,546
DISTRIBUTION FOR THE OTHER

2040
01:11:36,546 --> 01:11:37,514
VIRUSES AND RECEPTORS I DON'T

2041
01:11:37,514 --> 01:11:40,216
KNOW IF THERE IS SOMETHING

2042
01:11:40,216 --> 01:11:41,317
COMPREHENSIVE LIKE THAT.

2043
01:11:41,317 --> 01:11:42,952
>> YEAH, NEXT QUESTION
FROM

2044
01:11:42,952 --> 01:11:43,720
AMELIA [INDISCERNIBLE] THIS IS

2045
01:11:43,720 --> 01:11:46,456
WHEN YOU WERE TALKING ABOUT THE

2046
01:11:46,456 --> 01:11:47,323
METABOLIC EXPERIMENTS, THE

2047
01:11:47,323 --> 01:11:48,591
DIFFERENT MOUSE MODEL STRAINS

2048
01:11:48,591 --> 01:11:50,994
DIFFER IN OTHER WAYS EG A

2049
01:11:50,994 --> 01:11:53,797
DIFFERENT SET OF NONCLASSICAL

2050
01:11:53,797 --> 01:11:55,665
MHC RECEPTORS, THIS MAY CONFOUND

2051
01:11:55,665 --> 01:11:58,334
STUDIES COMPARING THE IMPACT OF

2052
01:11:58,334 --> 01:11:59,736
METABOLIC STRAINS BETWEEN

2053
01:11:59,736 --> 01:12:05,075
DIFFERENT METABOLIC MOUSE

2054
01:12:05,075 --> 01:12:05,408
STRAINS.

2055
01:12:05,408 --> 01:12:06,776
>> AGREED NAND AS A
QUESTION

2056
01:12:06,776 --> 01:12:07,911
ANYONE WHO ASKED A QUESTION

2057
01:12:07,911 --> 01:12:09,712
ONLINE IS WELCOME TO UNMUTE OR

2058
01:12:09,712 --> 01:12:11,581
ASK INSTEAD OF ME, BUT 1 MORE,

2059
01:12:11,581 --> 01:12:14,350
IT'S MORE OF A COMMENT FROM MARK

2060
01:12:14,350 --> 01:12:15,685
WILLIAMS AT NIAID, BECAUSE PR8

2061
01:12:15,685 --> 01:12:17,287
HAS BEEN USED IF ARE MANY YEARS

2062
01:12:17,287 --> 01:12:19,089
ARE THERE REFERENCE SEQUENCES OR

2063
01:12:19,089 --> 01:12:20,323
WELL CHARACTERIZED STOCKS SUCH

2064
01:12:20,323 --> 01:12:22,392
THAT HARMONIZED USE OF VALIDATED

2065
01:12:22,392 --> 01:12:24,427
PR8 WOULD MINIMIZE VARIABILITY

2066
01:12:24,427 --> 01:12:28,064
IN HOST RESPONSES AND/OR IMMUNO

2067
01:12:28,064 --> 01:12:32,802
PATHOLOGY CAUSED BY CHANGES IN

2068
01:12:32,802 --> 01:12:33,369
CRITICAL SEQUENCE ELEMENTS?

2069
01:12:33,369 --> 01:12:34,337
>> YEAH, THATIA SOMETHING
I

2070
01:12:34,337 --> 01:12:35,405
THINK THE VALIDATED STRAINS IN

2071
01:12:35,405 --> 01:12:36,473
TOCK STYLES WILL BE SOMETHING WE

2072
01:12:36,473 --> 01:12:38,141
TALK ABOUT THROUGH THE CIVIC AND

2073
01:12:38,141 --> 01:12:39,909
THE SEER AND TRYING TO DO THAT.

2074
01:12:39,909 --> 01:12:42,545
SO YOU'RE SOMEWHAT COMPARING

2075
01:12:42,545 --> 01:12:44,747
APPLES TO APPLES WHEN YOU DO

2076
01:12:44,747 --> 01:12:45,248
THESE DIFFERENT ANIMAL

2077
01:12:45,248 --> 01:12:46,082
EXPERIMENTS SO I THINK SOMETHING

2078
01:12:46,082 --> 01:12:47,750
LIKE THAT WOULD BE AVAILABLE,

2079
01:12:47,750 --> 01:12:49,219
BUT THEN ONCE YOU GET IN YOUR

2080
01:12:49,219 --> 01:12:51,521
LAB, AND YOU PROPAGATE IT, 1

2081
01:12:51,521 --> 01:12:53,156
TIME IN A CELL, YOUR POPULATION

2082
01:12:53,156 --> 01:12:55,592
WILL CHANGE AND I THINK YOU JUST

2083
01:12:55,592 --> 01:12:59,496
NEED TO BE WILLING TO DEEP

2084
01:12:59,496 --> 01:13:02,799
SEQUENCE AND REALLY CLASSIFY HOW

2085
01:13:02,799 --> 01:13:05,001
YOUR VIRUS HAS CHANGED, NOT JUST

2086
01:13:05,001 --> 01:13:06,636
OKAY, THE CONSENSUS IS THE SAME,

2087
01:13:06,636 --> 01:13:08,271
OKAY WE HAVE THESE NEW SINGLE

2088
01:13:08,271 --> 01:13:09,072
NUCLEOTIDE VALID AND RELIABLE

2089
01:13:09,072 --> 01:13:11,541
YABTS POPPING UP THAT ARE

2090
01:13:11,541 --> 01:13:14,611
DIFFERENT THAN WHAT RYAN HAS IN

2091
01:13:14,611 --> 01:13:16,713
HIS FREEZER OR SEEMA HAS IN

2092
01:13:16,713 --> 01:13:16,913
HERS.

2093
01:13:16,913 --> 01:13:17,881
BUT THERE WOULD BE THE

2094
01:13:17,881 --> 01:13:19,949
POSSIBILITY OF HAVING THIS SORT

2095
01:13:19,949 --> 01:13:21,951
OF STOCK PILE BUT KNOWING THE

2096
01:13:21,951 --> 01:13:23,052
CAVEAT THAT WILL CHANGE IT AS

2097
01:13:23,052 --> 01:13:25,421
SOON AS YOU GET IT INTO YOUR

2098
01:13:25,421 --> 01:13:27,724
HANDS, YOU AMPLIFY IT 1 TIME TO

2099
01:13:27,724 --> 01:13:29,159
GROW UP STOCK BUT THE SECOND AND

2100
01:13:29,159 --> 01:13:30,326
THIRD AND FOURTH TIME.

2101
01:13:30,326 --> 01:13:32,295
OTHERS THOUGHTS ON THAT?

2102
01:13:32,295 --> 01:13:34,731
BECAUSE THERE'S BEEN LOTS OF

2103
01:13:34,731 --> 01:13:37,233
DISCUSSIONS ABOUT GETTING

2104
01:13:37,233 --> 01:13:40,937
VALIDATED VIRAL STOCKS.

2105
01:13:40,937 --> 01:13:42,472
>> CAN I JUST ADD TO THAT,
YOU

2106
01:13:42,472 --> 01:13:44,807
KNOW AS WE TALK ABOUT STRAINS WE

2107
01:13:44,807 --> 01:13:47,043
WE TALK A LOT ABOUT IT FROM A

2108
01:13:47,043 --> 01:13:48,745
RISK ASSESSMENT PANDEMIC,

2109
01:13:48,745 --> 01:13:50,046
PREPAREDNESS, ANGLE, BUT I THINK

2110
01:13:50,046 --> 01:13:51,414
THAT'S SORT OF TRANSLATES INTO

2111
01:13:51,414 --> 01:13:52,382
JUST ALL OF IT.

2112
01:13:52,382 --> 01:13:54,851
AS WE THINK ABOUT STRAINS,

2113
01:13:54,851 --> 01:13:56,786
EITHER PR8 OR MOVING FORWARD

2114
01:13:56,786 --> 01:13:58,888
WITH 1S THAT ARE YOU KNOW MORE

2115
01:13:58,888 --> 01:14:00,390
CIRCULATED IN THE POPULATION,

2116
01:14:00,390 --> 01:14:02,292
YOU KNOW THE REVERSE GENETICS,

2117
01:14:02,292 --> 01:14:06,196
PLAZ MIDS MIDS AND NOW WITH THE

2118
01:14:06,196 --> 01:14:09,933
LICENSING EXPIRED, THERE IS AN

2119
01:14:09,933 --> 01:14:11,100
OPPORTUNITY HERE TO REALLY LEVEL

2120
01:14:11,100 --> 01:14:17,874
THE PLAYING FIELD SUCH THAT

2121
01:14:17,874 --> 01:14:19,776
ACCESSIBILITY WITH STRAINS WITH

2122
01:14:19,776 --> 01:14:22,579
THE SAME GENETIC SIGNATURE CAN

2123
01:14:22,579 --> 01:14:23,913
HAPPEN BY MAKING THOSE PLAZ MIDS

2124
01:14:23,913 --> 01:14:25,848
MIDS AVAILABLE THROUGH BEI OR

2125
01:14:25,848 --> 01:14:26,216
OTHER RESOURCES.

2126
01:14:26,216 --> 01:14:27,717
>> RIGHT, BUT YOU HAVE TO
BE

2127
01:14:27,717 --> 01:14:29,052
CAREFUL WITH THOSE, TOO, RIGHT

2128
01:14:29,052 --> 01:14:31,454
BECAUSE A LOT OF TIMES, WE MAKE

2129
01:14:31,454 --> 01:14:33,890
A VIRUS FROM PLAZ MIDS MIDS,

2130
01:14:33,890 --> 01:14:36,125
DOES NOT BEHAVE THE SAME WAY

2131
01:14:36,125 --> 01:14:37,560
THAT THAT WILD-TYPE VIRUS.

2132
01:14:37,560 --> 01:14:39,996
AT LEAST IN OUR--I THINK THAT'S

2133
01:14:39,996 --> 01:14:41,164
A REALLY GOOD POINT IS THAT

2134
01:14:41,164 --> 01:14:42,332
AGAIN YOU WOULD HAVE TO KNOW

2135
01:14:42,332 --> 01:14:44,834
THIS IS PREPARED FROM THESE PLAZ

2136
01:14:44,834 --> 01:14:46,069
MIDS MIDS AND HERE YOU'RE STILL

2137
01:14:46,069 --> 01:14:47,403
GOING TO HAVE TO SEQUENCE TO

2138
01:14:47,403 --> 01:14:49,872
KNOW WHAT YOU'RE DEALING WITH.

2139
01:14:49,872 --> 01:14:52,208
>> I KNOW THE DISCUSSION
ABOUT

2140
01:14:52,208 --> 01:14:54,244
VIRUS STRAINS HAS BYE-BYE A BIT

2141
01:14:54,244 --> 01:14:58,281
FLU SPECIFIC BUT I'M TARTING TO

2142
01:14:58,281 --> 01:15:00,149
SEE THE SAME THING OCCUR FOR

2143
01:15:00,149 --> 01:15:01,818
MOUSE MODELS IN FOR SARS-COV-2

2144
01:15:01,818 --> 01:15:03,953
ASK I'M CERTAIN WE WILL PROBABLY

2145
01:15:03,953 --> 01:15:06,789
TALK ABOUT THAT TODAY BUT, AT

2146
01:15:06,789 --> 01:15:08,758
SOME POINT THOSE OF US DOING

2147
01:15:08,758 --> 01:15:10,393
ANIMAL WORK, YOU JUST HAVE TO

2148
01:15:10,393 --> 01:15:12,462
HONE IN AND CHOOSE THE STRAIN

2149
01:15:12,462 --> 01:15:13,329
BECAUSE YOU CANNOT CONTINUE TO

2150
01:15:13,329 --> 01:15:15,298
DO AND ASK THE QUESTIONS YOU'RE

2151
01:15:15,298 --> 01:15:19,302
TRYING TO ASK WITH 3 AND 4

2152
01:15:19,302 --> 01:15:20,536
DIFFERENT STRAINS.

2153
01:15:20,536 --> 01:15:22,972
SO YOU'RE STARTING TO SO THAT

2154
01:15:22,972 --> 01:15:24,207
WE'RE AT THAT POINT SO THAT SOME

2155
01:15:24,207 --> 01:15:26,776
PEOPLE ARE STILL WORKING WITH

2156
01:15:26,776 --> 01:15:29,379
ANCESTRAL, OTHERS ARE WORKING

2157
01:15:29,379 --> 01:15:32,882
WITH MOUSE ADAPTED, OTHERS ARE

2158
01:15:32,882 --> 01:15:33,883
ON TO OMICRON.

2159
01:15:33,883 --> 01:15:36,753
>> I THINK THE SAME IS
TRUE FOR

2160
01:15:36,753 --> 01:15:37,053
RSV.

2161
01:15:37,053 --> 01:15:38,721
>> SAME IS TRUE FOR FLU.

2162
01:15:38,721 --> 01:15:40,423
>> YEAH, YEAH, THANK YOU
FOR

2163
01:15:40,423 --> 01:15:40,757
RAISING THAT.

2164
01:15:40,757 --> 01:15:41,758
NO THIS IS ACROSS THE BOARD.

2165
01:15:41,758 --> 01:15:43,960
THIS IS TRUE FOR THE RSV FIELD

2166
01:15:43,960 --> 01:15:48,064
AS WELL, WHERE IT MAKES A BIG

2167
01:15:48,064 --> 01:15:51,834
DIFFERENCE, NOBODY DOES ANYTHING

2168
01:15:51,834 --> 01:15:54,737
WITH RSVB, THIS IS NOT A FLU

2169
01:15:54,737 --> 01:15:55,004
SPECIFIC.

2170
01:15:55,004 --> 01:15:56,572
>>  OKAY, WELL WE ARE AT
TIME SO

2171
01:15:56,572 --> 01:16:00,743
I WOULD LIKE TO THANK STACEY FOR

2172
01:16:00,743 --> 01:16:04,047
A FANTASTIC PRESENTATION FOR ALL

2173
01:16:04,047 --> 01:16:04,547
OF THE GREAT DISCUSSION.

2174
01:16:04,547 --> 01:16:06,849
NEXT WE HAVE A BREAK, I THINK,

2175
01:16:06,849 --> 01:16:08,951
AND SO WE WILL BE BACK IN HERE

2176
01:16:08,951 --> 01:16:10,253
AT 10:00 O'CLOCK AND WE WILL

2177
01:16:10,253 --> 01:16:12,635
CONTINUE WITH THE AGENDA.

2178
01:16:12,635 --> 01:16:12,968
THANK YOU EVERYBODY.

2179
01:16:13,094 --> 01:16:15,129
COLLECTION OF TALKS GOING INTO

2180
01:16:15,129 --> 01:16:17,498
THE DATA, LIMITATIONS OF IT AND

2181
01:16:17,498 --> 01:16:20,201
THES OF DIFFERENT MODELS, AND

2182
01:16:20,201 --> 01:16:22,136
LOOKING ACROSS SARS-COV-2 ACUTE

2183
01:16:22,136 --> 01:16:23,337
INFECTION, LONG-TERM INFECTION

2184
01:16:23,337 --> 01:16:26,374
AS WELL AS INFLUENZA,--SORRY,

2185
01:16:26,374 --> 01:16:28,609
THEY'RE ALL CORONA VIRUS INFECS,

2186
01:16:28,609 --> 01:16:29,677
I ARKPOLOGYIZE.

2187
01:16:29,677 --> 01:16:31,546
SO OUR FIRST SPEAKER WILL BE

2188
01:16:31,546 --> 01:16:32,280
STANLEY PERLMAN FROM THE

2189
01:16:32,280 --> 01:16:34,649
UNIVERSITY OF IOWA WHO WILL TALK

2190
01:16:34,649 --> 01:16:36,484
TO STRENGTHS AND LIMITATIONS ON

2191
01:16:36,484 --> 01:16:38,219
MOUSE MODELS FOR ACUTE

2192
01:16:38,219 --> 01:16:42,990
SARS-COV-2 AND P A S-C.

2193
01:16:42,990 --> 01:16:44,325
>> THANK YOU AND THANK YOU
TO

2194
01:16:44,325 --> 01:16:45,893
THE ORGANIZERS FOR INVITING ME.

2195
01:16:45,893 --> 01:16:48,863
SO I WILL TALK ABOUT TODAY IS

2196
01:16:48,863 --> 01:16:50,698
REALLY I FEEL LIKE A SUBCHAPTER

2197
01:16:50,698 --> 01:16:52,533
IN THE TALK THAT STACEY GAVE,

2198
01:16:52,533 --> 01:16:55,002
STACEY GAVE A NICE OVERVIEW OF

2199
01:16:55,002 --> 01:16:56,637
THE WHOLE FIELD OF HOW 1 THINKS

2200
01:16:56,637 --> 01:17:03,511
ABOUT THIS AND I'M GOING TO TALK

2201
01:17:03,511 --> 01:17:13,921
MOSTLY ABOUT SARS-COV-2.

2202
01:17:23,898 --> 01:17:25,600
OKAY SO THIS WILL REQUIRE FINE

2203
01:17:25,600 --> 01:17:26,567
MUTER SKILLS.

2204
01:17:26,567 --> 01:17:29,537
SO I WILL JUST START AND GIVE

2205
01:17:29,537 --> 01:17:32,440
BROAD VIEWS OF CORONA VIRUS

2206
01:17:32,440 --> 01:17:33,774
INFECTIONS IN COVID-19

2207
01:17:33,774 --> 01:17:34,642
INFECTION.

2208
01:17:34,642 --> 01:17:36,644
SO STARTING WITH SARS-COV-2 AND

2209
01:17:36,644 --> 01:17:38,913
MOSTLY DEALING WITH THAT AND SO

2210
01:17:38,913 --> 01:17:41,616
WE KNOW THAT MANY ANIMALS CAN BE

2211
01:17:41,616 --> 01:17:43,684
INFECTED BY SARS-COV-2, BUT FEW

2212
01:17:43,684 --> 01:17:44,919
OF THEM DEVELOP CLINICAL SIGNS

2213
01:17:44,919 --> 01:17:46,621
OR SYMPTOMS AND AS WE TALK ABOUT

2214
01:17:46,621 --> 01:17:48,723
THE END OF THE DISCUSSION AFTER

2215
01:17:48,723 --> 01:17:51,592
STACEY'S TALK, HOW IMPORTANT IS

2216
01:17:51,592 --> 01:17:51,993
THIS?

2217
01:17:51,993 --> 01:17:53,327
AND SOMEBODY'S USED TO TAKE CARE

2218
01:17:53,327 --> 01:17:55,463
OF BABY ANDS CHILDREN WHO ARE

2219
01:17:55,463 --> 01:17:57,965
REALLY SICK, MY TENDENCY WAS TO

2220
01:17:57,965 --> 01:17:59,167
STUDY ANIMALS WHO WERE REALLY

2221
01:17:59,167 --> 01:18:01,335
SICK, SO I WAS MORE INTERESTED

2222
01:18:01,335 --> 01:18:04,405
IN THE REALLY PATHOGENIC SIDE OF

2223
01:18:04,405 --> 01:18:07,375
WHAT THESE VIRUSES CAN DO AND WE

2224
01:18:07,375 --> 01:18:09,277
HAVE ALWAYS BEEN INTERESTED IN

2225
01:18:09,277 --> 01:18:10,678
LABORATORY MICE, THAT'S WHO WE

2226
01:18:10,678 --> 01:18:12,013
WORK WITH AND LABORATORY MICE

2227
01:18:12,013 --> 01:18:17,218
CAN BE  INFECTED WITH THE

2228
01:18:17,218 --> 01:18:18,219
ANCESTRAL STRAIN OF SARS-COV-2,

2229
01:18:18,219 --> 01:18:19,820
THIS WAS THE PROBLEM FOR JUST A

2230
01:18:19,820 --> 01:18:21,355
FEW MONTHS BECAUSE AS EVERYONE

2231
01:18:21,355 --> 01:18:23,558
WAS AWARE, THE ALPHA STRAIN

2232
01:18:23,558 --> 01:18:26,627
WHICH AROSE THAT CAN INFECT MICE

2233
01:18:26,627 --> 01:18:28,829
BUT AT THE TIME WE WERE

2234
01:18:28,829 --> 01:18:31,199
DESPERATE TO FIND OUT WHY ARE

2235
01:18:31,199 --> 01:18:31,766
PEOPLE DYING?

2236
01:18:31,766 --> 01:18:34,035
WHY ARE PEOPLE GETTING SICK WITH

2237
01:18:34,035 --> 01:18:38,606
THESE VIRUSES, AND WHAT BECAME

2238
01:18:38,606 --> 01:18:40,908
CLEAR QUICKLY IS 1 THAT COULD

2239
01:18:40,908 --> 01:18:44,245
INFECT MICE AND AMINO ACIDS AND

2240
01:18:44,245 --> 01:18:48,282
THE MOUSE OR SPIKE PROTEIN.

2241
01:18:48,282 --> 01:18:52,119
SO THEY ALSO KNEW THAT MICE

2242
01:18:52,119 --> 01:18:53,854
WOULD BE USEFUL BECAUSE THERE'S

2243
01:18:53,854 --> 01:18:56,324
A VARIETY OF STRAINS WITH

2244
01:18:56,324 --> 01:18:57,124
VARYING SUSCEPTIBILITY TO

2245
01:18:57,124 --> 01:18:58,526
INFECTION AND WE HEARD ABOUT

2246
01:18:58,526 --> 01:19:00,695
THIS IN VARIOUS MEETINGS AND

2247
01:19:00,695 --> 01:19:02,129
SESSIONS WE HAVE ONLINE TALKING

2248
01:19:02,129 --> 01:19:03,664
ABOUT THESE VIRUSES AND THE

2249
01:19:03,664 --> 01:19:07,668
INFECTION, SO WE KNOW FOR

2250
01:19:07,668 --> 01:19:10,104
EXAMPLE, THAT BALB-C MICE ARE

2251
01:19:10,104 --> 01:19:17,678
READILY INFECTIBLE AT ALL AGES

2252
01:19:17,678 --> 01:19:20,147
WITH SARS-COV-2 AND SARS CAV,

2253
01:19:20,147 --> 01:19:22,383
AND OTHERS AT BALB-C, THERE'S

2254
01:19:22,383 --> 01:19:23,918
AGE DEPENDENCE IS THAT LEDITOUS

2255
01:19:23,918 --> 01:19:27,121
THINGS BEING INTERESTED IN AGE

2256
01:19:27,121 --> 01:19:27,955
DEPENDENCE IN SARS-COV-2 BECAUSE

2257
01:19:27,955 --> 01:19:31,559
WHAT WE KNOW FROM OTHER SARS

2258
01:19:31,559 --> 01:19:33,527
CORONA VIRUSES, WHETHER IT'S

2259
01:19:33,527 --> 01:19:34,962
SARS-COV-2, IS THAT OLDER

2260
01:19:34,962 --> 01:19:36,464
INDIVIDUALS ARE MORE SUSCEPTIBLE

2261
01:19:36,464 --> 01:19:40,835
TO INFECTION THAN OUR YOUNGER

2262
01:19:40,835 --> 01:19:41,002
1S.

2263
01:19:41,002 --> 01:19:42,436
SO SOME OF THE APPROACHES TO

2264
01:19:42,436 --> 01:19:43,938
MOUSE MODELS WHICH WE AND OTHERS

2265
01:19:43,938 --> 01:19:47,141
USE ARE AS FOLLOWS, BY

2266
01:19:47,141 --> 01:19:47,942
SENSITIZING MICE AGAIN, I'M

2267
01:19:47,942 --> 01:19:49,877
TALKING HERE ABOUT THE ANCESTRAL

2268
01:19:49,877 --> 01:19:50,244
STRAIN.

2269
01:19:50,244 --> 01:19:51,545
THIS WOULD HAVE BEEN DONE

2270
01:19:51,545 --> 01:19:52,680
DIFFERENTLY IF 1 OF THE STRAINS

2271
01:19:52,680 --> 01:19:55,449
THAT COULD DIRECTLY INFECT MICE

2272
01:19:55,449 --> 01:19:58,185
CAME UP ORIGINALLY AND WITH

2273
01:19:58,185 --> 01:20:00,021
SARS-COV, THAT WAS THE CASE, THE

2274
01:20:00,021 --> 01:20:03,024
VIRUS THAT WAS ORIGINALLY

2275
01:20:03,024 --> 01:20:04,492
ISOLATED COULD INFECT MICE CAUSE

2276
01:20:04,492 --> 01:20:07,995
ALMOST NO DISEASE BUT COULD

2277
01:20:07,995 --> 01:20:10,097
INFECT MICE DIRECTLY SO

2278
01:20:10,097 --> 01:20:11,365
SARS-COV-2 WAS JUST COMING OFF

2279
01:20:11,365 --> 01:20:12,900
THAT, SO HOW DO YOU DO THAT?

2280
01:20:12,900 --> 01:20:14,735
HOW DO YOU MAKE THEM ABLE TO

2281
01:20:14,735 --> 01:20:15,403
INFECT MICE?

2282
01:20:15,403 --> 01:20:18,272
THE FIRST APPROACH WAS 1 THAT WE

2283
01:20:18,272 --> 01:20:20,241
AND OTHERS HAD USED ACTUALLY

2284
01:20:20,241 --> 01:20:20,841
EARLY IN THE SARS PROJECTION

2285
01:20:20,841 --> 01:20:23,744
NEURONS OR PIONS DEMIC, SO WE

2286
01:20:23,744 --> 01:20:26,981
SENSITIZED MICE WITH ADENO-5

2287
01:20:26,981 --> 01:20:28,716
VECTORS EXPRESSING HUMAN ASE 2,

2288
01:20:28,716 --> 01:20:30,685
THE ADMIN RECORDS ANDAGE OF THIS

2289
01:20:30,685 --> 01:20:32,720
IS IN THEORY CAN YOU MAKE THE

2290
01:20:32,720 --> 01:20:34,655
CONSTRUCTS WITHIN A MONTH AND 1

2291
01:20:34,655 --> 01:20:36,724
HAS A MODEL NOT FOR SYMPTOMATIC

2292
01:20:36,724 --> 01:20:38,993
INFECTION OR NOT FOR VERY IMP

2293
01:20:38,993 --> 01:20:40,328
TOMATIC INFECTION, OR AT LEAST

2294
01:20:40,328 --> 01:20:42,697
FOR INFECTION, AND WE HAD AS

2295
01:20:42,697 --> 01:20:46,867
PART OF THE SARS EPIDEMIC WE

2296
01:20:46,867 --> 01:20:51,439
DEVELOP THESE K18 MICE AND THEY

2297
01:20:51,439 --> 01:20:52,306
BECAME USEFUL AND I WILL MENTION

2298
01:20:52,306 --> 01:20:55,076
THAT IN A BIT AND THEN WE MADE

2299
01:20:55,076 --> 01:20:57,144
MORE KNOCK-IN MICE AND 1 TO

2300
01:20:57,144 --> 01:20:59,347
CHANGE THE MOUSE IS TO

2301
01:20:59,347 --> 01:21:01,449
MANIPULATE THE VIRUS SO THAT IT

2302
01:21:01,449 --> 01:21:03,651
COMBINED AND AS I SAID THE

2303
01:21:03,651 --> 01:21:05,152
ANCESTRAL STRAIN OTHER THAN

2304
01:21:05,152 --> 01:21:11,025
DELTA THAT CAN INFECT MICE

2305
01:21:11,025 --> 01:21:11,759
DIRECTLY.

2306
01:21:11,759 --> 01:21:13,361
SO, GOING THROUGH THE STRAINS

2307
01:21:13,361 --> 01:21:14,562
SINGLE MUTATIONS OF THESE

2308
01:21:14,562 --> 01:21:19,266
DIFFERENT APPROACHES, SO FOR THE

2309
01:21:19,266 --> 01:21:21,469
A D5 SYSTEM WHICH IS DEVELOPED

2310
01:21:21,469 --> 01:21:24,372
BY MY COLLEAGUE PAUL MCCRAE.

2311
01:21:24,372 --> 01:21:26,006
IT'S QUICKLY MADE.

2312
01:21:26,006 --> 01:21:28,743
IT'S USEFUL, YOU INFECT MICE OR

2313
01:21:28,743 --> 01:21:30,378
TRANSDUCE MICE WITH THE ADEN O

2314
01:21:30,378 --> 01:21:32,413
VIRUS CONSTRUCT AND THEN YOU

2315
01:21:32,413 --> 01:21:34,448
INFECT THEM WITH SARS-COV-2.

2316
01:21:34,448 --> 01:21:37,985
YOU USE HIGH DOSES AND ANY

2317
01:21:37,985 --> 01:21:39,720
STRAIN OF SARS-COV-2 WILL WORK

2318
01:21:39,720 --> 01:21:40,955
IN THESE MICE BECAUSE HAVE YOU

2319
01:21:40,955 --> 01:21:42,223
THE HUMAN RECEPTOR AND THESE

2320
01:21:42,223 --> 01:21:43,824
CONTRACTS ARE AVAILABLE FROM BEI

2321
01:21:43,824 --> 01:21:45,659
IF 1 DOESN'T WANT TO MAKE THEM

2322
01:21:45,659 --> 01:21:46,994
THEMSELVES, AND THE ADVANTAGES

2323
01:21:46,994 --> 01:21:49,563
ARE NOT ONLY CAN YOU SENSITIZE

2324
01:21:49,563 --> 01:21:50,664
ANY STRAIN OF MICE BUT YOU CAN

2325
01:21:50,664 --> 01:21:53,868
USE THEM FOR DOING THINGS LIKE

2326
01:21:53,868 --> 01:21:56,003
IDENTIFYING T-CELL RESONS

2327
01:21:56,003 --> 01:21:56,704
SPONSES, ANTIBODY RESPONSES,

2328
01:21:56,704 --> 01:21:57,738
TEST VACCINES AND THERAPEUTICS

2329
01:21:57,738 --> 01:21:58,773
AND THIS WAS IMPORTANT IN THE

2330
01:21:58,773 --> 01:22:00,908
BEIMINNING OF THE PANDEMIC WHEN

2331
01:22:00,908 --> 01:22:02,143
WE REALLY DIDN'T HAVE VERY MUCH

2332
01:22:02,143 --> 01:22:04,345
TO USE IN TERMS OF MICE.

2333
01:22:04,345 --> 01:22:05,546
HAMSTERS FROM THE BEGINNING WERE

2334
01:22:05,546 --> 01:22:07,982
KNOWN TO BE INFECTIBLE AND WE

2335
01:22:07,982 --> 01:22:09,984
WILL HEAR ABOUT THAT SO THAT WAS

2336
01:22:09,984 --> 01:22:10,918
USEFUL.

2337
01:22:10,918 --> 01:22:12,186
THE LIMITATIONS OF THE SYSTEM IS

2338
01:22:12,186 --> 01:22:16,524
THAT YOU GET MINIMAL CLINICAL

2339
01:22:16,524 --> 01:22:18,826
DISEASE AND SLIGHTLY MORE WEIGHT

2340
01:22:18,826 --> 01:22:20,194
LOSS, FOR THE IMMUNO DEFICIENT

2341
01:22:20,194 --> 01:22:22,229
MICE ARE TRANSDUCED AND VIRUS

2342
01:22:22,229 --> 01:22:23,197
CLEARED VERY QUICKLY WITHIN A

2343
01:22:23,197 --> 01:22:25,599
WEEK AND 1 OF THE REASONS THAT I

2344
01:22:25,599 --> 01:22:28,269
THINK THAT MICE DO WELL IS

2345
01:22:28,269 --> 01:22:30,204
BECAUSE THE AT1 CELLS WHICH ARE

2346
01:22:30,204 --> 01:22:31,505
IMPORTANT FOR AIR EXCHANGE

2347
01:22:31,505 --> 01:22:32,907
ACTUALLY SURVIVE IN THESE MICE.

2348
01:22:32,907 --> 01:22:38,979
LET ME SEE IF I CAN--YES, SO,

2349
01:22:38,979 --> 01:22:40,281
THIS JUST BRIEFLY HOW DOES THE

2350
01:22:40,281 --> 01:22:44,618
ARROW WORK IN DO YOU KNOW?

2351
01:22:44,618 --> 01:22:50,324
YEAH, OKAY, SO, WE HAD MADE

2352
01:22:50,324 --> 01:22:51,926
THESE VIRUSES SARS-COV-2 THAT

2353
01:22:51,926 --> 01:22:54,161
EXPRESS CREE AND VENUS AND THE

2354
01:22:54,161 --> 01:22:56,430
VIRUS IS BASICALLY VIRULENT AS

2355
01:22:56,430 --> 01:22:57,598
WILD-TYPE VIRUS IN MICE AND WHAT

2356
01:22:57,598 --> 01:23:00,835
THIS DOES IS THE VENUS ALLOWS

2357
01:23:00,835 --> 01:23:03,637
YOU TO IDENTIFY A CELL INFECTED

2358
01:23:03,637 --> 01:23:05,172
AND EARLY TIMES OF INFECTION AND

2359
01:23:05,172 --> 01:23:10,277
CREE IF 1 INFECTS MICE THAT HAS

2360
01:23:10,277 --> 01:23:12,079
A FOX [INDISCERNIBLE] IT CAN

2361
01:23:12,079 --> 01:23:14,248
IDENTIFY THE CELLS THAT WERE

2362
01:23:14,248 --> 01:23:15,349
INFECTED AND IN THIS EXPERIMENT,

2363
01:23:15,349 --> 01:23:18,786
WE TOOK THE MICE, SHOWING

2364
01:23:18,786 --> 01:23:20,287
PREVIOUSLY INFECTED CELLS IN

2365
01:23:20,287 --> 01:23:22,323
ADEN O VIRUS, MOST OF THE CELLS

2366
01:23:22,323 --> 01:23:24,758
THAT ARE SURVIVING ARE AT1 CELLS

2367
01:23:24,758 --> 01:23:26,760
THATTA SHOWN HERE AND IS A FEW

2368
01:23:26,760 --> 01:23:29,163
AT2 CELLS WHILE IN THE MORE

2369
01:23:29,163 --> 01:23:30,197
VIRULENT STRAINS WHICH I WILL

2370
01:23:30,197 --> 01:23:32,533
TALK ABOUT IN A COUPLE MINUTES

2371
01:23:32,533 --> 01:23:33,801
ISSUE THE AT-2 CELLS ARE THE

2372
01:23:33,801 --> 01:23:35,970
ONLY 1S THAT ARE SURF VIEFING O

2373
01:23:35,970 --> 01:23:38,272
BY HAVING AT2 CELLS SURVIVE,

2374
01:23:38,272 --> 01:23:41,008
THESE CAN BE PRECURSORS, BUT IF

2375
01:23:41,008 --> 01:23:42,643
THE AT1 CELLS ARE DYING, THE

2376
01:23:42,643 --> 01:23:45,079
MICE DIE BECAUSE THEY NEED THAT

2377
01:23:45,079 --> 01:23:46,313
FOR OXYGEN EXCHANGE.

2378
01:23:46,313 --> 01:23:48,449
SO THIS SYSTEM SHOWS POSSIBLY 1

2379
01:23:48,449 --> 01:23:58,959
OF THE REASONS THAT ADENOVIRUS

2380
01:24:01,962 --> 01:24:04,865
MICE DO BUT WE KNOW THAT AD-5

2381
01:24:04,865 --> 01:24:06,600
MAY MODESTLY INDUCE AN IMMUNE

2382
01:24:06,600 --> 01:24:09,103
RESPONSE AND THAT'S WHY WE HAVE

2383
01:24:09,103 --> 01:24:10,404
WAYS TO TEST MICE AND WE KNOW

2384
01:24:10,404 --> 01:24:12,206
THE NUMBER OF SUSCEPTIBLE CELLS

2385
01:24:12,206 --> 01:24:14,441
IS LIMITED BECAUSE OF THE

2386
01:24:14,441 --> 01:24:14,775
TRANSDUCTION.

2387
01:24:14,775 --> 01:24:17,578
BUT STILL A BIT OF A MYSTERY FOR

2388
01:24:17,578 --> 01:24:21,749
THESE MICE TO SHOW RESISTANT TO

2389
01:24:21,749 --> 01:24:23,217
THE VIRUS.

2390
01:24:23,217 --> 01:24:26,420
THE SECOND APPROACH IS TO USE

2391
01:24:26,420 --> 01:24:28,155
THESE K18 MICE AND THESE ARE THE

2392
01:24:28,155 --> 01:24:31,158
1S THAT JACKSON LAB DID A GREAT

2393
01:24:31,158 --> 01:24:32,526
JOB IN RESUSCITATING OR RECOVERY

2394
01:24:32,526 --> 01:24:35,596
EARLY IN THE PANDEMIC, SO WE HAD

2395
01:24:35,596 --> 01:24:37,965
HAD THESE MICE, WE USED THEM IN

2396
01:24:37,965 --> 01:24:39,667
SARS COV AND WE DIDN'T LIKE THEM

2397
01:24:39,667 --> 01:24:41,635
VERY MUCH BECAUSE NICE ALL GOT

2398
01:24:41,635 --> 01:24:43,837
NEUROLOGICAL DISEASE AND THEY

2399
01:24:43,837 --> 01:24:47,541
DIED COMFORTABLY, BUT FOR

2400
01:24:47,541 --> 01:24:49,543
SARS-COV-2 IT SEEMS LIKE

2401
01:24:49,543 --> 01:24:51,011
NEUROLOGIC DEC NOT TOTALLY CLEAR

2402
01:24:51,011 --> 01:24:53,581
BECAUSE WE HADN'T HAD SIDE BY

2403
01:24:53,581 --> 01:24:55,549
SIDE COMPARISON, WITH SARS-COV-2

2404
01:24:55,549 --> 01:24:57,551
BUT SO IN THESE RESUSCITATED WE

2405
01:24:57,551 --> 01:24:58,485
WERE WORRIED THESE WERE NOT

2406
01:24:58,485 --> 01:24:59,954
GOING TO BE VERY USEFUL BUT THEY

2407
01:24:59,954 --> 01:25:04,525
TURNED OUT TO BE INCREDIBLY

2408
01:25:04,525 --> 01:25:07,194
USEFUL BECAUSE NOT ALL MICE USE

2409
01:25:07,194 --> 01:25:09,363
NEUROLOGICAL DISEASE BUT ALSO

2410
01:25:09,363 --> 01:25:12,132
BECAUSE IT WAS SO SUSCEPTIBLE TO

2411
01:25:12,132 --> 01:25:13,067
INFECTION.

2412
01:25:13,067 --> 01:25:15,035
AND SO JUST A COUPLE COMMENTS ON

2413
01:25:15,035 --> 01:25:16,003
THEM, THEY WERE AVAILABLE EARLY

2414
01:25:16,003 --> 01:25:17,571
IN THE PANDEMIC AND I THINK 1 OF

2415
01:25:17,571 --> 01:25:19,473
THE THINGS THAT BOTH JACKSON

2416
01:25:19,473 --> 01:25:21,208
LABS AND UNIVERSITY AND THE

2417
01:25:21,208 --> 01:25:26,547
UNIVERSITY OF IOWA DID IS THEY

2418
01:25:26,547 --> 01:25:28,616
MADE THESE MICE AVAILABLE AT

2419
01:25:28,616 --> 01:25:31,051
REALLY RELATIVELY LOW PRICES

2420
01:25:31,051 --> 01:25:33,854
OPPOSED TO DESIGNER MICE WHICH

2421
01:25:33,854 --> 01:25:34,755
WERE VERY EXPENSIVE.

2422
01:25:34,755 --> 01:25:35,522
THESE MICE COST INITIALLY TWICE

2423
01:25:35,522 --> 01:25:38,759
AS MUCH AS A B6 MOUSE SO IT WAS

2424
01:25:38,759 --> 01:25:42,262
AFFORDABLE AND SO, JACKSON LABS

2425
01:25:42,262 --> 01:25:43,631
ACTUALLY INCREASED THEIR

2426
01:25:43,631 --> 01:25:45,366
PRODUCTIVITY OF THESE HIGHLY AND

2427
01:25:45,366 --> 01:25:46,800
THEY BECAME WIDELY USED.

2428
01:25:46,800 --> 01:25:49,670
THESE HAVE CERTAIN ADVANTAGES

2429
01:25:49,670 --> 01:25:50,738
AND CERTAIN DISADVANTAGES THESE

2430
01:25:50,738 --> 01:25:52,539
MICE, SO THE STRENGTH IS THAT

2431
01:25:52,539 --> 01:25:57,311
THEY DEVELOP A CLINICAL DEC AND

2432
01:25:57,311 --> 01:25:59,580
DOSE DEPENDENT FASHION, MALE AND

2433
01:25:59,580 --> 01:26:00,681
FEMALE MICE WERE SUSCEPTIBLE TO

2434
01:26:00,681 --> 01:26:02,916
INFECTION, AND TELL BE

2435
01:26:02,916 --> 01:26:03,817
THE--THERE'S A FUNNY BUSINESS

2436
01:26:03,817 --> 01:26:05,953
WITH THESE MICE BECAUSE

2437
01:26:05,953 --> 01:26:06,754
NEUROLOGICAL DISEASE DEVELOPS

2438
01:26:06,754 --> 01:26:07,855
MOSTLY IN YOUNGER MICE BUT AT

2439
01:26:07,855 --> 01:26:09,556
THE SAME TIME BECAUSE THESE MICE

2440
01:26:09,556 --> 01:26:11,792
WERE ON A B6 BACKGROUND, THEY

2441
01:26:11,792 --> 01:26:13,861
BECOME MORE SENSITIVE, AS MICE

2442
01:26:13,861 --> 01:26:14,328
AGE.

2443
01:26:14,328 --> 01:26:18,065
SO EARLY ON, THEY DIVE FROM MICE

2444
01:26:18,065 --> 01:26:19,833
MAY DIE FROM RESPIRATORY OR

2445
01:26:19,833 --> 01:26:21,335
NEUROLOGICAL DISEASE, BUT LATER

2446
01:26:21,335 --> 01:26:22,636
ON THEY DIE FROM RESPIRATORY

2447
01:26:22,636 --> 01:26:22,870
DISEASE.

2448
01:26:22,870 --> 01:26:24,772
AND WE SEE A LOT OF THINGS THAT

2449
01:26:24,772 --> 01:26:26,173
ARE SIMILAR TO THE HUMAN

2450
01:26:26,173 --> 01:26:31,278
INFECTION, WE SEE INFECTION OF

2451
01:26:31,278 --> 01:26:33,247
SUSTEN TACTULAR CELLS IN THE

2452
01:26:33,247 --> 01:26:34,248
NAISAL CAVITY, WHICH I WILL TALK

2453
01:26:34,248 --> 01:26:38,952
ABOUT IF A GET TO THEM, AND THE

2454
01:26:38,952 --> 01:26:43,624
INFECTION OF ALVEOLAR CELLS AND

2455
01:26:43,624 --> 01:26:44,458
THROMBIOLOGICAL AND IT'S STUDIES

2456
01:26:44,458 --> 01:26:46,427
THAT PEOPLE USE FOR THERAPEUTICS

2457
01:26:46,427 --> 01:26:48,595
AND VACCINES, AND THE WEAKNESSES

2458
01:26:48,595 --> 01:26:52,399
ARE THAT THESE SOMETIMES FELT

2459
01:26:52,399 --> 01:26:53,500
ENCEPHALITIS, SARS KICKOFF

2460
01:26:53,500 --> 01:26:55,335
RARELY IF EVER AFFECTS THE HUMAN

2461
01:26:55,335 --> 01:26:56,036
BRAIN, THIS WAS VERY

2462
01:26:56,036 --> 01:26:57,671
CONTROVERSIAL IN THE BEGINNING

2463
01:26:57,671 --> 01:27:00,174
OF THE PANDEMIC AND I THINK

2464
01:27:00,174 --> 01:27:00,808
STILL IS SOMEWHAT CONTROVERSIAL

2465
01:27:00,808 --> 01:27:03,243
BUT NOT AS MUCH, BRAIN INFECTION

2466
01:27:03,243 --> 01:27:05,646
IN THESE MICE OCCURS IN THE

2467
01:27:05,646 --> 01:27:08,282
EPITHELIUM, PERHAPS THE BLOOD

2468
01:27:08,282 --> 01:27:09,183
AND   PERSIEVEERAL NERVES.

2469
01:27:09,183 --> 01:27:13,187
AND IT'S BECAUSE BY BEING

2470
01:27:13,187 --> 01:27:14,722
EXPRESSED BEHIND THE CYTOKERATIN

2471
01:27:14,722 --> 01:27:16,990
PROMOTER, IT'S NOT THE SAME

2472
01:27:16,990 --> 01:27:18,525
EXPRESSION PATTERN AS YOU SEE IN

2473
01:27:18,525 --> 01:27:22,296
HUMANS OR MICE OF PHASE 2.

2474
01:27:22,296 --> 01:27:26,934
AND SO THE NEXT APPROACH IS 1

2475
01:27:26,934 --> 01:27:28,635
THAT WAS USED BY OUR LAB AND

2476
01:27:28,635 --> 01:27:28,869
OTHERS.

2477
01:27:28,869 --> 01:27:31,605
SO THE IDEA WAS HERE TO CHANGE

2478
01:27:31,605 --> 01:27:39,646
THE MOUSE, THE VIRUS RATHER SO

2479
01:27:39,646 --> 01:27:48,188
WE COULD BETTER USE  MACE2, AND

2480
01:27:48,188 --> 01:27:57,464
BASED ON THIS ANALYSIS, THE

2481
01:27:57,464 --> 01:27:59,633
LAB,--DEVELOPED A VIRUS THAT CAN

2482
01:27:59,633 --> 01:28:03,403
INFECT MICE BY CHANGING 2

2483
01:28:03,403 --> 01:28:05,572
RESIDUES AND JOE'S LAB, ISOLATED

2484
01:28:05,572 --> 01:28:07,741
A RIEROUS THAT COULD INFECT MICE

2485
01:28:07,741 --> 01:28:10,477
DIRECTLY WITHOUT ANY FURTHER

2486
01:28:10,477 --> 01:28:11,678
MANIPULATION AND THIS WAS

2487
01:28:11,678 --> 01:28:14,214
CURIOSITY BECAUSE THE WAY HE DID

2488
01:28:14,214 --> 01:28:15,849
IT, THE WAY THE LAB DID IT IS

2489
01:28:15,849 --> 01:28:18,085
THEY WERE ABLE TO TAKE THE

2490
01:28:18,085 --> 01:28:19,386
NORMAL STOPS OF ANCESTRAL VIRUS

2491
01:28:19,386 --> 01:28:21,021
AND WE KNOW THAT AS WAS

2492
01:28:21,021 --> 01:28:23,323
MENTIONED ALL THESE VIRUSES OF

2493
01:28:23,323 --> 01:28:25,626
THESE SPECIES, SO HE WAS ABLE IN

2494
01:28:25,626 --> 01:28:29,029
THAT GROUP TO ISOLATE A VIRUS

2495
01:28:29,029 --> 01:28:30,931
THAT COULD DIRECTLY INFECT THE

2496
01:28:30,931 --> 01:28:34,935
MOUSE, MICE AND SO, WE DEVELOPED

2497
01:28:34,935 --> 01:28:37,838
A--YOU WILL USE IN 501 MUTATION

2498
01:28:37,838 --> 01:28:39,540
WHICH TURNED OUT TO BE CRITICAL

2499
01:28:39,540 --> 01:28:41,008
FOR THE HUMAN INFECTIONS AFTER

2500
01:28:41,008 --> 01:28:44,278
THAT, WE USE THIS TO MAKE A

2501
01:28:44,278 --> 01:28:45,078
REVERSE GENETIC--USE REVERSE

2502
01:28:45,078 --> 01:28:46,380
GENETICS TO MAKE A MOUSE THAT

2503
01:28:46,380 --> 01:28:47,681
COULD THEN INFECT MICE AND 1 OF

2504
01:28:47,681 --> 01:28:49,783
THE THINGS ABOUT ALL THOSE VIRUS

2505
01:28:49,783 --> 01:28:50,984
SYSTEM THAT THEY'RE ALL

2506
01:28:50,984 --> 01:28:53,220
ATTENUATE IN MICE, INITIALLY

2507
01:28:53,220 --> 01:28:55,055
EXCEPT THE BATTA VARIANT MAY

2508
01:28:55,055 --> 01:28:57,524
HAVE MORE VIRULENCE AND AFTER

2509
01:28:57,524 --> 01:28:58,926
PASSAGE THROUGH A MOUSE LUNGS,

2510
01:28:58,926 --> 01:29:02,062
FOR A PERIOD OF TIME, WE WILL

2511
01:29:02,062 --> 01:29:05,332
HEAR LATER ABOUT M810, WE

2512
01:29:05,332 --> 01:29:10,838
PASSAGE OURS THIRD TIMES AND WE

2513
01:29:10,838 --> 01:29:12,105
GOTIE VERY VIRULENT VIRUS CELL.

2514
01:29:12,105 --> 01:29:14,541
SO I ONLY SHOW THIS SLIDE FOR 1

2515
01:29:14,541 --> 01:29:16,310
POINT, SO THIS SLIDE MOSTLY

2516
01:29:16,310 --> 01:29:17,511
INFECTS THE LUNGS BUT 1 THING

2517
01:29:17,511 --> 01:29:21,281
THAT WAS CURIOUS IS THAT THEY

2518
01:29:21,281 --> 01:29:23,183
TOO HAD TITERS IN VARIOUS ORGANS

2519
01:29:23,183 --> 01:29:24,551
WHETHER IT'S THE BRAIN, HEART,

2520
01:29:24,551 --> 01:29:26,253
LIVER UAND THE REASON I SHOW

2521
01:29:26,253 --> 01:29:27,654
THIS IS BECAUSE 1 THING THAT'S

2522
01:29:27,654 --> 01:29:28,922
BEEN INTERESTING, I THINK

2523
01:29:28,922 --> 01:29:30,791
EVERYBODY IN THE FIELD IS HOW

2524
01:29:30,791 --> 01:29:33,460
EXACTLY DO PEOPLE GET THE

2525
01:29:33,460 --> 01:29:35,329
LONG-TERM SEQUEL I OF

2526
01:29:35,329 --> 01:29:36,230
SARS-COV-2, IS THERE ANYTHING

2527
01:29:36,230 --> 01:29:37,297
THAT OCCURRED EARLY IN THE

2528
01:29:37,297 --> 01:29:38,232
INFECTION THAT COULD BE DOING

2529
01:29:38,232 --> 01:29:41,468
THIS AND SO THIS--I DON'T KNOW

2530
01:29:41,468 --> 01:29:43,937
WHERE VIRUS IN 2 DAYS, IT GOES

2531
01:29:43,937 --> 01:29:46,607
AWAY, THERE'S NO PUREOLOGICAL

2532
01:29:46,607 --> 01:29:48,108
EVIDENCE, AND CONTRIBUTE ARING

2533
01:29:48,108 --> 01:29:49,776
COULD GET LONG-TERM EFFECTS AND

2534
01:29:49,776 --> 01:29:51,345
WE LOOK INNED BLOOD HERE AND

2535
01:29:51,345 --> 01:29:53,447
THERE'S VERY, VERY LITTLE VIRUS

2536
01:29:53,447 --> 01:29:55,449
IN THE BLOOD, SO IT'S NOT--I

2537
01:29:55,449 --> 01:29:57,217
CAN'T BELIEVE IT'S JUST BLOOD

2538
01:29:57,217 --> 01:29:59,953
CONTAMINATION SO THIS IS STILL

2539
01:29:59,953 --> 01:30:02,055
CURIOSITY IS THE VIRUS DOING

2540
01:30:02,055 --> 01:30:03,257
SOMETHING WITHIN THE ENDOTHELIAL

2541
01:30:03,257 --> 01:30:04,524
CELLS, I DON'T KNOW THE ANSWER

2542
01:30:04,524 --> 01:30:07,027
TO THAT, SO THE ADVANTAGES OF

2543
01:30:07,027 --> 01:30:08,528
MOUSE ADAPTED SET THE SEVERAL

2544
01:30:08,528 --> 01:30:10,197
VARIATIONS DONE, THIS IS DONE IN

2545
01:30:10,197 --> 01:30:11,732
SEVERAL LABS, PEOPLE EVEN

2546
01:30:11,732 --> 01:30:13,467
PASSAGED OTHER STRAINS LIKE THE

2547
01:30:13,467 --> 01:30:15,102
BETA STRAIN THAT'S BEEN

2548
01:30:15,102 --> 01:30:18,005
PASSAGED, AND 1 GETS A VIRULENT

2549
01:30:18,005 --> 01:30:19,773
VIRUS THAT'S A LITTLE DIFFERENT,

2550
01:30:19,773 --> 01:30:21,642
THIS IS ALL CAUSE OF A

2551
01:30:21,642 --> 01:30:24,645
RESPIRATORY INFECTION IN A DOSE

2552
01:30:24,645 --> 01:30:26,313
DEPENDENT FACTION, THESE VIRUSES

2553
01:30:26,313 --> 01:30:30,817
HAVE THE AT1 AND 2 CELLS AS

2554
01:30:30,817 --> 01:30:32,953
OPPOSE IN PATIENTS, THERE'S NO

2555
01:30:32,953 --> 01:30:43,463
MENTION OF BRAIN OR PULMONARY

2556
01:30:47,034 --> 01:30:49,403
INFECTION, AND OFFICIALLY THIS

2557
01:30:49,403 --> 01:30:50,637
THE QUESTION THAT 1 HAS TO PUT

2558
01:30:50,637 --> 01:30:52,306
IN THE BIG PICTURE OF HOW

2559
01:30:52,306 --> 01:30:53,473
IMPORTANT THIS IS, THIS VIRUS,

2560
01:30:53,473 --> 01:30:55,409
THE 1 WE DEVELOPED HAS 7

2561
01:30:55,409 --> 01:30:57,277
MUTATIONS, 5 ARE IN THE SURFACE

2562
01:30:57,277 --> 01:30:59,713
FOR DPLIEK O PROTEIN, ALL 5 ARE

2563
01:30:59,713 --> 01:31:02,649
DOWN IN THE OMICRON VARIANTS, 2

2564
01:31:02,649 --> 01:31:04,885
ARE IN NONSTRUCTURAL PROTEINS

2565
01:31:04,885 --> 01:31:09,356
WE'VE DONE A SET OF THIS FOR 4

2566
01:31:09,356 --> 01:31:11,858
AND 8 IS ALL YOU NEED FOR MOUSE

2567
01:31:11,858 --> 01:31:14,561
ADAPTATION, WE DON'T KNOW WHY.

2568
01:31:14,561 --> 01:31:15,996
BUT VERY LITTLE IS NEEDED AND

2569
01:31:15,996 --> 01:31:18,098
NOT FOR MOUSE ADAPTATION, IT'S

2570
01:31:18,098 --> 01:31:22,269
TO MACK A VIRULENT VIRUS BECAUSE

2571
01:31:22,269 --> 01:31:24,237
THE PROTEINS BY--THE N501 Y WILL

2572
01:31:24,237 --> 01:31:32,746
GIVE YOU A VIRUS THAT WILL

2573
01:31:32,746 --> 01:31:33,347
INFECT MICE.

2574
01:31:33,347 --> 01:31:34,881
OKAY, SO IN THE LAST FEW MINUTES

2575
01:31:34,881 --> 01:31:37,584
I HAVE, I WILL TALK ABOUT OTHER

2576
01:31:37,584 --> 01:31:38,618
ADVANTAGES AND DISADVANTAGES OF

2577
01:31:38,618 --> 01:31:39,553
THESE MODELS.

2578
01:31:39,553 --> 01:31:41,321
SO WE'VE BECOME INTERESTED IN P

2579
01:31:41,321 --> 01:31:44,791
A SC, THE POST ACUTE SEQUEL I OF

2580
01:31:44,791 --> 01:31:46,293
COVID-19, AT THIS POINT WE READ

2581
01:31:46,293 --> 01:31:47,894
INTO THE NEWSPAPERS AND HEAR

2582
01:31:47,894 --> 01:31:48,996
ABOUT THE INCREASED NUMBER OF

2583
01:31:48,996 --> 01:31:52,332
PATIENTS THAT WE HAVE NOW

2584
01:31:52,332 --> 01:31:53,700
SARSARS-KICKOFF 2, PEOPLE ARE

2585
01:31:53,700 --> 01:31:55,802
NOT BEING HOSPITALIZED, THERE'S

2586
01:31:55,802 --> 01:31:56,937
STILL MORE HOSPITALIZATION AND

2587
01:31:56,937 --> 01:31:58,672
MORE DEATH THAN WE WOULD LIKE

2588
01:31:58,672 --> 01:32:00,640
PARTLY BECAUSE PEOPLE ARE NOT

2589
01:32:00,640 --> 01:32:01,508
UPTAKING THE VACCINE THE WAY WE

2590
01:32:01,508 --> 01:32:02,676
WOULD LIKE AND A LOT OF PEOPLE

2591
01:32:02,676 --> 01:32:05,679
WHO ARE DYING ARE ACTUALLY

2592
01:32:05,679 --> 01:32:07,080
THEY'RE AGED OR IMMUNO

2593
01:32:07,080 --> 01:32:08,548
COMPROMISED SO THOSE ARE

2594
01:32:08,548 --> 01:32:10,283
POPULATIONS THAT I THINK AS

2595
01:32:10,283 --> 01:32:12,052
STACEY WAS TALKING ABOUT, I

2596
01:32:12,052 --> 01:32:12,886
THINK THEY'RE REALLY FOR AT

2597
01:32:12,886 --> 01:32:15,622
LEAST A LOT OF THESE DISEASES,

2598
01:32:15,622 --> 01:32:16,623
REALLY THE POPULATIONS HAVE THAT

2599
01:32:16,623 --> 01:32:18,325
WE WANT TO THINK ABOUT BECAUSE

2600
01:32:18,325 --> 01:32:23,730
THOSE ARE THE PEOPLE WHO ARE

2601
01:32:23,730 --> 01:32:25,265
INFECTED AND GET SEVERE DISEASE.

2602
01:32:25,265 --> 01:32:28,802
THE THING ABOUT P A SC, OR

2603
01:32:28,802 --> 01:32:31,304
AFFECTS MANY ORGANS, WHO HAVE P

2604
01:32:31,304 --> 01:32:33,273
A SC ARE OFTEN FATIGUES AND A

2605
01:32:33,273 --> 01:32:36,943
LOT OF THESE GO AWAY WITH TIME.

2606
01:32:36,943 --> 01:32:39,579
I'M NOT GOING TO SHOW A SLIDE

2607
01:32:39,579 --> 01:32:42,382
BUT ROUGHLY MY CALCULATION IS

2608
01:32:42,382 --> 01:32:44,317
ABOUT 1% OF PEOPLE AFTER 2020

2609
01:32:44,317 --> 01:32:47,154
HAVE P A SC AFTER 1 YEAR, OTHER

2610
01:32:47,154 --> 01:32:49,156
ESTIMATES ARE HIGHER.

2611
01:32:49,156 --> 01:32:51,024
IF 1 LOOKS AT LARGE STUDY ANDS

2612
01:32:51,024 --> 01:32:53,393
THERE WAS JUST A BIG STUDY

2613
01:32:53,393 --> 01:32:54,061
PUBLISHED THAT OVER 3 YEARS

2614
01:32:54,061 --> 01:32:56,696
PEOPLE THAT HAD PUNISHING ASC,

2615
01:32:56,696 --> 01:32:58,865
IT'S REALLY DIMINISHED IN ALL

2616
01:32:58,865 --> 01:33:00,600
CATEGORIES WHETHER IT'S CARDIAC

2617
01:33:00,600 --> 01:33:03,003
OR NEUROLOGICAL SO THIS IS

2618
01:33:03,003 --> 01:33:06,873
SOMETHING THAT MAY

2619
01:33:06,873 --> 01:33:07,607
NOT--CERTAINLY NOT BE PERMANENT

2620
01:33:07,607 --> 01:33:09,776
FOR MOST PEOPLE AND I THINK

2621
01:33:09,776 --> 01:33:12,212
PEOPLE ADAPT, TO, BUT SOME WHO

2622
01:33:12,212 --> 01:33:13,513
ARE STILL ASHINGED SO WE WANT TO

2623
01:33:13,513 --> 01:33:14,714
LEARN SOMETHING ABOUT WHY THIS

2624
01:33:14,714 --> 01:33:16,516
IS HAPPENING, IT SEEMS TO BE

2625
01:33:16,516 --> 01:33:18,618
DECREASED BY VACCINATION AND IT

2626
01:33:18,618 --> 01:33:21,021
SEEMS TO BE LESSER AN EXTENT

2627
01:33:21,021 --> 01:33:23,790
AFTER INFECTION WITH THE OMICRON

2628
01:33:23,790 --> 01:33:24,524
VARIANTS.

2629
01:33:24,524 --> 01:33:26,359
SO THIS IS--I'M NOT GOING TO

2630
01:33:26,359 --> 01:33:28,328
MENTION THIS, EXCEPT THAT WE'VE

2631
01:33:28,328 --> 01:33:29,529
BECOME VERY INTERESTED IN THE

2632
01:33:29,529 --> 01:33:33,366
LOSS OF THE SENSE OF SMELL WHICH

2633
01:33:33,366 --> 01:33:35,035
IS A BIG DEAL, STILL.

2634
01:33:35,035 --> 01:33:37,337
I RECEIVED A CALL A MONTH AGO

2635
01:33:37,337 --> 01:33:40,207
WHO HAD BEEN INFEC INDEED

2636
01:33:40,207 --> 01:33:41,141
NOVEMBER 2022, SOMEBODY IN CHILE

2637
01:33:41,141 --> 01:33:43,310
AND SHE SAYS THAT RIGHT NOW HER

2638
01:33:43,310 --> 01:33:45,512
SMELL RANGE IS EVERYTHING SHE

2639
01:33:45,512 --> 01:33:47,080
TASTES RANGES FROM NOTHING TO

2640
01:33:47,080 --> 01:33:47,414
TERRIBLE.

2641
01:33:47,414 --> 01:33:50,684
SO THERE'S NOTHING THAT SHE

2642
01:33:50,684 --> 01:33:51,184
ENJOYS ANYMORE.

2643
01:33:51,184 --> 01:33:52,586
SO FOR SOME PEOPLE THIS IS A

2644
01:33:52,586 --> 01:33:53,787
HUGE DEAL AND THEN THE OTHER

2645
01:33:53,787 --> 01:33:57,557
THING THAT HAPPENS IS, YOU GET P

2646
01:33:57,557 --> 01:33:59,926
A RASMIA, IS XA'S PROBABLY WHAT

2647
01:33:59,926 --> 01:34:01,528
THIS WOMAN HAD, SHE COULD SMELL

2648
01:34:01,528 --> 01:34:04,197
THINGS BUT NONE OF THE SMELLS

2649
01:34:04,197 --> 01:34:06,533
SHOULD NOT HAVE BEEN WHAT THEY

2650
01:34:06,533 --> 01:34:07,901
SHOULD HAVE BEEN.

2651
01:34:07,901 --> 01:34:09,202
STRAWBERRIES SMELLED LIKE SEWAGE

2652
01:34:09,202 --> 01:34:10,403
OR WHATEVER, SO WE'VE BEEN

2653
01:34:10,403 --> 01:34:13,607
INTERESTED IN THAT, TOO, AND YOU

2654
01:34:13,607 --> 01:34:16,843
CAN INVESTIGATE THIS IN MICE AND

2655
01:34:16,843 --> 01:34:18,245
HAMSTERS, SPRMAL ANIMALS OFTEN

2656
01:34:18,245 --> 01:34:22,983
GET THE SAME SYMPTOMS, SO WE USE

2657
01:34:22,983 --> 01:34:25,152
THIS VIRUS OR M830 VIRUS BECAUSE

2658
01:34:25,152 --> 01:34:27,320
IT INFEBS THE CELLS AND 1 OF THE

2659
01:34:27,320 --> 01:34:28,955
THINGS ABOUT WHETHER IT BE

2660
01:34:28,955 --> 01:34:30,490
HUMANS OR MICE OR HAMSTERS, IS

2661
01:34:30,490 --> 01:34:32,959
THE ONLY THING THAT ARE INFECTED

2662
01:34:32,959 --> 01:34:39,666
ARE THESE CELLS, WHICH ARE THE

2663
01:34:39,666 --> 01:34:41,434
SUPPORTING CELLS OF THE NAISAL

2664
01:34:41,434 --> 01:34:42,969
EPITHELIUM, SO THE NEURONS ARE

2665
01:34:42,969 --> 01:34:44,271
CARRIED AT THE BACK OF THE BRAIN

2666
01:34:44,271 --> 01:34:46,806
BUT THESE CELLS ARE NOT INFECTED

2667
01:34:46,806 --> 01:34:49,276
BUT THEY'RE AFFECTED AND NEURONS

2668
01:34:49,276 --> 01:34:51,478
CAN'T BE INFECTED SO HOW THIS IS

2669
01:34:51,478 --> 01:34:58,585
EXACTLY WORKING IS I THINK A

2670
01:34:58,585 --> 01:35:00,954
REALLY IMPORTANT RESEARCH

2671
01:35:00,954 --> 01:35:04,124
QUESTION .

2672
01:35:04,124 --> 01:35:05,859
I DON'T HAVE A SOLID ANSWER

2673
01:35:05,859 --> 01:35:07,160
ABOUT WHAT'S GOING ON HERE BUT 1

2674
01:35:07,160 --> 01:35:10,664
CAN SEE HERE THIS IS THE WAY

2675
01:35:10,664 --> 01:35:11,731
OLFACTORY NEURONS WORK, EACH 1

2676
01:35:11,731 --> 01:35:13,833
HAS A SINGLE RECEPTOR, EACH 1

2677
01:35:13,833 --> 01:35:15,302
HAS A CILIA THAT HAS THE

2678
01:35:15,302 --> 01:35:16,937
RECEPTOR ON IT, THE CILIA ARE

2679
01:35:16,937 --> 01:35:18,004
NOT KILLED HERE, BUT YOU CAN SEE

2680
01:35:18,004 --> 01:35:20,707
IF THIS IS A NORMAL CILIA,

2681
01:35:20,707 --> 01:35:22,776
THEY'VE FALLEN OVER SO THEY'RE

2682
01:35:22,776 --> 01:35:24,811
NOT HAPPY CILIA.

2683
01:35:24,811 --> 01:35:27,414
AND WE THINK THAT TRIBUTES TO

2684
01:35:27,414 --> 01:35:29,716
ANOSMIA, BUT WE ALSO KNOW IT

2685
01:35:29,716 --> 01:35:31,551
RECOVERS VERY QUICKLY SO THESE

2686
01:35:31,551 --> 01:35:35,622
MICE HAD NORMAL CILIA BUT THEN

2687
01:35:35,622 --> 01:35:36,790
HAD ANASMIA, AND OTHERS THAT I

2688
01:35:36,790 --> 01:35:38,625
WILL FALL IN FOR THE LAST FEW

2689
01:35:38,625 --> 01:35:39,292
MINUTES.

2690
01:35:39,292 --> 01:35:40,794
SO THIS ANOTHER RESULT WHICH IS

2691
01:35:40,794 --> 01:35:42,062
KIND OF PUZZLING TO US BECAUSE

2692
01:35:42,062 --> 01:35:46,566
WHAT WE MEASURE SIDE OLFACTORY

2693
01:35:46,566 --> 01:35:47,867
RECEPTOR EXPRESSION.

2694
01:35:47,867 --> 01:35:49,536
WHAT WE FOUND IS--THIS WAS

2695
01:35:49,536 --> 01:35:52,772
REPORTED BY OTHERS AS WELL, IS

2696
01:35:52,772 --> 01:35:54,040
THAT WITH--SOON AFTER INFECTION,

2697
01:35:54,040 --> 01:35:55,742
THIS IS 2 DAY AFTER INFECTION,

2698
01:35:55,742 --> 01:35:58,678
THIS IS DECREASED IN OLFACTORY

2699
01:35:58,678 --> 01:36:01,581
RECEPTOR, EXPRESSION AT THE IN,

2700
01:36:01,581 --> 01:36:11,758
RNA LEVEL.

2701
01:36:13,860 --> 01:36:14,194
--MRNA LEVEL.

2702
01:36:14,194 --> 01:36:16,963
SO THIS IS UNEXPECTED SO WHY

2703
01:36:16,963 --> 01:36:18,932
WOULD MRNA BE AFFECTED OR

2704
01:36:18,932 --> 01:36:20,500
DECREASED BY SOMETHING GOING ON

2705
01:36:20,500 --> 01:36:22,335
IN THE NEIGHBORING SUPPORTING

2706
01:36:22,335 --> 01:36:23,103
CELLS AND REMEMBER, I DIDN'T

2707
01:36:23,103 --> 01:36:26,406
SHOW A FIGURE OF THIS BUT NOT

2708
01:36:26,406 --> 01:36:29,175
ALL THE CELLS ARE INFECTED, ONLY

2709
01:36:29,175 --> 01:36:31,444
A MINORITY ARE SO THERE'S

2710
01:36:31,444 --> 01:36:33,346
PROBABLY SOME INFLAMMATORY

2711
01:36:33,346 --> 01:36:35,849
RELATED MOLECULE THAT'S DOING

2712
01:36:35,849 --> 01:36:37,984
SOME OF THIS EMPLOY THE OTHER

2713
01:36:37,984 --> 01:36:38,718
THING THAT'S CURIOUS IS I THINK

2714
01:36:38,718 --> 01:36:49,162
THIS IS PROBABLY THE MOST

2715
01:36:54,034 --> 01:36:54,968
CURIOUS.

2716
01:36:54,968 --> 01:36:56,436
IS THAT AFTER OLFACTORY

2717
01:36:56,436 --> 01:36:57,504
RECOVERY, YOU CAN SEE THIS

2718
01:36:57,504 --> 01:36:58,538
HIGHER LEVELS IN HERE.

2719
01:36:58,538 --> 01:37:00,307
WHY DOES THIS MATTER IN 1 CAN

2720
01:37:00,307 --> 01:37:01,975
IMAGINE IF 1'S IMETTING A SIGNAL

2721
01:37:01,975 --> 01:37:04,311
FROM A NEURON AND THAT NEURON IS

2722
01:37:04,311 --> 01:37:06,413
NOW RESPONDING DIFFERENTLY OR

2723
01:37:06,413 --> 01:37:07,447
THE NEURONS BEHAVING DIFFERENTLY

2724
01:37:07,447 --> 01:37:13,253
IN TERMS OF HOW THEY'RE DOING

2725
01:37:13,253 --> 01:37:17,257
WITH ODORANTS BECAUSE EVERY

2726
01:37:17,257 --> 01:37:19,726
SMELL ACTUALLY A COMBINATION OF

2727
01:37:19,726 --> 01:37:21,528
THE DIFFERENT ODORANTS BINDING

2728
01:37:21,528 --> 01:37:22,228
TO DIFFERENT RECEPTORS.

2729
01:37:22,228 --> 01:37:24,230
SO 1 CAN SEE THAT IF SOME ARE

2730
01:37:24,230 --> 01:37:26,599
COMING BACK AT HIGHER LEVELS OR

2731
01:37:26,599 --> 01:37:28,668
LOWER LEVELS WHAT 1 WOULD HAVE

2732
01:37:28,668 --> 01:37:30,437
NORMALLY IMIVEN A CERTAIN SMELL

2733
01:37:30,437 --> 01:37:34,007
MIGHT GIVE A DIFFERENT SMELL

2734
01:37:34,007 --> 01:37:34,240
NOW.

2735
01:37:34,240 --> 01:37:37,610
O WE THINK THAT THAT CONTRIBUTES

2736
01:37:37,610 --> 01:37:38,244
ALSO TO ANASMIA.

2737
01:37:38,244 --> 01:37:40,447
SO WHAT HAPPENS AFTER THE

2738
01:37:40,447 --> 01:37:43,183
OLFACTORY NEURONS ARE DAMAGED?

2739
01:37:43,183 --> 01:37:45,618
SO OLFACTORY NEURONS CONNECK TO

2740
01:37:45,618 --> 01:37:47,287
THE OLFACTORY BULB AND THERE'S A

2741
01:37:47,287 --> 01:37:50,824
MOLECULE IN THE OLFACTORY BULB

2742
01:37:50,824 --> 01:37:56,129
VERY IMPORTANTLY WITH TYROVENE

2743
01:37:56,129 --> 01:37:57,931
HYDROX CLAYS FOR THE MIEWRONS

2744
01:37:57,931 --> 01:38:00,100
AND WHAT WE SEE IN THESE ANIMALS

2745
01:38:00,100 --> 01:38:03,336
IS THAT THE AMOUNT OF TYROSEEN

2746
01:38:03,336 --> 01:38:05,205
HYDROX LACE DECREASED AND THAT'S

2747
01:38:05,205 --> 01:38:08,007
SHOWN HERE SO THIS IS THE NUMBER

2748
01:38:08,007 --> 01:38:09,609
OF TH-POSITIVE CELLS SO THIS IS

2749
01:38:09,609 --> 01:38:11,211
NOT AT THE MRNA LEVEL, THIS IS

2750
01:38:11,211 --> 01:38:14,714
AT THE PROTEIN LEVEL.

2751
01:38:14,714 --> 01:38:16,950
AND WE SEE THE SAME THING AT 120

2752
01:38:16,950 --> 01:38:18,051
DAYS AFTER INFECTION, SO THIS IS

2753
01:38:18,051 --> 01:38:20,487
USEFUL FOR OUR STUDIES OF TRYING

2754
01:38:20,487 --> 01:38:24,357
TO UNDERSTAND LONG-TERM EFFECTS

2755
01:38:24,357 --> 01:38:28,027
OF ANASMIA, SO WE SEE DECREASED

2756
01:38:28,027 --> 01:38:30,663
TYROSEEN RIDROKS LACE AT THE

2757
01:38:30,663 --> 01:38:33,700
RTHIS,A AND PROTEIN LEVELS, AND

2758
01:38:33,700 --> 01:38:35,635
WE SEE INCREASED AMOUNTS OF

2759
01:38:35,635 --> 01:38:37,070
INTERFERON BETA AND SEVERAL

2760
01:38:37,070 --> 01:38:37,804
OTHER INFLAMMATION BASED

2761
01:38:37,804 --> 01:38:43,309
MOLECULES BUT NOT ALL.

2762
01:38:43,309 --> 01:38:45,044
CCL5 DECREASED CXCL10 IS

2763
01:38:45,044 --> 01:38:47,080
DECREASED, WHY DON'T KNOW WHAT

2764
01:38:47,080 --> 01:38:48,615
THIS MEANS, SOME GO UP AND SOME

2765
01:38:48,615 --> 01:38:52,085
GO DOWN BUT THE FACT THAT

2766
01:38:52,085 --> 01:38:53,887
THERE'S INFLAMMATORY MOLECULE

2767
01:38:53,887 --> 01:38:54,687
CHANGES, WE IT CONTRIBUTES TO

2768
01:38:54,687 --> 01:38:56,122
THE WHAT WE SEE IN OLYMPIC FAC.

2769
01:38:56,122 --> 01:39:00,427
SO THE NEXT THING WE WANTED TO

2770
01:39:00,427 --> 01:39:01,995
DEAL WITH, IS WHAT ABOUT OTHER

2771
01:39:01,995 --> 01:39:08,101
EFFECTS AND OTHER PARTS OF THE

2772
01:39:08,101 --> 01:39:12,439
BRAIN, SO AS TYROSEEN, OUR

2773
01:39:12,439 --> 01:39:15,608
NEURONS OF EXPRESSING TYROSINE

2774
01:39:15,608 --> 01:39:16,810
RIDROKS LACE, SO WE LOOKED IN

2775
01:39:16,810 --> 01:39:20,280
THE PART OF THE BRAIN CALLED THE

2776
01:39:20,280 --> 01:39:21,781
SUBSTANTIA NIAGARA, FOR THOSE

2777
01:39:21,781 --> 01:39:23,183
WHO THINK ABOUT NEUROLOGICAL

2778
01:39:23,183 --> 01:39:24,951
ISSUES KNOW THIS IS THE AREA

2779
01:39:24,951 --> 01:39:26,119
THAT'S INVOFFED IN PARKINSON'S

2780
01:39:26,119 --> 01:39:28,922
DEC AND THIS IS THE AREA THAT

2781
01:39:28,922 --> 01:39:34,093
WAS STRONGLY INFECT INDEED 1918

2782
01:39:34,093 --> 01:39:34,527
INFLUENZA EPIDEMIC.

2783
01:39:34,527 --> 01:39:36,296
AND THIS DATA IS SHOWING THAT

2784
01:39:36,296 --> 01:39:38,998
THE 1918 FLU EPIDEMIC ACTUALLY

2785
01:39:38,998 --> 01:39:40,533
OR PANDEMIC RESULTED IN

2786
01:39:40,533 --> 01:39:42,168
INCREASED CASES OF PARKINSON'S

2787
01:39:42,168 --> 01:39:42,435
DISEASE.

2788
01:39:42,435 --> 01:39:47,106
SO WHAT WE DID HERE IS WE LOOKED

2789
01:39:47,106 --> 01:39:48,875
ON THE SUBITANTIA NIAGARA AND WE

2790
01:39:48,875 --> 01:39:53,213
FOUND THAT HERE AS WELL AS IN

2791
01:39:53,213 --> 01:39:59,185
THE OLFACTORY BULB, IS DECREASED

2792
01:39:59,185 --> 01:40:01,321
NUMBERS OF TYROSINE HYDROX LACE

2793
01:40:01,321 --> 01:40:03,957
EXPRESSING CELLS.

2794
01:40:03,957 --> 01:40:07,494
BUT MORE IMPORTANTLY THESE CELLS

2795
01:40:07,494 --> 01:40:10,630
WERE ALL DECREASED IN THE

2796
01:40:10,630 --> 01:40:11,764
SUBSTANTIA NIGRA, AND THEY

2797
01:40:11,764 --> 01:40:15,335
APPEAR TO BE THE MOST COMMONLY

2798
01:40:15,335 --> 01:40:16,803
WE SEE ACROSS THE BOARD AND IN

2799
01:40:16,803 --> 01:40:22,542
THESE PARTS OF THE BRAIN WAS

2800
01:40:22,542 --> 01:40:22,809
INCREASED.

2801
01:40:22,809 --> 01:40:23,943
AND TO SEE IF THIS IS RELEVANT

2802
01:40:23,943 --> 01:40:26,412
FOR YOU HAD HANS, WE OBTAINED

2803
01:40:26,412 --> 01:40:27,580
AUTOPSIES SAMPLES AND WE SEE

2804
01:40:27,580 --> 01:40:30,850
AGAIN IN THE SUBSTANTIA NIGRA,

2805
01:40:30,850 --> 01:40:33,219
THERE'S INCREASED NUMBERS OF

2806
01:40:33,219 --> 01:40:33,853
POSITIVE CELLS.

2807
01:40:33,853 --> 01:40:38,224
AND SO WE DID TESTING HERE.

2808
01:40:38,224 --> 01:40:48,167
THIS A TEST--IT'S SUBSTANTIA

2809
01:40:48,167 --> 01:40:49,602
NIGRA, BUT WE PUT THESE ON RODS

2810
01:40:49,602 --> 01:40:51,504
AND MADE IT FASTER AND DEPENDING

2811
01:40:51,504 --> 01:40:53,239
ON HOW COMPETENT THE MICE ARE IN

2812
01:40:53,239 --> 01:40:57,710
DEALING WITH THE MUSCLE FUNCTION

2813
01:40:57,710 --> 01:40:59,979
THEN 1 SEES THE MICE FALLING OFF

2814
01:40:59,979 --> 01:41:01,548
THE ROD, SO 1 HERE DECREASED THE

2815
01:41:01,548 --> 01:41:04,350
ABILITY TO STAY ON THESE ROD IN

2816
01:41:04,350 --> 01:41:06,653
THESE MICE 100 DAYS AFTER

2817
01:41:06,653 --> 01:41:07,053
INFECTION.

2818
01:41:07,053 --> 01:41:09,656
THIS IS NOT INFECTED ANIMALS AND

2819
01:41:09,656 --> 01:41:10,623
THESE ARE INFECTED ANIMALS.

2820
01:41:10,623 --> 01:41:12,191
SO THE WHYED IS THAT WE'RE

2821
01:41:12,191 --> 01:41:13,960
SEEING DYSFUNCTION IN THE

2822
01:41:13,960 --> 01:41:17,497
OLFACTORY BULB BUT THE

2823
01:41:17,497 --> 01:41:18,998
SUBSTANTIA NIGRA IS HAVING

2824
01:41:18,998 --> 01:41:19,499
CLINICAL EFFECTS.

2825
01:41:19,499 --> 01:41:20,867
AND THEN IS ANOTHER OPEN FIELD

2826
01:41:20,867 --> 01:41:22,735
TEST AND WITHOUT LOOKING AT THE

2827
01:41:22,735 --> 01:41:25,371
GRAPHS 1 COULD SEE IF THE

2828
01:41:25,371 --> 01:41:27,373
FIGURES THAT INFECKED MICE RUN

2829
01:41:27,373 --> 01:41:30,476
DIFFERENT THAN THE MICE THAT

2830
01:41:30,476 --> 01:41:31,778
WERE MOCK INFECKED AND WE COULD

2831
01:41:31,778 --> 01:41:33,313
QUANTIFY THIS AS WELL, SHOWING

2832
01:41:33,313 --> 01:41:36,382
THESE CHANGES IN THE OPEN FIELD

2833
01:41:36,382 --> 01:41:37,050
TEST.

2834
01:41:37,050 --> 01:41:42,155
SO THE CONCLUSIONS HERE IS THAT

2835
01:41:42,155 --> 01:41:44,123
THESE MICE, DEAL WITH MANY SIGNS

2836
01:41:44,123 --> 01:41:46,359
OF ACUTE COVID-19 IN P A SC.

2837
01:41:46,359 --> 01:41:48,094
BUT IT'S IMPORTANT TO EMPHASIZE,

2838
01:41:48,094 --> 01:41:50,363
MICE DO NOT DEVELOP ALL THE

2839
01:41:50,363 --> 01:41:54,267
FINDINGS PRESENT IN PATIENTS AND

2840
01:41:54,267 --> 01:41:56,202
AT LEAST NOT TO THE SAME EXTENT.

2841
01:41:56,202 --> 01:42:00,139
EVEN THOUGH I SHOWED 1 SLIDE OR

2842
01:42:00,139 --> 01:42:02,475
I MENTIONED THAT

2843
01:42:02,475 --> 01:42:03,109
THROMBO-INVOLVED PHENOMENA COULD

2844
01:42:03,109 --> 01:42:04,510
BE SEEN IN SOME CASES, IT'S NOT

2845
01:42:04,510 --> 01:42:05,678
SEEN ENOUGH SO THAT CAN CAN

2846
01:42:05,678 --> 01:42:07,146
STUDY THEM HERE AND CERTAINLY A

2847
01:42:07,146 --> 01:42:09,682
LOT THINGS THAT THAT PEOPLE

2848
01:42:09,682 --> 01:42:11,084
COMPLAIN ABOUT, BRAIN FOG,

2849
01:42:11,084 --> 01:42:15,054
NONNEUROLOGICAL P A SC, BRAIN

2850
01:42:15,054 --> 01:42:17,223
FOG MICE, WE DON'T KNOW IF THEY

2851
01:42:17,223 --> 01:42:21,928
HAVE THAT NOT OR NOT AND FOR

2852
01:42:21,928 --> 01:42:22,695
NONNEUROLOGICAL WE HAVEN'T

2853
01:42:22,695 --> 01:42:24,597
INVESTIGATED THE HEART OR OTHER

2854
01:42:24,597 --> 01:42:27,600
NEUROLOGICAL TESTS AND FUNCTIONS

2855
01:42:27,600 --> 01:42:28,334
BUT SO DON'T KNOW.

2856
01:42:28,334 --> 01:42:29,602
BUT IN GENERAL, I THINK MICE

2857
01:42:29,602 --> 01:42:31,504
GIVEN ALL THE CAVEATS OF MICE,

2858
01:42:31,504 --> 01:42:32,705
THEY'RE PRETTY USEFUL FOR

2859
01:42:32,705 --> 01:42:34,807
STUDYING SOME OF THESE SEQUEL I,

2860
01:42:34,807 --> 01:42:36,542
WE HAVE TO BE CAREFUL ABOUT WHAT

2861
01:42:36,542 --> 01:42:39,879
WE EXPECT FROM THEM AND WHAT WE

2862
01:42:39,879 --> 01:42:40,680
COULD HOPEFULLY GET.

2863
01:42:40,680 --> 01:42:42,882
THE OTHER THING I SHOULD SAY,

2864
01:42:42,882 --> 01:42:44,083
WE'VE DONE EXPERIMENTS TREATING

2865
01:42:44,083 --> 01:42:45,818
THESE MICE EARLY ON WITH

2866
01:42:45,818 --> 01:42:46,986
ANTIVIRALS AND IT HAS NO EFFECT

2867
01:42:46,986 --> 01:42:48,955
ON THE DEVELOPMENT OF P A SC,

2868
01:42:48,955 --> 01:42:49,956
AND THE THING THAT'S INTERESTING

2869
01:42:49,956 --> 01:42:51,658
ABOUT THIS IS THAT WHEN WE WERE

2870
01:42:51,658 --> 01:42:54,627
DOING IT, THE SAME TRIALS WERE

2871
01:42:54,627 --> 01:42:56,229
BEING PUBLISHED BY HUMANS WHO

2872
01:42:56,229 --> 01:43:00,500
ALSO DIDN'T HAVE P A SC HELP

2873
01:43:00,500 --> 01:43:01,634
THEM WITH--DIDN'T HAVE

2874
01:43:01,634 --> 01:43:03,036
ANTIVIRALS HELP THEM ONCE THEY

2875
01:43:03,036 --> 01:43:04,437
DEVELOP P A SC WHICH IS NOT THE

2876
01:43:04,437 --> 01:43:07,206
SAME THING BUT IT MAY BE THAT

2877
01:43:07,206 --> 01:43:08,608
ANTIVIRALS HAVE REALLY NO ROLE

2878
01:43:08,608 --> 01:43:10,910
IN THIS, WHATEVER'S OCCURRING

2879
01:43:10,910 --> 01:43:12,812
AND IS VERY DIFFICULT TO

2880
01:43:12,812 --> 01:43:13,046
PREVENT.

2881
01:43:13,046 --> 01:43:19,919
SO WITH THAT I WILL TAKE ANY

2882
01:43:19,919 --> 01:43:23,656
QUESTIONS. 

2883
01:43:23,656 --> 01:43:23,923
QUESTIONS.

2884
01:43:23,923 --> 01:43:25,725
>> THANK YOU.

2885
01:43:25,725 --> 01:43:26,859
QUESTIONS NOW.

2886
01:43:26,859 --> 01:43:27,093
STACEY?

2887
01:43:27,093 --> 01:43:28,995
>> BEAUTIFUL PRESENTATION,
SO

2888
01:43:28,995 --> 01:43:30,496
I'M SURE AS YOU KNOW IPT GREATER

2889
01:43:30,496 --> 01:43:33,800
FOMNIA IS 1 OF THE FIRST

2890
01:43:33,800 --> 01:43:34,767
INDICATORS OF NEURODEGENERATIVE

2891
01:43:34,767 --> 01:43:37,103
DISEASES SO I WONDER IF YOU

2892
01:43:37,103 --> 01:43:40,006
LOOKED AT MICROGLIA ACTIVATION

2893
01:43:40,006 --> 01:43:42,275
THAT'S QUESTION NUMBER 1.

2894
01:43:42,275 --> 01:43:44,811
QUESTION # 2 IS FOR ALZHEIMERS

2895
01:43:44,811 --> 01:43:46,212
THE PEANUT BUTTER SMELL TEST IS

2896
01:43:46,212 --> 01:43:48,347
A REAL THING ASK IT SHOWS YOU

2897
01:43:48,347 --> 01:43:53,686
EARLY INDICATIONS OF HOW IS

2898
01:43:53,686 --> 01:43:55,421
HAVING INSOMNIA FROM COVID GOING

2899
01:43:55,421 --> 01:43:56,823
TO IMPACT PEOPLE USING THOSE

2900
01:43:56,823 --> 01:43:59,459
TYPES OF TESTS FOR

2901
01:43:59,459 --> 01:44:00,760
NEURODEGENERATIVE DISEASES.

2902
01:44:00,760 --> 01:44:01,394
>> YEAH, IT'S AN IMPORTANT

2903
01:44:01,394 --> 01:44:04,964
QUESTION BECAUSE I THINK THAT IF

2904
01:44:04,964 --> 01:44:06,666
PEOPLE--I THINK ACUTELY, OF

2905
01:44:06,666 --> 01:44:09,769
COURSE YOU COULDN'T USE A PEANUT

2906
01:44:09,769 --> 01:44:10,403
BUTTER TEST.

2907
01:44:10,403 --> 01:44:12,438
YOU WOULD THINK A YEAR OR SOME

2908
01:44:12,438 --> 01:44:15,975
MONTHS LATER IT MIGHT BE USEFUL

2909
01:44:15,975 --> 01:44:18,978
AND PEOPLE HAVE PERSISTENT

2910
01:44:18,978 --> 01:44:20,046
NASMIA, BUT WHETHER PEOPLE USE

2911
01:44:20,046 --> 01:44:21,914
IT, THIS IS THE BIG CONCERN THAT

2912
01:44:21,914 --> 01:44:24,851
PEOPLE WILL DWEF SOME SORT OF

2913
01:44:24,851 --> 01:44:25,985
NEURODEGENERATIVE DISEASE AND

2914
01:44:25,985 --> 01:44:28,354
YES MICROGLIA ARE ACTIVATED.

2915
01:44:28,354 --> 01:44:30,323
WE HAVE ACTUALLY ANALYSIS OF

2916
01:44:30,323 --> 01:44:30,523
THOSE.

2917
01:44:30,523 --> 01:44:32,225
I DIDN'T HAVE TIME TO SHOW IT

2918
01:44:32,225 --> 01:44:41,000
BUT WE SEE THAT THEY'RE

2919
01:44:41,000 --> 01:44:41,300
ACTIVATED.

2920
01:44:41,300 --> 01:44:44,137
STANLEY I HAVE A QUESTION SO IN

2921
01:44:44,137 --> 01:44:46,639
TERMS OF EXTRA PULMONARY ORGAN

2922
01:44:46,639 --> 01:44:48,341
INFECTION, WHEN YOU PASSAGE

2923
01:44:48,341 --> 01:44:50,510
SARS-COV-2 IN MICE TO GET THAT

2924
01:44:50,510 --> 01:44:53,146
SEVERE DISEASE OR THE MOUSE 30

2925
01:44:53,146 --> 01:44:55,882
STRAIN, IS THERE A CORRELATION

2926
01:44:55,882 --> 01:44:57,550
BETWEEN DISEASE SEVERITY VIRUS

2927
01:44:57,550 --> 01:44:59,218
RUPLICATION IN THE LUNGS WITH

2928
01:44:59,218 --> 01:45:00,052
HOW MUCH REPLICATION YOU ARE

2929
01:45:00,052 --> 01:45:01,354
SEEING IN THE OTHER ORGANS

2930
01:45:01,354 --> 01:45:04,323
OUTSIDE OF THE LUNGS?

2931
01:45:04,323 --> 01:45:06,225
>> I DON'T THINK WE'VE
DONE THAT

2932
01:45:06,225 --> 01:45:07,360
CAREFULLY BECAUSE WE HAVE DOSE

2933
01:45:07,360 --> 01:45:10,363
CURVES ON THE LUNGS.

2934
01:45:10,363 --> 01:45:12,665
I DON'T THINK WE WANT ALL THE

2935
01:45:12,665 --> 01:45:13,900
ORGANS AT DIFFERENT DOSES, MY

2936
01:45:13,900 --> 01:45:15,601
GUESS IS THERE WOULD BE BESES

2937
01:45:15,601 --> 01:45:18,104
BUT I DON'T KNOW THAT BECAUSE

2938
01:45:18,104 --> 01:45:19,772
IT'S ALL PROPORGAL TO THE LUNG

2939
01:45:19,772 --> 01:45:20,039
INFECTION.

2940
01:45:20,039 --> 01:45:22,308
>> I WAS TRYING TO FIGURE
OUT

2941
01:45:22,308 --> 01:45:22,909
HOW MUCH HEMORRHAGES WAS

2942
01:45:22,909 --> 01:45:25,378
OCCURRING IN THE LUNGS IN THOSE

2943
01:45:25,378 --> 01:45:26,646
SEVERELY INFECTED MICE AND HOW

2944
01:45:26,646 --> 01:45:28,414
MUCH OF THAT OVER FROM THE LUNGS

2945
01:45:28,414 --> 01:45:31,450
BUT JUST ENOUGH TO GET THOSE

2946
01:45:31,450 --> 01:45:33,019
PERIPHERAL ORGANS SEATED MAY NOT

2947
01:45:33,019 --> 01:45:35,922
BE ENOUGH TO BE DETECTED BY PC R

2948
01:45:35,922 --> 01:45:36,355
OR PLAQUE ASSAY.

2949
01:45:36,355 --> 01:45:38,257
>> I DON'T THINK THERE'S
ANY

2950
01:45:38,257 --> 01:45:39,392
VIRUS--I DON'T KNOW WHAT'S GOING

2951
01:45:39,392 --> 01:45:41,327
ON IN 2 DAYS, BECAUSE WHAT WE'VE

2952
01:45:41,327 --> 01:45:43,062
DONE IS WITH THAT VIRUS THAT I

2953
01:45:43,062 --> 01:45:45,965
SHOWED WHERE WE COULD LABEL

2954
01:45:45,965 --> 01:45:48,634
SURVIVING CELLS BECAUSE WE USE

2955
01:45:48,634 --> 01:45:51,270
THE VIRUSES EXPRESSING CREE, WE

2956
01:45:51,270 --> 01:45:52,839
SEE NO SURVERIFYING CELL OR I

2957
01:45:52,839 --> 01:45:54,140
SHOULD SAY WE DON'T SEE NONE.

2958
01:45:54,140 --> 01:45:56,209
IF WE LOOK AT 5 SLIDES EACH YOU

2959
01:45:56,209 --> 01:45:59,212
FIND 1 CELL OR 1.5 CELLS.

2960
01:45:59,212 --> 01:46:03,482
SO VERY, VERY LEGISLATES LITTLE

2961
01:46:03,482 --> 01:46:04,183
EXTRA PULMONARY INFECTION.

2962
01:46:04,183 --> 01:46:05,518
>> I WANT TO SMOTE NAWE
WILL

2963
01:46:05,518 --> 01:46:07,086
HAVE ADDITIONAL TIME DURING

2964
01:46:07,086 --> 01:46:09,689
DISCUSSIONINGS DURING THE PANEL

2965
01:46:09,689 --> 01:46:12,258
DISCUSSION. 

2966
01:46:12,258 --> 01:46:15,661
>> THANK YOU SO MUCH.

2967
01:46:15,661 --> 01:46:19,565
OUR NEXT SPEAKER WILL BE LISA

2968
01:46:19,565 --> 01:46:20,766
GRALINSKI, FROM UNIVERSITY OF

2969
01:46:20,766 --> 01:46:23,069
NORTH CAROLINA CHAPEL HILL, SHE

2970
01:46:23,069 --> 01:46:27,874
WILL TALK ABOUT MOUSE MODELS OF

2971
01:46:27,874 --> 01:46:29,008
HIGHLY PATHOGENIC HUMAN CORONA

2972
01:46:29,008 --> 01:46:30,109
VIRUS INFECTION.

2973
01:46:30,109 --> 01:46:30,943
NALL RIGHT, THANK YOU EVERYONE,

2974
01:46:30,943 --> 01:46:33,246
THIS WILL BE A NICE FOLLOW UP TO

2975
01:46:33,246 --> 01:46:34,547
STANLEY'S TALK.

2976
01:46:34,547 --> 01:46:37,250
SOME OF THE SAME THEMES BUT A

2977
01:46:37,250 --> 01:46:38,417
TOALTALLY GOOD NIGHT VIRUS

2978
01:46:38,417 --> 01:46:41,587
BECAUSE ALL THE CORONA I

2979
01:46:41,587 --> 01:46:43,256
HAVOLOGYIST WANTED TO MAKE TOOLS

2980
01:46:43,256 --> 01:46:45,091
TO DIVE INTO WHAT WAS HAPPENING

2981
01:46:45,091 --> 01:46:46,492
IN ANIMAL MODELS AS QUICKLY AS

2982
01:46:46,492 --> 01:46:48,227
POSSIBLE IN 2020 SO THIS TALK IS

2983
01:46:48,227 --> 01:46:50,529
REPRESENTING WORK FROM MY LAB

2984
01:46:50,529 --> 01:46:54,000
AND OUR BROADER GROUP AT UNC, SO

2985
01:46:54,000 --> 01:46:56,235
WE'VE NAMED OURSELVES THE

2986
01:46:56,235 --> 01:47:00,840
CAROLINA WERE GROUP, OR CDRF P

2987
01:47:00,840 --> 01:47:03,643
AND WE'RE ALL IN THE SAME BL3,

2988
01:47:03,643 --> 01:47:05,745
CONITANTLY HELPING EACH OTHER

2989
01:47:05,745 --> 01:47:06,879
ANYWAYS AS 1 DOES WHEN THERE ARE

2990
01:47:06,879 --> 01:47:11,918
A LOT OF MICE HAPPENING.

2991
01:47:11,918 --> 01:47:13,119
NALL RIGHT, SO I'M GOING TO

2992
01:47:13,119 --> 01:47:16,255
SPEND MOST OF THIS TALK SPEAKING

2993
01:47:16,255 --> 01:47:17,523
ABOUT SARS-COV-2 MOUSE MODELS

2994
01:47:17,523 --> 01:47:20,293
SINCE THAT'S OUR CURRENT ACTIVE

2995
01:47:20,293 --> 01:47:23,129
STILL CIRCULATING THE GLOBE

2996
01:47:23,129 --> 01:47:24,597
VIRUS SPEAKING ABOUT BOTH THE

2997
01:47:24,597 --> 01:47:26,165
ACUTE DEC OF THE PHASE AND

2998
01:47:26,165 --> 01:47:27,366
GETTING INTO THE CHRONIC DEC

2999
01:47:27,366 --> 01:47:29,635
BECAUSE FOLLOWING UP ON THESE

3000
01:47:29,635 --> 01:47:30,636
LONG-TERM SEQUEL I ARE A AN AREA

3001
01:47:30,636 --> 01:47:32,605
OF INTEREST ARE IF A LOT OF US

3002
01:47:32,605 --> 01:47:34,840
AND AN AREA THAT'S GROWING A LOT

3003
01:47:34,840 --> 01:47:36,042
AND A TOUCH ON SYSTEMIC CENTER

3004
01:47:36,042 --> 01:47:38,844
FOR EXCELLENCE ON AGINGS OF THE

3005
01:47:38,844 --> 01:47:39,011
DEC.

3006
01:47:39,011 --> 01:47:40,379
BUT THEN ALSO TALK ABOUT

3007
01:47:40,379 --> 01:47:41,681
VARIANTS OF CONCERN AND HOW

3008
01:47:41,681 --> 01:47:43,215
WE'RE UPDATING THESE MODELS AND

3009
01:47:43,215 --> 01:47:45,284
AT THE END REALLY BRIEFLY GET

3010
01:47:45,284 --> 01:47:48,120
INTO MERS AND I WILL NOT TALK

3011
01:47:48,120 --> 01:47:49,055
ABOUT ORIGINAL SARS BECAUSE OF

3012
01:47:49,055 --> 01:47:50,189
TIME AND NOT THAT MEAN PEOPLE

3013
01:47:50,189 --> 01:47:51,657
ARE WORKING ON THE VIRUS WITH

3014
01:47:51,657 --> 01:47:53,960
THE SELECT AGENT CONCERNS AS

3015
01:47:53,960 --> 01:47:55,895
WELL, BUT IT IS 1 OF MY FAVORITE

3016
01:47:55,895 --> 01:47:57,730
VIRUSES SO IF YOU LIKE IT, WE

3017
01:47:57,730 --> 01:47:58,331
CAN TALK AFTERWARDS.

3018
01:47:58,331 --> 01:47:59,598
SO WE ALREADY TALKED ABOUT THE

3019
01:47:59,598 --> 01:48:02,168
NEED FOR SMALL ANIMAL MODELS.

3020
01:48:02,168 --> 01:48:04,337
AT UNC WE'RE A MOUSE-CENTRIC

3021
01:48:04,337 --> 01:48:05,705
ORGANIZATION AND THAT'S WHERE

3022
01:48:05,705 --> 01:48:07,940
OUR EXPERTISE AND OUR BL3

3023
01:48:07,940 --> 01:48:10,609
EQUIPMENT WAS FOCUSED AND SO WE

3024
01:48:10,609 --> 01:48:12,178
WANTED TO GENERATE MOUSE MODELS

3025
01:48:12,178 --> 01:48:13,579
AS QUICKLY AS POSSIBLE INSTEAD

3026
01:48:13,579 --> 01:48:16,015
OF SWITCHING OVER TO A NEW

3027
01:48:16,015 --> 01:48:19,118
ANIMAL SPECIES AND HAVING TO

3028
01:48:19,118 --> 01:48:19,352
RESTART.

3029
01:48:19,352 --> 01:48:22,922
SO LUCKILY WITH THE HISTORY OF

3030
01:48:22,922 --> 01:48:24,890
RESEARCH ON HUMAN AND THAT

3031
01:48:24,890 --> 01:48:26,625
CORONA VIRUSES, THERE WAS A

3032
01:48:26,625 --> 01:48:27,693
REALLY GOOD AMOUNT OF

3033
01:48:27,693 --> 01:48:28,828
FOUNDATIONAL KNOWLEDGE ABOUT

3034
01:48:28,828 --> 01:48:30,596
WHAT THOSE CONTACT RESIDUES WERE

3035
01:48:30,596 --> 01:48:31,964
FOR BINDING WITH THE SPIKE

3036
01:48:31,964 --> 01:48:34,000
PROTEIN OF THE VIRUS AND THE ACE

3037
01:48:34,000 --> 01:48:35,401
2 RECEPTOR BECAUSE WE LEARNED

3038
01:48:35,401 --> 01:48:37,970
VERY QUICKLY THAT ACE 2 IS ALSO

3039
01:48:37,970 --> 01:48:39,238
THE RECEPTOR FOR SARS 2.

3040
01:48:39,238 --> 01:48:42,575
SO KENNY WAS A GRADUATE STUDENT

3041
01:48:42,575 --> 01:48:43,576
OF [INDISCERNIBLE] AND HE WORKED

3042
01:48:43,576 --> 01:48:44,710
WITH SEVERAL OF US ON THE

3043
01:48:44,710 --> 01:48:46,612
PROJECT BUT HE QUICKLY MODELED

3044
01:48:46,612 --> 01:48:48,280
THE CONTACT RESIDUES AND TAKING

3045
01:48:48,280 --> 01:48:50,149
ADVANTAGE OF THIS PREVIOUS

3046
01:48:50,149 --> 01:48:52,752
RESEARCH WAS ABLE TO IDENTIFY

3047
01:48:52,752 --> 01:48:55,187
THAT AT RESIDUE 498 BUT THERE

3048
01:48:55,187 --> 01:48:57,456
WAS A GLUTAMINE HERE INSTEAD OF

3049
01:48:57,456 --> 01:48:59,392
A PRETTY CONSERVED TYROSEEN AND

3050
01:48:59,392 --> 01:49:01,060
OTHER SPIKES THAT WAS ABLE TO

3051
01:49:01,060 --> 01:49:03,662
MEDIATE THAT CONTACT WITH ACE 2.

3052
01:49:03,662 --> 01:49:06,532
SO HE SPECIFICALLY MUTATED

3053
01:49:06,532 --> 01:49:08,300
RESIDUE 498 AND ADJACENT RESIDUE

3054
01:49:08,300 --> 01:49:10,069
499 BECAUSE THAT WAS A TYPE OF

3055
01:49:10,069 --> 01:49:14,140
PROLEAN AND HE THOUGHT IT WAS

3056
01:49:14,140 --> 01:49:15,041
INTERVIEWS A WEIRD KINK IN THE

3057
01:49:15,041 --> 01:49:16,242
STRUCTURE OF THE THAT WAS NOT

3058
01:49:16,242 --> 01:49:17,710
ABLE TO RESTORE BUT INTRODUCE

3059
01:49:17,710 --> 01:49:19,311
BINDING TO HOUSE ACE 2, THAT WAS

3060
01:49:19,311 --> 01:49:21,847
MORE SIMILAR TO WHAT'S SEEN WITH

3061
01:49:21,847 --> 01:49:23,049
HUMAN ACE 2, THESE HYDROGEN

3062
01:49:23,049 --> 01:49:23,983
BONDS WERE RESTORED AND WE'RE

3063
01:49:23,983 --> 01:49:27,620
ABLE TO DEVELOP A MODEL THAT

3064
01:49:27,620 --> 01:49:28,821
DOES INFACT INFECT MICE, THAT

3065
01:49:28,821 --> 01:49:32,191
WAS REALLY A REPLICATION ONLY

3066
01:49:32,191 --> 01:49:33,692
MODEL, HOWEVER, SO SUBSEQUENT

3067
01:49:33,692 --> 01:49:36,028
WORK WAS DONE PASSAGING THIS IN

3068
01:49:36,028 --> 01:49:38,564
VIVO, THROUGH THE LUNGS OF

3069
01:49:38,564 --> 01:49:39,765
BALB-C MICE AND AFTER 10

3070
01:49:39,765 --> 01:49:41,867
PASSAGES WE HAD A HIGHLY

3071
01:49:41,867 --> 01:49:43,736
VIRULENT VIRUS NAIN A DOSE AND

3072
01:49:43,736 --> 01:49:45,004
AGE DEPENDENT MANNER COULD

3073
01:49:45,004 --> 01:49:48,874
EITHER BE PRETTY MILD DISEASE OR

3074
01:49:48,874 --> 01:49:50,076
EXTREMELY LETHAL DISEASE SO

3075
01:49:50,076 --> 01:49:51,277
HERE'S WRUOF THE A SCHEMATIC OF

3076
01:49:51,277 --> 01:49:54,380
THAT WHOLE GENOME OF THE MATTEN

3077
01:49:54,380 --> 01:49:56,015
VIRUS WITH THE 2 MUTATIONS THAT

3078
01:49:56,015 --> 01:49:56,816
WE INTIEWS SPECIFICALLY, AND

3079
01:49:56,816 --> 01:49:58,918
THEN THE 5 ADDITIONAL MUTATIONS

3080
01:49:58,918 --> 01:50:05,124
THAT CAME UP THROUGH PASSAGE.

3081
01:50:05,124 --> 01:50:07,159
SO USING THAT VIRUS WE DID ALL

3082
01:50:07,159 --> 01:50:09,662
THE BASIC I HAVE ROW LONGICAL

3083
01:50:09,662 --> 01:50:09,962
OBSERVATION.

3084
01:50:09,962 --> 01:50:11,530
DOSE RESPONSE, TIME COURSE,

3085
01:50:11,530 --> 01:50:13,199
SETTLED IN ON PRETTY STANDARD

3086
01:50:13,199 --> 01:50:14,033
CHARACTERISTICS THAT HAVE ALL

3087
01:50:14,033 --> 01:50:15,801
BEEN PUBLISHED AND I DON'T WANT

3088
01:50:15,801 --> 01:50:19,538
TO SPEND TOO MUCH TIME ON THAT.

3089
01:50:19,538 --> 01:50:20,739
BUT WHAT I THINK IS MOST

3090
01:50:20,739 --> 01:50:22,174
INTERESTING TO A LOT OF US IS

3091
01:50:22,174 --> 01:50:23,476
DIVING IN ON WHAT IS REALLY

3092
01:50:23,476 --> 01:50:25,144
HAPPENING IN THE LUNG, IN THE

3093
01:50:25,144 --> 01:50:28,547
ORGANS THAT ARE INFECTED, MICE

3094
01:50:28,547 --> 01:50:30,216
LOSE WEIGHT THAT'S A GREAT

3095
01:50:30,216 --> 01:50:31,750
QUANTITATIVE MARKER BUT IT'S NOT

3096
01:50:31,750 --> 01:50:34,153
SUPER REFLECTIVE OF HUMAN DEC,

3097
01:50:34,153 --> 01:50:37,423
IT'S NOT THE MOST RELEVANT OF

3098
01:50:37,423 --> 01:50:38,390
THE PHENOTYPE 2, BUT WHAT'S

3099
01:50:38,390 --> 01:50:40,092
HAPPENING IN THE ORGANISM,

3100
01:50:40,092 --> 01:50:41,093
WHAT'S HAPPENING DISEASE WISE?

3101
01:50:41,093 --> 01:50:42,962
WE COULD SEE WHAT WOULD HAPPEN

3102
01:50:42,962 --> 01:50:44,997
FROM OTHER CORONA VIRUSES THAT

3103
01:50:44,997 --> 01:50:48,701
WE HAVE PEAK TITER EARLY, SO

3104
01:50:48,701 --> 01:50:50,836
STAIN FOR NUCLEIC CAPSID HERE IN

3105
01:50:50,836 --> 01:50:52,004
THOSE AIRWAY EPITHELIAL CELLS,

3106
01:50:52,004 --> 01:50:54,707
AND ALSO THE TYPE 2 SITES IN THE

3107
01:50:54,707 --> 01:50:56,275
LUNG, THIS REPLICATION DECREASES

3108
01:50:56,275 --> 01:50:59,512
OVERTIME BUT OUR LUNG PATHOLOGY

3109
01:50:59,512 --> 01:51:01,147
INCREASES EMPLOY A PRETTY

3110
01:51:01,147 --> 01:51:03,682
STANDARD STORY FOR A LOT OF

3111
01:51:03,682 --> 01:51:04,483
RESPIRATORY VIRUSES.

3112
01:51:04,483 --> 01:51:06,519
BUT GETTING BEYOND THESE INITIAL

3113
01:51:06,519 --> 01:51:07,486
CHARACTERIZATIONS, WE'VE DONE A

3114
01:51:07,486 --> 01:51:11,123
LOT OF WORK MORE RECENTLY WITH

3115
01:51:11,123 --> 01:51:12,525
DIFFERENT DIGITAL PARTICIPATE IN

3116
01:51:12,525 --> 01:51:14,160
A TRIALIAL FILING PLATFORMS

3117
01:51:14,160 --> 01:51:15,461
GETTING INTO MORE FUN MODERN

3118
01:51:15,461 --> 01:51:16,562
TECHNOLOGY AND WITH THESE ARK

3119
01:51:16,562 --> 01:51:18,264
PROACHS, I THINK WE CAN REALLY

3120
01:51:18,264 --> 01:51:20,032
LEARN A LOT ABOUT WHAT'S

3121
01:51:20,032 --> 01:51:26,205
HAPPENING IN THE LUNGS.

3122
01:51:26,205 --> 01:51:27,640
SO IN THIS WORK BY NICK

3123
01:51:27,640 --> 01:51:29,575
[INDISCERNIBLE] IN OUR GROUP,

3124
01:51:29,575 --> 01:51:31,710
HE'S DONE DIGIT AT SPATIAL

3125
01:51:31,710 --> 01:51:31,977
PROFILING.

3126
01:51:31,977 --> 01:51:33,579
THIS IS 1 OF MANY WE'RE TESTING

3127
01:51:33,579 --> 01:51:35,181
OUT TRYING TO GET AS MUCH DATA

3128
01:51:35,181 --> 01:51:36,815
AS WE CAN FROM ALL THESE

3129
01:51:36,815 --> 01:51:37,650
DEFINITE PLATFORMS BEFORE WE

3130
01:51:37,650 --> 01:51:39,185
SETTLE IN ON SOMETHING, BUT I

3131
01:51:39,185 --> 01:51:40,653
THINK IT'S ALSO REALLY

3132
01:51:40,653 --> 01:51:41,420
COMPLIMENTARY.

3133
01:51:41,420 --> 01:51:43,556
SO THIS IS LOOKING AT ACUTE

3134
01:51:43,556 --> 01:51:45,824
INFECTION, POWER DAYS POST

3135
01:51:45,824 --> 01:51:46,091
INFECTION.

3136
01:51:46,091 --> 01:51:49,094
YOU CAN SEE JUST THE H&  E

3137
01:51:49,094 --> 01:51:50,129
STAINED IMAGES DOWN HERE AND

3138
01:51:50,129 --> 01:51:51,463
THEN LOOKING AT EXPRESSION OF

3139
01:51:51,463 --> 01:51:53,499
SEVERAL GENES THAT WERE

3140
01:51:53,499 --> 01:51:55,601
INTERESTED IN, SO KRT8 IS A

3141
01:51:55,601 --> 01:51:58,571
MARKER OF REPAIR OF THOSE

3142
01:51:58,571 --> 01:51:59,405
ALVEOLAR CELLS.

3143
01:51:59,405 --> 01:52:02,141
WE'RE LOOKING AT SURFACTIN

3144
01:52:02,141 --> 01:52:02,741
EXPRESSION, CLASSICALLY, THIS

3145
01:52:02,741 --> 01:52:05,978
GOES DOWN AFTER INFECTION, WE

3146
01:52:05,978 --> 01:52:08,347
SAW THIS IN SARS 1, WE SEE IT IN

3147
01:52:08,347 --> 01:52:09,648
THE TYPE 2 PNEUMOSIGHTS ARE

3148
01:52:09,648 --> 01:52:12,885
KILLED OFF, THEY'RE NOT ABLE TO

3149
01:52:12,885 --> 01:52:14,119
PRODUCE SURFACTIN ANYMORE AND

3150
01:52:14,119 --> 01:52:15,421
THIS GOES WITH OVERALL

3151
01:52:15,421 --> 01:52:16,155
DEPRIVATIONMENT OF LUNG DEC AND

3152
01:52:16,155 --> 01:52:18,357
THEN WE ALSO SEE INCREASED

3153
01:52:18,357 --> 01:52:20,092
EXPRESSION OF GENES LIKE HIP 1

3154
01:52:20,092 --> 01:52:22,027
ALPHA WHICH IS INDICATIVE OF

3155
01:52:22,027 --> 01:52:23,195
HYPOXIA THAT'S HAPPENING IN

3156
01:52:23,195 --> 01:52:26,131
THESE LUNGS AND GIVING US A NICE

3157
01:52:26,131 --> 01:52:27,933
COMPREHENSIVE PICTURE OF LUNG

3158
01:52:27,933 --> 01:52:29,602
DEC, YOU CAN SEE SPATIALLY WHERE

3159
01:52:29,602 --> 01:52:31,003
THIS IS HAPPENING RELATIVE TO

3160
01:52:31,003 --> 01:52:33,005
LIKE YOUR LARGE AIR WAYS, YOUR

3161
01:52:33,005 --> 01:52:34,073
VASCULATURE, AND WE WERE GOING

3162
01:52:34,073 --> 01:52:37,243
TO BE SPENDING A LOT MORE TIME

3163
01:52:37,243 --> 01:52:37,776
ON THIS.

3164
01:52:37,776 --> 01:52:40,579
IF ONLY WE CAN DO IT FOR EVERY

3165
01:52:40,579 --> 01:52:41,847
MOUSE BUT DEFINITELY NOT

3166
01:52:41,847 --> 01:52:42,381
POSSIBLE.

3167
01:52:42,381 --> 01:52:44,583
WE'VE ALSO BEEN WORKING WITH

3168
01:52:44,583 --> 01:52:49,355
BOARDS ON EMPLOY CAMPUS, GETTING

3169
01:52:49,355 --> 01:52:52,391
SET UP WITH A RECYCLER, LOOKING

3170
01:52:52,391 --> 01:52:55,494
AT RNA PROTEIN EXPRESSION AND

3171
01:52:55,494 --> 01:52:56,428
IT'S NICELY COMPLIMENTARY AND IF

3172
01:52:56,428 --> 01:52:58,097
ONLY WE HAD THE TIME AND

3173
01:52:58,097 --> 01:53:00,199
RESOURCES TO DO IT ON A

3174
01:53:00,199 --> 01:53:03,269
FULL-TIME COURSE OR AN ARRAY OF

3175
01:53:03,269 --> 01:53:04,870
GENETIC PACK GROUNDS BUT JUST

3176
01:53:04,870 --> 01:53:07,273
FROM BASIC CHARACTER EYATION

3177
01:53:07,273 --> 01:53:08,340
WITH THIS ACUTE IN INFECTION,

3178
01:53:08,340 --> 01:53:10,042
YOU CAN SEE THAT IN COMPARISON

3179
01:53:10,042 --> 01:53:11,510
TO THE MOCK INFECTED LOWNGOT

3180
01:53:11,510 --> 01:53:13,579
LEFT HERE AND ON THE RIGHT WHERE

3181
01:53:13,579 --> 01:53:14,580
THE MATTEN INFECS HAPPEN, IN

3182
01:53:14,580 --> 01:53:16,548
GREEN YOU CAN SEE THAT THE

3183
01:53:16,548 --> 01:53:17,583
SURFACTIN THAT'S NICELY

3184
01:53:17,583 --> 01:53:18,484
EXPRESSED ALL THROUGHOUT THE

3185
01:53:18,484 --> 01:53:26,058
LUNG HERE HAS REALLY DISAPPEARED

3186
01:53:26,058 --> 01:53:28,827
SPERKS LEECIALLY IN AREAS WHERE

3187
01:53:28,827 --> 01:53:31,096
YOU SEE THE RED, WE HAVE

3188
01:53:31,096 --> 01:53:32,931
INCREASED BLUE HERE, THIS IS

3189
01:53:32,931 --> 01:53:34,867
MUCIN, ALL IN ALL A REALLY NICE

3190
01:53:34,867 --> 01:53:35,834
PICTURE OF WHAT'S HAPPENING WITH

3191
01:53:35,834 --> 01:53:37,803
THE LUNGS SO WE'RE NOT JUST

3192
01:53:37,803 --> 01:53:39,171
LOOKING AT BULK RNA OR PROTEIN,

3193
01:53:39,171 --> 01:53:42,041
BUT YOU CAN SEE REALLY FOCUS

3194
01:53:42,041 --> 01:53:43,676
REGIONS OF DISEASE, SO UP HERE

3195
01:53:43,676 --> 01:53:44,977
THERE ISN'T THAT MUCH INFECTION

3196
01:53:44,977 --> 01:53:46,412
AND THE LUNG LOOKS PRETTY

3197
01:53:46,412 --> 01:53:52,951
NORMAL, DOWN HERE WE HAVE A

3198
01:53:52,951 --> 01:53:54,787
REALLY NICE PATCH OF VOCAL

3199
01:53:54,787 --> 01:53:55,721
DISEASE EMPLOY OF COURSE WE'VE

3200
01:53:55,721 --> 01:53:59,992
BEEN DOING A LOT OF RNAseq AND

3201
01:53:59,992 --> 01:54:01,627
IN THIS CASE IT'S NICE BECAUSE

3202
01:54:01,627 --> 01:54:03,095
WE CAN DIVE INTO WHAT'S

3203
01:54:03,095 --> 01:54:04,963
HAPPENING IN PARTICULAR AND

3204
01:54:04,963 --> 01:54:06,465
DISTINCT LUNG CELLS AND FIND OUT

3205
01:54:06,465 --> 01:54:07,933
HOW THEY'RE RESPONDING TO

3206
01:54:07,933 --> 01:54:10,703
INFECTION IN SO HERE'S THAT

3207
01:54:10,703 --> 01:54:12,237
CLASSIC UMAP PICTURE OF SNCHT

3208
01:54:12,237 --> 01:54:12,871
CELL POPULATIONS THAT WE'RE

3209
01:54:12,871 --> 01:54:22,614
SEEING IN THE LUNG.

3210
01:54:22,614 --> 01:54:23,982
LOOKING AT THAT POPULATION AND

3211
01:54:23,982 --> 01:54:24,883
SEE THAT INFECKED ANIMALS THERE

3212
01:54:24,883 --> 01:54:28,354
ARE A LOT OF ISGs BEING

3213
01:54:28,354 --> 01:54:29,555
EXPRESSED AS 1 WOULD EXEC, THERE

3214
01:54:29,555 --> 01:54:31,590
ARE A LOT OF MATURATION AND

3215
01:54:31,590 --> 01:54:32,524
ACTIVATION TELLING US HAY, IT

3216
01:54:32,524 --> 01:54:34,126
WILL BE NICE TO DIVE IN MORE

3217
01:54:34,126 --> 01:54:36,095
ABOUT WHAT'S HAPPENING ON

3218
01:54:36,095 --> 01:54:37,229
NUTRIFILLS, LET'S DO DEPLETION

3219
01:54:37,229 --> 01:54:44,503
SPRMS, LET'S FOLLOW UP WITH

3220
01:54:44,503 --> 01:54:52,111
WHAT'S HAPPENING HERE AND IT

3221
01:54:52,111 --> 01:54:54,012
WILL CONTINUE BEING A PRIMARY

3222
01:54:54,012 --> 01:54:57,816
RESEARCH OF FOCUS WE KNOW THERE

3223
01:54:57,816 --> 01:54:58,384
ARE NONPULMONARY CENTER FOR

3224
01:54:58,384 --> 01:54:59,251
EXCELLENCE ON AGINGS OF COVID-19

3225
01:54:59,251 --> 01:55:00,753
AND IT CAN BE DIFFICULT TO ASK

3226
01:55:00,753 --> 01:55:05,858
THE MICE HOW ARE YOU FEELING?

3227
01:55:05,858 --> 01:55:07,726
DO YOU HAVE BRAIN FOG?

3228
01:55:07,726 --> 01:55:09,495
ARE YOU ACHING, THOSE REALLY

3229
01:55:09,495 --> 01:55:20,038
NICE BEHAVIORIAL ASSAYS SO WE'RE

3230
01:55:23,242 --> 01:55:25,611
JEALOUS ABOUT THAT SO WE KNOW IN

3231
01:55:25,611 --> 01:55:26,912
HUMAN 19 COVID PATIENTS THIS CAN

3232
01:55:26,912 --> 01:55:29,982
BE AN EFFECT IN THE RESPIRATORY

3233
01:55:29,982 --> 01:55:31,383
SYSTEM AND THROUGHOUT THE REST

3234
01:55:31,383 --> 01:55:32,584
OF THE BODY AND HALLMARKS OF

3235
01:55:32,584 --> 01:55:35,220
THIS ARE THAT YOU HAVE INCREASED

3236
01:55:35,220 --> 01:55:37,689
FIEB RENO GENERATED GENERATION,

3237
01:55:37,689 --> 01:55:41,460
THROMBIN, ENHANCED PLAZ MIDS

3238
01:55:41,460 --> 01:55:41,794
--PLASMID, SO

3239
01:55:41,794 --> 01:55:43,662
THIS WHOLE SYSTEM IS HIGHLY,

3240
01:55:43,662 --> 01:55:44,730
HIGHLY ACTIVE.

3241
01:55:44,730 --> 01:55:48,300
SO YOU ARE GETTING A LOT OF

3242
01:55:48,300 --> 01:55:49,168
PLOTS BEING DEPOSITED AND

3243
01:55:49,168 --> 01:55:52,204
THEY'RE NOT BREAKING UP AS THEY

3244
01:55:52,204 --> 01:55:52,738
NORMALLY WOULD.

3245
01:55:52,738 --> 01:55:54,473
IN OUR SARS-COV-2 INFECTED MICE

3246
01:55:54,473 --> 01:55:55,974
WE SEE SIM LAWYER LIGFATTURES AS

3247
01:55:55,974 --> 01:55:57,409
MUCH AS WE CAN SO FAR AND THIS

3248
01:55:57,409 --> 01:55:59,144
IS JUST LOOKING AT FIEB RIN

3249
01:55:59,144 --> 01:56:06,985
DEPOSITION IN THE LUNGS AFTER

3250
01:56:06,985 --> 01:56:07,386
INFECTION.

3251
01:56:07,386 --> 01:56:09,121
IF WE ZOOM IN YOU CAN SEE THE

3252
01:56:09,121 --> 01:56:10,956
STAINING AND IT'S NOT JUST IN

3253
01:56:10,956 --> 01:56:12,591
THE VASCULAR SPACES SO THIS IS

3254
01:56:12,591 --> 01:56:17,663
NOT HEALTHY, THIS IS NOT

3255
01:56:17,663 --> 01:56:19,198
SOMETHING THAT THAT WE WANT TO

3256
01:56:19,198 --> 01:56:21,533
SEE, IF WE GO IN AND LOOK

3257
01:56:21,533 --> 01:56:23,368
SPECIFICALLY AT PLOTTING MARKERS

3258
01:56:23,368 --> 01:56:25,270
THAT YOU SEE INCREASED PLASMA

3259
01:56:25,270 --> 01:56:26,872
GENERATION, HIGHER PEEK AND

3260
01:56:26,872 --> 01:56:29,174
FASTER TIME TO THAT PEEK AND

3261
01:56:29,174 --> 01:56:29,875
ALSO INCREASE THROMBIN

3262
01:56:29,875 --> 01:56:37,549
GENERATION AND A FASTER TIME TO

3263
01:56:37,549 --> 01:56:37,916
THAT PEEK.

3264
01:56:37,916 --> 01:56:39,485
SO WHILE IT CAN BE INTERESTING

3265
01:56:39,485 --> 01:56:40,953
TO LOOK AT THESE FACTORS IN

3266
01:56:40,953 --> 01:56:42,521
MICE, WE ARE STILL SEEING

3267
01:56:42,521 --> 01:56:43,856
SIGNATURES OF WHAT HAPPENS IN

3268
01:56:43,856 --> 01:56:44,289
HUMANS.

3269
01:56:44,289 --> 01:56:46,525
AND THEN DIVING IN MORE DEEPLY

3270
01:56:46,525 --> 01:56:49,328
SOME OF THAT BECAUSE WE HAVE

3271
01:56:49,328 --> 01:56:50,162
NICE GENETIC MODELS AVAILABLE TO

3272
01:56:50,162 --> 01:56:54,967
US IN MOUSE SYSTEMS WE CAN LOOK

3273
01:56:54,967 --> 01:56:57,503
AT PLASMA DEFICIENT MICE OR

3274
01:56:57,503 --> 01:56:58,170
FIBROGENERATED DEFICIENT MICE

3275
01:56:58,170 --> 01:57:00,105
AND SO THAT THEY MUTATED IN

3276
01:57:00,105 --> 01:57:01,340
THOSE WAYS.

3277
01:57:01,340 --> 01:57:04,910
PLUS SEE THAT THE MICE ARE

3278
01:57:04,910 --> 01:57:06,979
PROTECTED FROM DISEASE COMPARED

3279
01:57:06,979 --> 01:57:09,515
TO THE HETEROZYGOUS ROLES AND WE

3280
01:57:09,515 --> 01:57:10,782
ALSO HAVE CHANGES IN MACROPHAGE

3281
01:57:10,782 --> 01:57:12,584
AND PERSISTENT IN THE LUNGS OUT

3282
01:57:12,584 --> 01:57:14,119
AT LATER TIME POINTS IN THE

3283
01:57:14,119 --> 01:57:15,320
DEFICIENT MICE, SO A LOT OF

3284
01:57:15,320 --> 01:57:25,564
AREAS WE CAN FOLLOW UP HERE AND

3285
01:57:25,564 --> 01:57:26,732
WE DISSECT OUT SPECIFIC CELL

3286
01:57:26,732 --> 01:57:28,467
TYPES EVEN FURTHER BUT I THINK

3287
01:57:28,467 --> 01:57:34,907
THESE ARE STRENGTHS OF OUR MOUSE

3288
01:57:34,907 --> 01:57:36,875
MODELS WE'VE ALSO WORKED ON

3289
01:57:36,875 --> 01:57:39,077
THESE AND THAT IS DONE IN

3290
01:57:39,077 --> 01:57:40,812
COLLABORATION WITH GREGORY VIX'S

3291
01:57:40,812 --> 01:57:41,914
LAB AT THE UNIVERSITY, AND SO

3292
01:57:41,914 --> 01:57:44,249
SHE HAS DONE A LOT OF INFECTIONS

3293
01:57:44,249 --> 01:57:54,793
AND SENT OFF CNS TISSUE TO THEIR

3294
01:57:58,497 --> 01:58:00,132
LAB FOR ANALYSIS.

3295
01:58:00,132 --> 01:58:01,967
AND WHAT'S REALLY INTERESTING

3296
01:58:01,967 --> 01:58:04,169
THAT THERE'S A DECREASE IN THE

3297
01:58:04,169 --> 01:58:05,137
TIGHT JUNCTION MARKERS SO

3298
01:58:05,137 --> 01:58:06,705
IMPLYING THAT THERE IS, POSSIBLY

3299
01:58:06,705 --> 01:58:08,206
SOME BREAK DOWN OF THAT BLOOD

3300
01:58:08,206 --> 01:58:08,840
BRAIN BIRRIER SURFACESSIER IN

3301
01:58:08,840 --> 01:58:11,176
THE MICE THAT ARE INFEC WIDE

3302
01:58:11,176 --> 01:58:13,011
MA-10 AND I KNOW THEY HAVE A LOT

3303
01:58:13,011 --> 01:58:17,916
MORE WORK PLANNED IN THIS AREA.

3304
01:58:17,916 --> 01:58:19,451
SO THAT'S MOSTLY BEEN ACUTE

3305
01:58:19,451 --> 01:58:20,786
DISEASE BUT WE'RE ALSO VERY

3306
01:58:20,786 --> 01:58:21,720
INTERESTED IN WHAT'S HAPPENING

3307
01:58:21,720 --> 01:58:23,655
LONG-TERM IN THESE MICE THAT

3308
01:58:23,655 --> 01:58:24,623
HAVE BEEN INFECTED.

3309
01:58:24,623 --> 01:58:26,158
SO THIS IS DATA THAT WAS

3310
01:58:26,158 --> 01:58:27,593
PUBLISHED A LITTLE BIT AGO, SO I

3311
01:58:27,593 --> 01:58:29,795
WILL GO THROUGH IT REALLY

3312
01:58:29,795 --> 01:58:32,464
QUICKLY, BUT WE SHOWED ACUTE

3313
01:58:32,464 --> 01:58:33,865
INFECTION BY MOST TRADITIONAL

3314
01:58:33,865 --> 01:58:34,766
MEASURES THAT WE CAN OBSERVE IN

3315
01:58:34,766 --> 01:58:39,371
THE  LABORATORY.

3316
01:58:39,371 --> 01:58:41,873
THE MICE HAVE RECOVERED BY 15

3317
01:58:41,873 --> 01:58:46,511
DAYS POST INFECTION. 

3318
01:58:46,511 --> 01:58:48,080
WHAT GETS INTERESTING IS--CAN WE

3319
01:58:48,080 --> 01:58:58,523
MAKE THE SLIDES COME BACK?

3320
01:59:08,233 --> 01:59:08,634
THANK YOU.

3321
01:59:08,634 --> 01:59:11,169
IT SHOULD BE ON THE NEXT SLIDE,

3322
01:59:11,169 --> 01:59:14,606
BUT WHEN WE LOOK AT THESE MOST

3323
01:59:14,606 --> 01:59:16,241
INFECTION, THIS IS A MEASURE OF

3324
01:59:16,241 --> 01:59:18,310
FIBROSIS THAT THESE LUNGS ARE

3325
01:59:18,310 --> 01:59:19,811
NOT NORMAL, THEY HAVE NOT COME

3326
01:59:19,811 --> 01:59:22,047
BACK TO BASE LINE AND IF WE DO

3327
01:59:22,047 --> 01:59:23,815
SPECIFIC STAINING, THIS IS AT 15

3328
01:59:23,815 --> 01:59:24,983
AND 30 DAYS POST INFECTION, CAN

3329
01:59:24,983 --> 01:59:27,185
YOU SEE THERE IS A LOT OF SMOOTH

3330
01:59:27,185 --> 01:59:30,555
MUSCLE ACTING, A LOT OF SERIOUS

3331
01:59:30,555 --> 01:59:36,194
RED STAINING, MARKERS OF

3332
01:59:36,194 --> 01:59:36,595
FIBROSIS.

3333
01:59:36,595 --> 01:59:38,630
WE DID SPATIAL PROFILING ON

3334
01:59:38,630 --> 01:59:40,932
THESE LONGER TERM MICE AS WELL,

3335
01:59:40,932 --> 01:59:42,534
AND QUANTIFIED MARKERS OF

3336
01:59:42,534 --> 01:59:45,137
FIBROSIS TO CONFIRM OUR INITIAL

3337
01:59:45,137 --> 01:59:45,604
SUSPICIONS.

3338
01:59:45,604 --> 01:59:48,974
A LOT OF COLLAGENS, FIEK ROUGH

3339
01:59:48,974 --> 01:59:51,443
ATOM NECTIN, SBP1 IS A MARKER OF

3340
01:59:51,443 --> 01:59:52,377
MACROPHAGES, ALL OF THESE GO UP

3341
01:59:52,377 --> 02:00:01,453
AND STAY UP IN THE LUNGS OF

3342
02:00:01,453 --> 02:00:02,387
SARS-COV-2 INFECTED MICE.

3343
02:00:02,387 --> 02:00:04,656
NOW THIS CAME UP IN STACEY'S

3344
02:00:04,656 --> 02:00:06,658
TALK SO I'M GLAD THIS SLIDE CAME

3345
02:00:06,658 --> 02:00:06,892
IN.

3346
02:00:06,892 --> 02:00:09,895
SO THESE ARE MICE FROM THE

3347
02:00:09,895 --> 02:00:11,496
CC POPULATION AT UHC, IT'S A

3348
02:00:11,496 --> 02:00:12,564
GENETIC POPULATION THAT WAS

3349
02:00:12,564 --> 02:00:14,933
DERIVED FROM 8 FOUNDER LINES,

3350
02:00:14,933 --> 02:00:17,002
THEY WERE BRED TOGETHER IN THESE

3351
02:00:17,002 --> 02:00:18,236
BREEDING SCHEMES OVER AND OVER

3352
02:00:18,236 --> 02:00:28,780
AND OVER AND THEN INBRED FOR 30

3353
02:00:29,614 --> 02:00:32,050
OR SO GENERATIONS BEFORE THEY

3354
02:00:32,050 --> 02:00:32,551
WERE RELATIVELY FIXED.

3355
02:00:32,551 --> 02:00:34,953
SO WHEN YOU LOOK AT THE MICE,

3356
02:00:34,953 --> 02:00:37,456
THEY HAVE BITS OF EACH OF THE 8

3357
02:00:37,456 --> 02:00:38,690
FOUNDERS, THEY'RE COLOR COATED

3358
02:00:38,690 --> 02:00:40,926
SO A BLACK BIT INDICATES THAT

3359
02:00:40,926 --> 02:00:43,829
CAME FROM B6 AND A YELLOW BIT

3360
02:00:43,829 --> 02:00:46,498
INDICATES IT CAME FROM AJ, AND

3361
02:00:46,498 --> 02:00:49,267
THE CC REPRESENT BOO 90% OF THE

3362
02:00:49,267 --> 02:00:51,336
GENETIC DIVERSITY IN THE GENOME,

3363
02:00:51,336 --> 02:00:54,906
MOST OF THAT GENETIC SIGNIFY

3364
02:00:54,906 --> 02:00:56,308
DIVERSITY CAME FROM THE PARENTS

3365
02:00:56,308 --> 02:00:58,076
THERE BUT THERE ARE 5 MORE

3366
02:00:58,076 --> 02:00:59,478
STANDARD LAB LINES THAT WERE

3367
02:00:59,478 --> 02:01:03,048
INVOLVED IN THIS AS WELL.

3368
02:01:03,048 --> 02:01:06,218
SO SARAH, ALEX AND JOHN POWERS

3369
02:01:06,218 --> 02:01:10,021
AND NICK, AND SPENT A LOT OF

3370
02:01:10,021 --> 02:01:12,457
TIME INFECTING A NUMBER OF

3371
02:01:12,457 --> 02:01:14,259
CC-LINES, WE DID SOMEWHAT

3372
02:01:14,259 --> 02:01:16,661
PRESLICT FOR MICE THAT WEREN'T

3373
02:01:16,661 --> 02:01:18,830
ALL GOING TO DIE, WHEN WE DID

3374
02:01:18,830 --> 02:01:19,865
SHORTER TERM INFECTIONS THERE

3375
02:01:19,865 --> 02:01:21,633
WERE SCREENING FOR ANIMALS THAT

3376
02:01:21,633 --> 02:01:22,801
WERE NOT IMPOSSIBLE TO WORK WITH

3377
02:01:22,801 --> 02:01:23,902
AS WELL BECAUSE IF YOU HAD THE

3378
02:01:23,902 --> 02:01:25,170
PLEASURE, YOU KNOW SOME OF THEM

3379
02:01:25,170 --> 02:01:27,239
RETAINED A LOT OF THEIR WILD

3380
02:01:27,239 --> 02:01:33,011
CHARACTERISTICS AND THAT'S NOT

3381
02:01:33,011 --> 02:01:34,312
AN ANIMAL YOU CAN HAVE IN 30

3382
02:01:34,312 --> 02:01:34,513
DAYS.

3383
02:01:34,513 --> 02:01:36,014
SO WHAT YOU CAN SEE FROM 12 OR

3384
02:01:36,014 --> 02:01:38,150
SO LINE SYSTEM THAT THERE'S A

3385
02:01:38,150 --> 02:01:39,918
HIGH AMOUNT OF VARIABILITY AND

3386
02:01:39,918 --> 02:01:40,886
RESPONSE TO INFECTION, THESE

3387
02:01:40,886 --> 02:01:44,222
WERE ALL INFECT WHD THEY WERE 12

3388
02:01:44,222 --> 02:01:46,324
WEEKS OLD, BUT A VERY WIDE RANGE

3389
02:01:46,324 --> 02:01:49,661
OF OUTCOMES BECAUSE OF THAT

3390
02:01:49,661 --> 02:01:50,061
GENETIC DIVERSITY.

3391
02:01:50,061 --> 02:01:53,765
SO 3 FELT LINES I WANT TO

3392
02:01:53,765 --> 02:02:00,539
HIGHLIGHT HERE, CC4 AND CC10, IN

3393
02:02:00,539 --> 02:02:03,375
THIS THE ORANGE AND GRAY HAD

3394
02:02:03,375 --> 02:02:06,478
MODERATE WEIGHT LOSS BUT CC25 IN

3395
02:02:06,478 --> 02:02:08,780
THE RED HAD MORE WEIGHT LOSS AND

3396
02:02:08,780 --> 02:02:10,415
THE MICE WITH INFEC.

3397
02:02:10,415 --> 02:02:12,317
WHEN WE TOOK THESE OUT TO 30

3398
02:02:12,317 --> 02:02:13,985
DAYS POST INFECTION AND REALLY

3399
02:02:13,985 --> 02:02:15,520
WERE FOCUSED ON FIBROSIS

3400
02:02:15,520 --> 02:02:17,756
PHENOTYPES, THE SLIDES THAT WERE

3401
02:02:17,756 --> 02:02:18,690
ORIGE NAWILLLY STAINED HERE WENT

3402
02:02:18,690 --> 02:02:22,794
OFF TO JOCK AT MICHIGAN STATE

3403
02:02:22,794 --> 02:02:23,662
UNIVERSITY FOR EXTENSIVE

3404
02:02:23,662 --> 02:02:25,063
PATHOLOGY SCWOAR SCORING AND HE

3405
02:02:25,063 --> 02:02:26,731
WAS REALLY FOCUSED ON A NUMBER

3406
02:02:26,731 --> 02:02:30,335
OF PARAMETERS ASSOCIATED WITH

3407
02:02:30,335 --> 02:02:30,635
HIEBROSIS.

3408
02:02:30,635 --> 02:02:33,338
SO LOOKING AT THE RANGE OF

3409
02:02:33,338 --> 02:02:34,339
SCORES HERE, JUST GENERAL

3410
02:02:34,339 --> 02:02:38,476
FIBROSIS, YOU CAN SEE THAT ON

3411
02:02:38,476 --> 02:02:39,778
CC10, AT DESCENT FIBROSIS WHERE

3412
02:02:39,778 --> 02:02:41,012
THEY HAD NOTHING EVEN THOUGH

3413
02:02:41,012 --> 02:02:43,014
THEY HAD SIMILAR WEIGHT LOSS,

3414
02:02:43,014 --> 02:02:45,717
CC25 HAD PRETTY EXTREME WEIGHT

3415
02:02:45,717 --> 02:02:47,586
LOSS WAS ALSO HIGH BUT NONE OF

3416
02:02:47,586 --> 02:02:49,788
THESE LINES HAD MUCH IN THE WAY

3417
02:02:49,788 --> 02:02:51,523
OF MUCUS CELL OR DISPLASSIA EVEN

3418
02:02:51,523 --> 02:02:52,457
THOUGH THERE WERE SOME LINES

3419
02:02:52,457 --> 02:02:52,858
THAT DO.

3420
02:02:52,858 --> 02:02:55,827
WHEN WE ELECTRIC AT WHAT'S

3421
02:02:55,827 --> 02:02:57,562
ACTUALLY HAPPENING ON H&  E

3422
02:02:57,562 --> 02:02:59,197
STAINED SLIDES HERE YOU CAN SEE

3423
02:02:59,197 --> 02:03:01,967
THAT THE CC4 MICE AND THE CC10

3424
02:03:01,967 --> 02:03:02,601
VERY DIFFERENT LOOKING EACH

3425
02:03:02,601 --> 02:03:04,236
THOUGH THEY HAVE THAT SIMILAR

3426
02:03:04,236 --> 02:03:07,105
WEIGHT LOSS, SO WE HAVE SOME

3427
02:03:07,105 --> 02:03:08,206
TERTIARY LYMPHOID STRUCTURE

3428
02:03:08,206 --> 02:03:11,843
THERE, IN THE CC10S AS WELL AS A

3429
02:03:11,843 --> 02:03:13,044
LOT OF FOAMY MACROPHAGES AND A

3430
02:03:13,044 --> 02:03:14,079
LOT OF INTERESTING STUFF WE

3431
02:03:14,079 --> 02:03:19,384
WOULD LIKE TO DIVE IN MORE

3432
02:03:19,384 --> 02:03:20,919
DEEPLY THERE AND THEN IN THE

3433
02:03:20,919 --> 02:03:24,456
CC25S THERE ISN'T A LOT OF AND

3434
02:03:24,456 --> 02:03:28,627
SO OTHER ASPECTS OF FIBROSIS.

3435
02:03:28,627 --> 02:03:32,397
OKAY SO ALL OF THIS IS BUILT ON

3436
02:03:32,397 --> 02:03:39,804
THE MA-10 PLATFORM WHICH IS

3437
02:03:39,804 --> 02:03:40,872
BASED ON SEQUENCE WHICH WE

3438
02:03:40,872 --> 02:03:51,082
HAVEN'T SEEN IN A LONG, LONG

3439
02:03:51,082 --> 02:03:52,284
TIME AND SOMETHING--SO SOME WORK

3440
02:03:52,284 --> 02:03:54,953
THAT JOHN POWERS IN THE LAB HAS

3441
02:03:54,953 --> 02:03:57,555
LED, HAS REALLY TAKEN ADVANTAGE

3442
02:03:57,555 --> 02:03:59,124
OF THE FRAGMENT SYSTEM THAT WE

3443
02:03:59,124 --> 02:04:04,562
USE TO GENERATE OUR INFECTIOUS

3444
02:04:04,562 --> 02:04:06,898
CLONE, TYPICALLY WE USE 6 OR 7

3445
02:04:06,898 --> 02:04:12,938
FRAGMENTS AND THIS IS FROM AND

3446
02:04:12,938 --> 02:04:17,175
TOGETHER WITH THE TRANSCRIBED,

3447
02:04:17,175 --> 02:04:19,344
SO, WE DESIGNED FRAGMENT F TO

3448
02:04:19,344 --> 02:04:21,713
ENCODE THE ENTIRETY OF THE SPIKE

3449
02:04:21,713 --> 02:04:26,785
JOIN, AND SO THE REST OF THE

3450
02:04:26,785 --> 02:04:29,020
GENOME HAS THOSE AND THE SB4

3451
02:04:29,020 --> 02:04:33,191
MUTATIONS ARE THERE, BUT WE

3452
02:04:33,191 --> 02:04:35,026
SWAPPED OUT THE SPIKE OR

3453
02:04:35,026 --> 02:04:36,227
WHATEVER THE VARIANT OF SPIKE IS

3454
02:04:36,227 --> 02:04:38,530
THAT WE'RE INTERESTED IN, IN

3455
02:04:38,530 --> 02:04:41,399
THIS CASE ALL OF THESE MUTATIONS

3456
02:04:41,399 --> 02:04:43,702
WENT IN AND THEN A LOT OF TIMES

3457
02:04:43,702 --> 02:04:46,137
WE WILL MAKE A VERSION OF THE

3458
02:04:46,137 --> 02:04:48,573
IRS THAT HAS IT IN PLACE SO THAT

3459
02:04:48,573 --> 02:04:51,176
WE CAN HAVE A REPORTER VIRUS

3460
02:04:51,176 --> 02:04:57,816
TOOL AVAILABLE FOR LIVE VIRUS

3461
02:04:57,816 --> 02:04:58,283
NEUTRALIZATION ASSAYS.

3462
02:04:58,283 --> 02:05:01,419
SO THAT IN WORK HERE, CAN YOU

3463
02:05:01,419 --> 02:05:03,621
SEE THE OMICRON VIRUS CAUSES AGE

3464
02:05:03,621 --> 02:05:04,856
DEPENDENT DEC SO IN YOUNG,

3465
02:05:04,856 --> 02:05:06,725
THERE'S NOT MUCH GOING ON.

3466
02:05:06,725 --> 02:05:08,460
NO WEIGHT LOSS, THE VIRUS IS

3467
02:05:08,460 --> 02:05:10,562
REPLICATING JUST FINE AND WE

3468
02:05:10,562 --> 02:05:14,899
LOOK AT RESPIRATORY FUNCTION,

3469
02:05:14,899 --> 02:05:17,736
SIMPLE BODY TOMOGRAPHY, 10 H

3470
02:05:17,736 --> 02:05:19,037
SPOKES, LIKE DAY 2 OR 3, AGAIN

3471
02:05:19,037 --> 02:05:23,541
NOT MUCH OF A SIGNAL IN YOUNG

3472
02:05:23,541 --> 02:05:24,009
BAC1 INFECTED MICE.

3473
02:05:24,009 --> 02:05:26,945
WHEN WE GO TO A 12 MONTH OLD

3474
02:05:26,945 --> 02:05:29,914
BALC MODEL THOUGH, WE HAVE 2

3475
02:05:29,914 --> 02:05:31,016
DIFFERENT DOSES FOR MID10 TO THE

3476
02:05:31,016 --> 02:05:35,687
FOURTH AND FIFTH HERE.

3477
02:05:35,687 --> 02:05:36,755
THERE'S A LOT MORE WEIGHT LOSS

3478
02:05:36,755 --> 02:05:38,723
THAN THERE WAS WITH THE YOUNG SO

3479
02:05:38,723 --> 02:05:39,691
THERE'S ABSOLUTELY NOTHING BUT

3480
02:05:39,691 --> 02:05:42,060
STILL NOT AS MUCH DISEASE AS YOU

3481
02:05:42,060 --> 02:05:44,729
WOULD SEE IN THE MATTEN INFECTED

3482
02:05:44,729 --> 02:05:44,929
MICE.

3483
02:05:44,929 --> 02:05:47,132
OF COURSE WE'VE ALSO DONE THIS

3484
02:05:47,132 --> 02:05:49,167
WITH BA5 AND SUBSEQUENT FLAVORS

3485
02:05:49,167 --> 02:05:51,269
OF OMICRON, IN THIS CASE, BA5

3486
02:05:51,269 --> 02:05:54,672
HAS A SIMILAR DEC PENE O TYPE TO

3487
02:05:54,672 --> 02:05:55,607
MATTEN, WHERE THERE'S MORTALITY

3488
02:05:55,607 --> 02:05:59,511
THAT DEVELOPS AT A PRETTY

3489
02:05:59,511 --> 02:06:00,612
SIMILAR TIME POINT, RESPIRATORY

3490
02:06:00,612 --> 02:06:02,180
FUNCTIONS ARE SIMILAR SO THESE

3491
02:06:02,180 --> 02:06:05,850
TOOLS ARE REALLY IMPORTANT FOR

3492
02:06:05,850 --> 02:06:11,089
LOOKING AT BREDTH OF VACCINE

3493
02:06:11,089 --> 02:06:11,890
PROTECTION, DIFFERENT DISEASE

3494
02:06:11,890 --> 02:06:14,125
WHERE HAVING A ROBUST MODEL IS

3495
02:06:14,125 --> 02:06:14,526
REALLY IMPORTANT.

3496
02:06:14,526 --> 02:06:16,161
RALPH LIKES TO SAY IT'S EASY TO

3497
02:06:16,161 --> 02:06:18,229
SO YOUR VACCINE WORKS IF YOUR

3498
02:06:18,229 --> 02:06:19,731
CHALLENGE VIRUS DIDN'T MAKE THE

3499
02:06:19,731 --> 02:06:22,734
ANIMAL SICK TO BEGIN WITH SO WE

3500
02:06:22,734 --> 02:06:25,270
WANT A ROBUST VIRUS SO WE CAN BE

3501
02:06:25,270 --> 02:06:27,205
COMTENT IN WHATEVER WE'RE

3502
02:06:27,205 --> 02:06:27,505
TESTING.

3503
02:06:27,505 --> 02:06:29,674
>> YAWN HAS ALSO TAKEN THE
BA5

3504
02:06:29,674 --> 02:06:32,043
INFEBTED MICE OUT TO LATER TIME

3505
02:06:32,043 --> 02:06:32,277
POINTS.

3506
02:06:32,277 --> 02:06:33,912
MOSTLY WITH THE LOWER DOSE SO

3507
02:06:33,912 --> 02:06:34,879
THAT THEY ACTUALLY SURVIVE THAT

3508
02:06:34,879 --> 02:06:38,983
LONG, AND WE ALSO SEE SIGNS OF

3509
02:06:38,983 --> 02:06:39,818
FIBROSIS, THIS IS SERIOUS RED

3510
02:06:39,818 --> 02:06:41,386
STAINING HERE AT LATER TIME

3511
02:06:41,386 --> 02:06:47,192
POINTS IN THOSE BA5 INFECTED

3512
02:06:47,192 --> 02:06:47,425
LUNGS.

3513
02:06:47,425 --> 02:06:48,726
SO SIMILAR PATHOLOGY TO WHAT WE

3514
02:06:48,726 --> 02:06:51,963
SEE IN THE ME10 INFECTED MICE

3515
02:06:51,963 --> 02:06:53,298
WHEREAS WITH THE BAC1 ANIMALS

3516
02:06:53,298 --> 02:06:59,938
NOT SO MUCH WAS HAPPENING EMPLOY

3517
02:06:59,938 --> 02:07:01,272
SO FOR THE LAST LITTLE BIT OF

3518
02:07:01,272 --> 02:07:02,874
THE TALK, I WANT TO TALK ABOUT

3519
02:07:02,874 --> 02:07:04,909
OTHER MODELS AND OTHER CORONA

3520
02:07:04,909 --> 02:07:06,544
VIRUSES BECAUSE GOING WITH A

3521
02:07:06,544 --> 02:07:07,579
TYPICAL MOUSE ADAPTED VIRUS

3522
02:07:07,579 --> 02:07:09,347
APPROACH IS MOST COMMON BUT

3523
02:07:09,347 --> 02:07:11,416
THERE ARE SOME UNEEK TOOLS WE

3524
02:07:11,416 --> 02:07:12,117
CAN USE.

3525
02:07:12,117 --> 02:07:14,018
SO 1 OF THOSE THINS WE DID

3526
02:07:14,018 --> 02:07:18,690
EARLIER IN THE PANDEMIC WAS TO

3527
02:07:18,690 --> 02:07:21,826
WORK WITH J.VICTOR GARCIA'S LAB

3528
02:07:21,826 --> 02:07:23,795
AT UNC BUT MOST RECENTLY MOVED

3529
02:07:23,795 --> 02:07:25,096
TO UNIVERSITY OF ALABAMA.

3530
02:07:25,096 --> 02:07:30,902
HE WAS AN HIV RESEARCHER BUT HIS

3531
02:07:30,902 --> 02:07:33,104
LAB DEVELOPED THESE HUMAN

3532
02:07:33,104 --> 02:07:34,772
ORGANOID PLANT AND THEY CAN GROW

3533
02:07:34,772 --> 02:07:36,741
IT UNDER THE SKIN AND GROW THEM

3534
02:07:36,741 --> 02:07:39,344
AS LUNG CELLS OR SOMETIMES THEY

3535
02:07:39,344 --> 02:07:42,514
ADD HUMANIZATION OF THE MOUSE

3536
02:07:42,514 --> 02:07:44,516
IMMUNE SYSTEM WITH BONE MARROW,

3537
02:07:44,516 --> 02:07:45,683
LIVER, THYMUS, BUT YOU GET THIS

3538
02:07:45,683 --> 02:07:48,419
MOUSE THAT AS A BIG LUMP

3539
02:07:48,419 --> 02:07:49,721
UNDERNEATH ITS FUR AND WHEN A

3540
02:07:49,721 --> 02:07:52,423
CROSS SECTION IS TAKEN HERE AND

3541
02:07:52,423 --> 02:07:56,060
H&  E STAINED IT'S HIGHLY

3542
02:07:56,060 --> 02:07:56,995
VASCULARIZED.

3543
02:07:56,995 --> 02:07:58,129
THERE ARE APPROXIMATIONS OF WHAT

3544
02:07:58,129 --> 02:08:00,565
WOULD BE AN AIR WAY IF THIS WAS

3545
02:08:00,565 --> 02:08:01,533
ACTUALLY IN CONTACT WITH AIR.

3546
02:08:01,533 --> 02:08:04,536
SO YOU CAN SEE WHAT OUR

3547
02:08:04,536 --> 02:08:07,038
PREALVEOLAR SPACE IS, AND LUNG

3548
02:08:07,038 --> 02:08:07,939
STRUCTURE THAT IS IMPEDIMENTS

3549
02:08:07,939 --> 02:08:18,016
SIMILAR TO WHAT WOULD BE IN A

3550
02:08:18,016 --> 02:08:18,216
HUMAN.

3551
02:08:18,216 --> 02:08:21,519
SO THESE ARE HIGHLY INFECTIBLE,

3552
02:08:21,519 --> 02:08:23,188
AND YOU CAN SEE THAT IN THE LUNG

3553
02:08:23,188 --> 02:08:27,058
ONLY MICE THAT DON'T HAVE THE

3554
02:08:27,058 --> 02:08:28,826
RECONSITUTED IMMUNE SYSTEM, THAT

3555
02:08:28,826 --> 02:08:32,530
THIS INFECTION DOES PERSIST OVER

3556
02:08:32,530 --> 02:08:33,031
TIME.

3557
02:08:33,031 --> 02:08:34,465
WHEN WE STAIN, WHAT CELLS IN THE

3558
02:08:34,465 --> 02:08:36,134
LUNG ARE INFECTED HERE AND YOU

3559
02:08:36,134 --> 02:08:38,303
CAN SEE THE SARS NUCLEIC CAPSID

3560
02:08:38,303 --> 02:08:41,139
IS IN RED AND IT'S CO LOCALIZING

3561
02:08:41,139 --> 02:08:42,440
FOR MARKERS FOR EPITHELIAL CELLS

3562
02:08:42,440 --> 02:08:45,910
SO THIS IS CONSISTENT WITH WHAT

3563
02:08:45,910 --> 02:08:46,778
WE WOULD EXPECT.

3564
02:08:46,778 --> 02:08:48,813
AND SO YOU DO BASIC

3565
02:08:48,813 --> 02:08:49,781
CHARACTERIZATION HERE, IT IS

3566
02:08:49,781 --> 02:08:52,083
NICE YOU CAN TEST ANTIVIRALS IN

3567
02:08:52,083 --> 02:08:55,053
HUMAN CELLS IN A QUASI-IN VIVO

3568
02:08:55,053 --> 02:08:56,588
MODEL BUT WHAT I THINK IS REALLY

3569
02:08:56,588 --> 02:08:57,889
INTERESTING IS THAT IN THESE

3570
02:08:57,889 --> 02:08:59,290
MODELS WE'VE ALSO BEEN ABLE TO

3571
02:08:59,290 --> 02:09:01,526
GET INTO LONGER TERM INFECTION,

3572
02:09:01,526 --> 02:09:08,666
LOOKING AT LONG-TERM TOPOLOGY

3573
02:09:08,666 --> 02:09:15,206
AND EVEN IN THIS LONG-TERM

3574
02:09:15,206 --> 02:09:17,108
MEASURING SYSTEM, YOU SEE

3575
02:09:17,108 --> 02:09:18,476
MARKERS OF FIBROSIS MIMICKING

3576
02:09:18,476 --> 02:09:21,846
WHATY - SEE IN PEOPLE AND IN

3577
02:09:21,846 --> 02:09:24,649
MICE, SO I THINK BEING OPEN

3578
02:09:24,649 --> 02:09:25,583
MINDED TO NONTRADITIONAL MODELS

3579
02:09:25,583 --> 02:09:27,085
CAN BE PRETTY PRODUCTIVE.

3580
02:09:27,085 --> 02:09:33,391
AND THEN FINALLY I WANT TO TALK

3581
02:09:33,391 --> 02:09:35,460
ABOUT LONG-TERM MERS MODELS.

3582
02:09:35,460 --> 02:09:38,830
SO PREVIOUSLY WE HAD ADAM

3583
02:09:38,830 --> 02:09:42,767
COCKEREL WHO DEVELOPED A

3584
02:09:42,767 --> 02:09:48,006
TRANSGENIC 38 MODEL FOR

3585
02:09:48,006 --> 02:09:49,507
MERCOMPATTIBILITY AND THE

3586
02:09:49,507 --> 02:09:51,142
COMPATIBILITY WHERE IT CANNOT

3587
02:09:51,142 --> 02:09:57,649
BIEBD TO THE DP4454 RECEPTOR, HE

3588
02:09:57,649 --> 02:09:59,651
ENDED UP WITH A VIRUS THAT WAS

3589
02:09:59,651 --> 02:10:02,620
HIGHLY PATHOGENIC AND LETHAL IN

3590
02:10:02,620 --> 02:10:03,788
A MOUSE MODEL.

3591
02:10:03,788 --> 02:10:04,622
MORE RECENTLY HEATHER

3592
02:10:04,622 --> 02:10:05,723
[INDISCERNIBLE] HAS TAKEN THIS

3593
02:10:05,723 --> 02:10:07,825
AND INSTEAD OF LOOKING AT ONLY

3594
02:10:07,825 --> 02:10:09,227
ACUTE INFECTION, SHE WANTED TO

3595
02:10:09,227 --> 02:10:12,230
SEE IF IN A LONG-TERM MERS MODEL

3596
02:10:12,230 --> 02:10:14,732
TO WE SEE SIMILAR SIGNS OF DEC,

3597
02:10:14,732 --> 02:10:15,566
SIMILAR ASSPECS OF CHRONIC

3598
02:10:15,566 --> 02:10:18,603
INFECTION AS WE DO WITH SARS 2.

3599
02:10:18,603 --> 02:10:20,371
AND IT SEEMS LIKE THIS IS GOING

3600
02:10:20,371 --> 02:10:22,206
TO BE THE CASE.

3601
02:10:22,206 --> 02:10:23,574
WE HAVEN'T GOTTEN THAT DEEPLY

3602
02:10:23,574 --> 02:10:26,244
INTO IT AS STANLEY'S LAB HAS BUT

3603
02:10:26,244 --> 02:10:29,914
HEATHER IS DOING COOL STUFF

3604
02:10:29,914 --> 02:10:30,214
HERE.

3605
02:10:30,214 --> 02:10:32,517
SHE AND NICK HAVE DONE SINGLE

3606
02:10:32,517 --> 02:10:37,755
CELL ANALYSIS ON THESE MERS

3607
02:10:37,755 --> 02:10:39,757
INFECTED MICE, SEE ALL THE

3608
02:10:39,757 --> 02:10:40,825
DIFFERENT MAPPED POPULATIONS

3609
02:10:40,825 --> 02:10:41,025
HERE.

3610
02:10:41,025 --> 02:10:42,794
LOOKING AT 30 DAYS POST

3611
02:10:42,794 --> 02:10:44,529
INFECTION THEY DID, ON DAY 3 AND

3612
02:10:44,529 --> 02:10:47,098
30 TO CAPTURE EARLY AND LATE

3613
02:10:47,098 --> 02:10:50,835
TIME POINT AND LOOKING AT THE

3614
02:10:50,835 --> 02:10:51,669
TOP DIFFERENTIALLY EXPRESSED

3615
02:10:51,669 --> 02:10:52,904
GENES HERE AND COMPARING THEM TO

3616
02:10:52,904 --> 02:10:56,174
WHAT WE SEE IN A SARS-COV-2

3617
02:10:56,174 --> 02:10:57,675
INFECTION, SOME OF THE CLASSIC

3618
02:10:57,675 --> 02:10:58,643
CATEGORIES THAT ARE INTERESTED

3619
02:10:58,643 --> 02:11:00,845
AND ARE THERE MARKERS OF

3620
02:11:00,845 --> 02:11:03,081
FIBROSIS, COMPLEMENT COMES UP A

3621
02:11:03,081 --> 02:11:05,983
LOT IN SARS-COV-2 INFECTED

3622
02:11:05,983 --> 02:11:09,854
LUNGS, AND SO HERE, WE'RE

3623
02:11:09,854 --> 02:11:12,123
LOOKING AT SBP1 WHICH IS THE

3624
02:11:12,123 --> 02:11:12,890
MARKER OF FIBROTIC MACROPHAGES

3625
02:11:12,890 --> 02:11:16,060
AND YOU CAN SEE THAT IN THE

3626
02:11:16,060 --> 02:11:16,694
ALVEOLAR MACROPHAGE POPULATION

3627
02:11:16,694 --> 02:11:19,931
THAT EVEN IN ANIMALS THAT HAD

3628
02:11:19,931 --> 02:11:21,966
MODERATE DISEASE, AND ALSO MORE

3629
02:11:21,966 --> 02:11:23,167
SEVERE DISEASE AS MEASURED BY

3630
02:11:23,167 --> 02:11:26,270
THE WEIGHT LOSS THAT WE HAVE A

3631
02:11:26,270 --> 02:11:28,106
LOT OF THE SBP1 EXPRESSION IN

3632
02:11:28,106 --> 02:11:30,375
THIS POPULATION SO THIS ANALYSIS

3633
02:11:30,375 --> 02:11:32,009
IS REALLY PRELIMINARY BUT I KNOW

3634
02:11:32,009 --> 02:11:33,277
HEATHER IS EXCITED TO DO MORE

3635
02:11:33,277 --> 02:11:34,245
WITH IT.

3636
02:11:34,245 --> 02:11:35,646
SO WITH THAT, HOPEFULLY I'VE

3637
02:11:35,646 --> 02:11:38,416
SHOWN YOU THAT EVEN THOUGH HUMAN

3638
02:11:38,416 --> 02:11:40,752
CORONA VIRUSES DON'T ALWAYS

3639
02:11:40,752 --> 02:11:41,919
INFEJT MICE INITIALLY, WE CAN

3640
02:11:41,919 --> 02:11:44,222
KIND OF FIX THAT PROBLEM AND

3641
02:11:44,222 --> 02:11:45,456
WHILE THAT TAKES SOME

3642
02:11:45,456 --> 02:11:47,325
ENGINEERING WE END UP WITH

3643
02:11:47,325 --> 02:11:49,427
MODELS THAT ARE STILL HIGHLY

3644
02:11:49,427 --> 02:11:50,962
REFLECTIVE OF HUMAN DEC AND THAT

3645
02:11:50,962 --> 02:11:54,565
WE CAN USE TO TEASE APART SOME

3646
02:11:54,565 --> 02:11:56,534
FINELY MECHANISTIC DETAILS OF

3647
02:11:56,534 --> 02:11:58,002
WHAT'S HAPPENING, AND DISSECT

3648
02:11:58,002 --> 02:11:59,237
LUNG PATHOLOGY AND FUNCTION IN

3649
02:11:59,237 --> 02:12:00,838
WAYS WE CAN'T DO IN HUMAN

3650
02:12:00,838 --> 02:12:02,640
POPULATIONS AND 1 THING I LOVE

3651
02:12:02,640 --> 02:12:05,309
ABOUT THESE VIRUSES, SARS, MERS

3652
02:12:05,309 --> 02:12:08,079
AND SARS 2, ALL CAUSE PRETTY

3653
02:12:08,079 --> 02:12:09,947
SIMILAR DEC PATHWAYS AND THERE'S

3654
02:12:09,947 --> 02:12:12,183
A REAL OPPORTUNITY THERE I THINK

3655
02:12:12,183 --> 02:12:15,453
TO FIND COMMON PATH WAGHT IS,

3656
02:12:15,453 --> 02:12:20,525
COMMON THERAPEUTICS AND

3657
02:12:20,525 --> 02:12:22,326
HOPEFULLY BE PREPARED FORMENT

3658
02:12:22,326 --> 02:12:23,594
NEXT SARS VIRUS IS.

3659
02:12:23,594 --> 02:12:24,862
I WANT TO THANK ALL PEOPLE WHO

3660
02:12:24,862 --> 02:12:26,497
HELPED WITH THIS WORK.

3661
02:12:26,497 --> 02:12:28,232
I HIGHLIGHTED PEOPLE FROM THE

3662
02:12:28,232 --> 02:12:31,035
CBRG BUT THERE ARE A LOT MORE OF

3663
02:12:31,035 --> 02:12:32,804
US WHO ALSO AND SUPPORT IN

3664
02:12:32,804 --> 02:12:34,639
DIFFERENT WAYS, THE PATHOLOGIST

3665
02:12:34,639 --> 02:12:36,741
STEPHANIE AND JACK HAVE BEEN

3666
02:12:36,741 --> 02:12:40,778
REALLY, REALLY CRITICAL TO THIS.

3667
02:12:40,778 --> 02:12:45,750
THE MARSICO LUNG INSTITUTE,

3668
02:12:45,750 --> 02:12:47,251
COLLABORATORS, AND GARCIA LAB

3669
02:12:47,251 --> 02:12:47,985
COLLABORATORS, AND WITH THAT I

3670
02:12:47,985 --> 02:12:49,454
WOULD LOVE TO TAKE ANY

3671
02:12:49,454 --> 02:12:49,954
QUESTIONS.

3672
02:12:49,954 --> 02:12:50,788
>> THANK YOU SO MUCH.

3673
02:12:50,788 --> 02:12:55,560
WE HAVE TIME FOR QUESTIONS.

3674
02:12:55,560 --> 02:12:58,696
NNICE TALK, REALLY ENJOYED IT,

3675
02:12:58,696 --> 02:13:07,338
HOW ABOUT THE HOST STRAINS, YOU

3676
02:13:07,338 --> 02:13:10,174
FOUND THAT SUBLINEAGES OR

3677
02:13:10,174 --> 02:13:12,844
SUBSTRAIN THEY HAVE DIFFERENT

3678
02:13:12,844 --> 02:13:17,648
DEC SEVERITY, HAVE YOU

3679
02:13:17,648 --> 02:13:20,418
INVESTIGATE WITH WHAT KIND OF

3680
02:13:20,418 --> 02:13:22,186
GENETIC LOCI THAT CORRELATE WITH

3681
02:13:22,186 --> 02:13:22,487
THE DISEASE?

3682
02:13:22,487 --> 02:13:25,556
>> SO WE HAVE DONE A
NUMBER OF

3683
02:13:25,556 --> 02:13:28,559
KREENS LOOKING FOR LOCI THAT ARE

3684
02:13:28,559 --> 02:13:31,329
ASSOCIATED WITH ACUTE INFECTION,

3685
02:13:31,329 --> 02:13:36,767
WE HAVEN'T DONE A FULL LONG-TERM

3686
02:13:36,767 --> 02:13:38,536
DISEASE ANALYSIS YET JUST

3687
02:13:38,536 --> 02:13:39,837
BECAUSE THE NUMBER OF MICE WE

3688
02:13:39,837 --> 02:13:42,139
WOULD NEED TO TAKE OUT TO DAY 30

3689
02:13:42,139 --> 02:13:43,474
WOULD BE PRETTY EXTREME.

3690
02:13:43,474 --> 02:13:44,842
WHAT WE'RE MORE INTERESTED IN

3691
02:13:44,842 --> 02:13:47,512
DOING IS TAKING HIGH AND LOW

3692
02:13:47,512 --> 02:13:50,948
OUTLIERS WITH THAT DAY 30

3693
02:13:50,948 --> 02:13:52,683
FIBROSIS PHENOTYPE AND DOING AN

3694
02:13:52,683 --> 02:13:56,120
F2 PROMPT SO YOU CAN HAVE

3695
02:13:56,120 --> 02:13:56,487
ANALYSIS THERE.

3696
02:13:56,487 --> 02:14:01,859
WE DO KNOW THAT THE GENETICS OF

3697
02:14:01,859 --> 02:14:03,561
EVERY CC MOUSE SINCE THEY'RE

3698
02:14:03,561 --> 02:14:06,697
INBRED AT THIS POINT SO WE CAN

3699
02:14:06,697 --> 02:14:08,633
LOOK SPECIFICALLY FOR LINES THAT

3700
02:14:08,633 --> 02:14:10,568
MAYBE HAVE LOCI THAT WE KNEW

3701
02:14:10,568 --> 02:14:11,903
ABOUT PREVIOUSLY SO WE COULD SEE

3702
02:14:11,903 --> 02:14:13,671
DOES THIS STILL MATTER FOR

3703
02:14:13,671 --> 02:14:15,106
LONG-TERM DEC OR IF WE SAY WE

3704
02:14:15,106 --> 02:14:17,174
KEEP HITTING ON THE SAME

3705
02:14:17,174 --> 02:14:18,442
CHROMOSOME LINE LOCUST BECAUSE

3706
02:14:18,442 --> 02:14:19,677
IT SEEMS TO OVERPOWER EVERYTHING

3707
02:14:19,677 --> 02:14:25,449
ELSE, WE CAN SPECIFICALLY

3708
02:14:25,449 --> 02:14:26,284
EXCLUDE THAT.

3709
02:14:26,284 --> 02:14:28,419
THAT'S IN THE FUTURE.

3710
02:14:28,419 --> 02:14:28,853
>> STANLEY?

3711
02:14:28,853 --> 02:14:31,289
>> I HAD A QUESTION ABOUT
THE

3712
02:14:31,289 --> 02:14:32,390
COLLABORATIVE CROSS FIND, SO

3713
02:14:32,390 --> 02:14:33,791
ORIGINALLY THE IDEA WAS TO

3714
02:14:33,791 --> 02:14:34,392
DEVELOP A THOUSAND DIFFERENT

3715
02:14:34,392 --> 02:14:38,262
LINE ANDS I DON'T KNOW IF THEY

3716
02:14:38,262 --> 02:14:41,265
DEVELOPED THAT BUT UNC FOLKS

3717
02:14:41,265 --> 02:14:43,167
HAVE ACCESS TO THE FACILITY.

3718
02:14:43,167 --> 02:14:44,835
HOW DO YOU DECIDE WHICH 1 YOU

3719
02:14:44,835 --> 02:14:45,603
USE?

3720
02:14:45,603 --> 02:14:47,605
DO YOU JUST PICK 50 AND 25, YOU

3721
02:14:47,605 --> 02:14:49,040
GET A RANGE YOU DON'T HAVE TO

3722
02:14:49,040 --> 02:14:51,509
WORRY ABOUT THE OTHER THOUSAND?

3723
02:14:51,509 --> 02:14:53,177
NI THINK THERE ARE ABOUT SEIVET

3724
02:14:53,177 --> 02:14:55,479
LINEUPS THAT ACTUALLY MADE IT

3725
02:14:55,479 --> 02:14:57,181
FULL INBREEDING, 1000 IS A

3726
02:14:57,181 --> 02:14:58,349
CRAZY, CRAZY IDEA.

3727
02:14:58,349 --> 02:14:59,283
ONE HUNDRED WOULD BE NICE.

3728
02:14:59,283 --> 02:15:00,351
THEY DIDN'T GET THERE.

3729
02:15:00,351 --> 02:15:05,456
THERE WAS A MASSIVE BREEDING

3730
02:15:05,456 --> 02:15:06,524
CAPACITY BOTTLENECK THAT BRED IN

3731
02:15:06,524 --> 02:15:08,326
GENERATION 8 OR SO WHERE A LOT

3732
02:15:08,326 --> 02:15:09,860
OF LINES DIED OUT BUT WHAT IS

3733
02:15:09,860 --> 02:15:11,329
LEFT IS STILL INCREDIBLE

3734
02:15:11,329 --> 02:15:13,064
LOAMACYY USEABLE.

3735
02:15:13,064 --> 02:15:14,732
WE HAVE A STRONG HISTORY OF

3736
02:15:14,732 --> 02:15:17,735
HAVING INFECTED THESE MICE WITH

3737
02:15:17,735 --> 02:15:18,069
ORIGINAL SARS.

3738
02:15:18,069 --> 02:15:20,104
SARS 2, SO WE CAN PRETTY WELL GO

3739
02:15:20,104 --> 02:15:22,206
IN AND SAY, THESE LINES ISSUES

3740
02:15:22,206 --> 02:15:24,809
THESE LINES, IF YOU ARE COMING

3741
02:15:24,809 --> 02:15:26,944
INTO THE CC NOT HAVING USED IT

3742
02:15:26,944 --> 02:15:29,614
BUYER, WHAT I WOULD RECOMMEND IS

3743
02:15:29,614 --> 02:15:31,148
GET 10 LINES, ANY 10 LINE ANDS

3744
02:15:31,148 --> 02:15:32,917
YOU WILL ALMOST CERTAINLY SEE A

3745
02:15:32,917 --> 02:15:34,085
LOT OF PHENOTYPIC VARIATION

3746
02:15:34,085 --> 02:15:35,486
BETWEEN THOSE AND THEN PICK THE

3747
02:15:35,486 --> 02:15:37,355
1S THAT ARE INTERESTED TO YOU

3748
02:15:37,355 --> 02:15:40,157
AND DO AN F2 CROSS IS THE

3749
02:15:40,157 --> 02:15:40,891
FASTEST WAY TOWARDS MAPPING, IF

3750
02:15:40,891 --> 02:15:42,893
YOU WANT TO YOU CAN GET ALL 71

3751
02:15:42,893 --> 02:15:44,829
IN AND INFECT ALL OF THEM AND

3752
02:15:44,829 --> 02:15:47,832
GET THE FULL RANGE.

3753
02:15:47,832 --> 02:15:50,034
WHEN YOU'RE GETTING THOSE 10

3754
02:15:50,034 --> 02:15:51,302
LINES DEPENDING ON WHO'S DOING

3755
02:15:51,302 --> 02:15:52,737
THE EXPERIMENT IN OUR GROUP,

3756
02:15:52,737 --> 02:15:53,638
WHAT THEY'RE EXPERIENCE WITH

3757
02:15:53,638 --> 02:15:55,306
MICE IS, WE MIGHT SAY, LIKE GIVE

3758
02:15:55,306 --> 02:15:58,175
US THE 1S THAT AREN'T JERKS SO

3759
02:15:58,175 --> 02:16:00,378
THAT WE DON'T HAVE TO WORRY

3760
02:16:00,378 --> 02:16:03,447
ABOUT ESCAPES IN THE BL3.

3761
02:16:03,447 --> 02:16:05,082
OR IF IT'S SOMETHING WE KNOW WE

3762
02:16:05,082 --> 02:16:06,417
NEED TO GET THROUGH PRETTY

3763
02:16:06,417 --> 02:16:08,719
QUICKLY, WE WILL ASK FOR GOOD

3764
02:16:08,719 --> 02:16:10,454
BREEDERS BECAUSE SOME OF THEM

3765
02:16:10,454 --> 02:16:12,423
WILL HAVE LITTERS OF 2-3 MICE

3766
02:16:12,423 --> 02:16:14,191
ONLY SO GETTING ENOUGH ANIMALS

3767
02:16:14,191 --> 02:16:15,660
TO COMPLETE YOUR EXPERIMENT IN A

3768
02:16:15,660 --> 02:16:16,927
TIMELY MANNER WITH A ROBUST

3769
02:16:16,927 --> 02:16:18,295
NUMBER OF MICE CAN BE

3770
02:16:18,295 --> 02:16:19,163
CHALLENGING SO YOU DON'T WANT

3771
02:16:19,163 --> 02:16:21,132
THAT TO BE A LIMITATION DOWN THE

3772
02:16:21,132 --> 02:16:21,332
ROAD.

3773
02:16:21,332 --> 02:16:24,402
SO IF YOU'RE STARTING OFF 10

3774
02:16:24,402 --> 02:16:28,806
LINES, GOOD BREEDERS, NICE MICE.

3775
02:16:28,806 --> 02:16:29,874
>> ANOTHER QUESTION,
OTHERWISE

3776
02:16:29,874 --> 02:16:33,778
WE CAN ASK DURING THE PANEL

3777
02:16:33,778 --> 02:16:34,378
SESSION AS WELL.

3778
02:16:34,378 --> 02:16:34,812
ALL RIGHT.

3779
02:16:34,812 --> 02:16:36,447
WE WILL ASK IT DURING THE PANEL

3780
02:16:36,447 --> 02:16:37,682
SESSION EMPLOY SO THANK YOU VERY

3781
02:16:37,682 --> 02:16:47,491
MUCH. 

3782
02:16:47,491 --> 02:16:48,659
>> THANK YOU.

3783
02:16:48,659 --> 02:16:51,629
>> OUR NEXT SPEAKER IS
JUSTIN

3784
02:16:51,629 --> 02:16:54,031
FRERE, FROM NEW YORK UNIVERSITY

3785
02:16:54,031 --> 02:16:55,933
WHO WILL DISCUSS LEVERAGING THE

3786
02:16:55,933 --> 02:16:58,369
GOLDEN HAMSTER MODEL OF

3787
02:16:58,369 --> 02:17:00,571
SARS-COV-2 INFECTION TO DEFINE

3788
02:17:00,571 --> 02:17:03,607
SHORT AND LONG-TERM CONSEQUENCES

3789
02:17:03,607 --> 02:17:04,408
OF DISEASE EMPLOY.

3790
02:17:04,408 --> 02:17:06,243
>> SAW AM, THANK YOU SO
MUCH FOR

3791
02:17:06,243 --> 02:17:08,379
THE INTRODUCTION, I AM JUSTIN

3792
02:17:08,379 --> 02:17:11,182
FREER, AND I AM A POST DOC AT

3793
02:17:11,182 --> 02:17:14,151
THE LABORATORY AT NYU AND I'M

3794
02:17:14,151 --> 02:17:17,388
EXCITED TO TALK TO YOU ABOUT THE

3795
02:17:17,388 --> 02:17:18,789
SARS-COV-2 HAMSTER INMODEL

3796
02:17:18,789 --> 02:17:20,024
INFECTION.

3797
02:17:20,024 --> 02:17:22,359
SO CARS KICKOFF 2 AND OOTS A

3798
02:17:22,359 --> 02:17:24,428
RESPIRATORY VIRUS AND REPLICATES

3799
02:17:24,428 --> 02:17:25,563
RAPIDLY IN THE RESPIRATORY

3800
02:17:25,563 --> 02:17:25,996
TRACT.

3801
02:17:25,996 --> 02:17:28,499
THIS IN TURNS CAUSES A MASSIVE

3802
02:17:28,499 --> 02:17:32,269
AMOUNT OF INFLALLATION AND ALL

3803
02:17:32,269 --> 02:17:42,847
THE  PULMONARY DISTRESS--IT SEES

3804
02:17:45,616 --> 02:17:49,153
IN EVERY ORGAN FROM HEAD TO TOES

3805
02:17:49,153 --> 02:17:51,622
AND HAS BECOME DEFINED BY

3806
02:17:51,622 --> 02:17:53,824
NEUROLOGIC SEQUEL I SUCH AS

3807
02:17:53,824 --> 02:17:54,325
[INDISCERNIBLE].

3808
02:17:54,325 --> 02:17:56,927
SO THE CLINICAL PICTURE IT'S

3809
02:17:56,927 --> 02:17:59,930
MORE COMPLICATED THAT A LOT OF

3810
02:17:59,930 --> 02:18:01,332
PATIENTS, THE SYMPTOMS DON'T

3811
02:18:01,332 --> 02:18:03,400
FADE AFTER THE VIRUS CLEARED AND

3812
02:18:03,400 --> 02:18:06,604
THEY STILL HAVE SYMPTOMOLOGY OR

3813
02:18:06,604 --> 02:18:07,838
NEW SYMPTOMOLOGY KNOWN AS LONG

3814
02:18:07,838 --> 02:18:08,172
COVID.

3815
02:18:08,172 --> 02:18:09,507
SO AGAIN THIS AFFECTS EVERY

3816
02:18:09,507 --> 02:18:12,143
ORGAN FROM THE HEAD TO THE TOE

3817
02:18:12,143 --> 02:18:15,179
ANDS NOTABLY LYE CHARACTERIZED

3818
02:18:15,179 --> 02:18:17,748
BY ABNORMALITIES, BRAIN FOG,

3819
02:18:17,748 --> 02:18:19,016
DEPRESSION, ANXIETY, CHRONIC

3820
02:18:19,016 --> 02:18:19,383
PAIN.

3821
02:18:19,383 --> 02:18:21,018
SO IN THE LAB, A LOT OF OUR WORK

3822
02:18:21,018 --> 02:18:23,454
OVER THE PAST FEW YEARS HAS BEEN

3823
02:18:23,454 --> 02:18:25,723
TRYING TO SEE HOW IT'S MEDIATING

3824
02:18:25,723 --> 02:18:27,424
THESE PATHOLOGIES BOTH AT THE

3825
02:18:27,424 --> 02:18:28,893
ACUTE INFECTION TIME POINTSAs

3826
02:18:28,893 --> 02:18:30,261
WELL AS AFTER VIRAL CLEARANCE

3827
02:18:30,261 --> 02:18:32,763
AND HOW IS IT DOING THIS IN

3828
02:18:32,763 --> 02:18:34,098
INFECTED TISSUES LIKE THE LUNGS

3829
02:18:34,098 --> 02:18:36,534
AS WELL AS UNINFECTED TISSUES

3830
02:18:36,534 --> 02:18:38,035
OUTSIDE THE RESPIRATORY TRACT.

3831
02:18:38,035 --> 02:18:41,205
AND DOING THIS IS USING THE

3832
02:18:41,205 --> 02:18:42,273
GOLDEN HAMSTER MODEL, AND IT'S

3833
02:18:42,273 --> 02:18:44,441
BEEN REALLY NICE FOR US BECAUSE

3834
02:18:44,441 --> 02:18:47,645
IT HAS INDIG NOSA2, THE I HAVE

3835
02:18:47,645 --> 02:18:50,548
ROLL RECEPTOR FOR SARS-COV-2 AND

3836
02:18:50,548 --> 02:18:52,116
THAT'S SIMILAR TO HUMAN ACE 2,

3837
02:18:52,116 --> 02:18:54,084
AND IT INTERACTING WITH THE

3838
02:18:54,084 --> 02:18:54,418
SPIKE PROTEIN.

3839
02:18:54,418 --> 02:18:57,121
AND WHAT'S NICE IS THAT HAS ARK

3840
02:18:57,121 --> 02:18:58,322
LOWEDITOUS INFECT WILD-TYPE

3841
02:18:58,322 --> 02:18:59,857
HAMSTERS WITH NATURALLY

3842
02:18:59,857 --> 02:19:01,358
OCCURRING VARIANTS OF SARS-COV-2

3843
02:19:01,358 --> 02:19:03,327
WITHOUT HAVING TO GENETIC LIE

3844
02:19:03,327 --> 02:19:05,496
MODIFY THE HAMSTER OR THE VIRUS

3845
02:19:05,496 --> 02:19:09,266
ITSELF SO WE DON'T REALLY NEED

3846
02:19:09,266 --> 02:19:09,633
HAMSTER TRAINS.

3847
02:19:09,633 --> 02:19:12,336
SO 1 OF THE UPSIDES OF THIS IS

3848
02:19:12,336 --> 02:19:14,939
IT'S PRETTY SIMILAR TO WHAT WE

3849
02:19:14,939 --> 02:19:18,676
SEE IN HUMAN ANDS AS A RESULT WE

3850
02:19:18,676 --> 02:19:22,479
SEE GOOD TISSUE IN THE HAM

3851
02:19:22,479 --> 02:19:24,381
TERHOST, SO WE CAN SEE THE

3852
02:19:24,381 --> 02:19:25,816
STAINING HERE IN SARS-COV-2 AND

3853
02:19:25,816 --> 02:19:28,319
S, RED AND GREEN, IN THE LUNGS

3854
02:19:28,319 --> 02:19:30,654
AND IN THE LUNGS OF INFECTED

3855
02:19:30,654 --> 02:19:34,658
HAMSTERS AND HERE ON THE RIGHT

3856
02:19:34,658 --> 02:19:36,727
WE SEE 3D IMMUNO HISTOCHEMICAL

3857
02:19:36,727 --> 02:19:38,596
LABELING AND 3D IMAGING IN THE

3858
02:19:38,596 --> 02:19:41,298
LUNGS OF THESE SAME HAMSTERS IN

3859
02:19:41,298 --> 02:19:42,566
ADDITION ALVEOLAR SECTION, WE

3860
02:19:42,566 --> 02:19:43,300
CAN USELESS SEE INFECTION OF

3861
02:19:43,300 --> 02:19:46,003
SOME OF THESE SMALL AND MEDIUM

3862
02:19:46,003 --> 02:19:47,037
SIZED BRONCHIALS WHICH AGAIN IS

3863
02:19:47,037 --> 02:19:49,139
VERY SIMILAR TO WHAT WE SEE IN

3864
02:19:49,139 --> 02:19:49,506
HUMANS.

3865
02:19:49,506 --> 02:19:51,308
SO AGAIN, THE OTHER NICE THING

3866
02:19:51,308 --> 02:19:53,110
IS THAT AS VARIANTS HAVE EMERGED

3867
02:19:53,110 --> 02:19:54,278
IN HUMANS THROUGHOUT THE

3868
02:19:54,278 --> 02:19:55,913
PANDEMIC, THE FACT THAT THE ICE

3869
02:19:55,913 --> 02:19:58,949
2 RECEPTOR IN HAMSTERS IS PRETTY

3870
02:19:58,949 --> 02:20:00,751
SIMILAR TO THE RECEPTOR IN

3871
02:20:00,751 --> 02:20:03,153
HUMANS MEANS THE HAMSTERS CAN BE

3872
02:20:03,153 --> 02:20:05,923
INFECKED WITHOUT HAVING TO

3873
02:20:05,923 --> 02:20:06,991
GENETICALLY MODIFY THEM OR ADAPT

3874
02:20:06,991 --> 02:20:09,426
THEM IN IMI WAY, AND WHAT'S NICE

3875
02:20:09,426 --> 02:20:11,428
IS THEY CAUSE PATHOLOGY, SO

3876
02:20:11,428 --> 02:20:12,463
WE'RE SHOWING THE PATHOLOGY

3877
02:20:12,463 --> 02:20:16,000
CAUSED BY A COUPLE OF DIFFERENT

3878
02:20:16,000 --> 02:20:16,267
VARIANTS.

3879
02:20:16,267 --> 02:20:18,168
SO IN HEALTHY LUNGS HAVE YOU

3880
02:20:18,168 --> 02:20:19,904
WHITE OPEN AIR WAY SPACES, THIS

3881
02:20:19,904 --> 02:20:21,538
IS IMPORTANT FOR LUNG

3882
02:20:21,538 --> 02:20:22,840
FUNCTIONING AND HOWEVER ONCE WE

3883
02:20:22,840 --> 02:20:24,241
GET INFECTED WITH THE WASHINGTON

3884
02:20:24,241 --> 02:20:26,377
STRAIN, CAN YOU SEE DARK PURPLE

3885
02:20:26,377 --> 02:20:28,112
OCCURRING IN THE LUNGS SO THIS

3886
02:20:28,112 --> 02:20:29,313
THE SCIENCE OF THESE INTO THE

3887
02:20:29,313 --> 02:20:32,316
LUNGS AND FURTHER MORE WHEN WE

3888
02:20:32,316 --> 02:20:34,551
INFECT HAMSTERS, YOU CAN SEE

3889
02:20:34,551 --> 02:20:35,686
VERY SIMILAR PATHOLOGIES EVEN

3890
02:20:35,686 --> 02:20:37,821
SOMETIMES CHANGING IN THEIR

3891
02:20:37,821 --> 02:20:39,323
SEVERITY WITH SPECIFIC VARIANT

3892
02:20:39,323 --> 02:20:42,493
STRAINS, THIS HAS BEEN A NICE

3893
02:20:42,493 --> 02:20:43,127
TOOL FOR THAT.

3894
02:20:43,127 --> 02:20:44,828
BUT EVEN MORE THAN SARS, THE

3895
02:20:44,828 --> 02:20:47,898
HAMSTER IS ALSO A MODEL FOR

3896
02:20:47,898 --> 02:20:51,568
INFLUENZA VIRUS IN PARTICULAR

3897
02:20:51,568 --> 02:20:53,437
H1N1 INFLUENZA WE WERE WITH THE

3898
02:20:53,437 --> 02:20:55,205
2009 STRAIN AND WE CAN SEE IN

3899
02:20:55,205 --> 02:21:01,946
HAMSTER LUNGS, HERE WE'RE

3900
02:21:01,946 --> 02:21:03,280
STAINING FOR IBAC1, AND AS IN

3901
02:21:03,280 --> 02:21:06,750
FLU, YOU SEE SIGNS OF FLU

3902
02:21:06,750 --> 02:21:09,753
PNEUMONIA, AND YOU GET NICE

3903
02:21:09,753 --> 02:21:10,187
INFILTRATION.

3904
02:21:10,187 --> 02:21:11,722
SO THIS FLU MODEL HAS BEEN

3905
02:21:11,722 --> 02:21:13,123
USEFUL IN OUR STUDY OF SARS AS

3906
02:21:13,123 --> 02:21:15,326
WE'VE BEEN ABLE TO COMPLETE SARS

3907
02:21:15,326 --> 02:21:16,860
AND KICKOFF 2 AND FLU SIDE BY

3908
02:21:16,860 --> 02:21:18,495
SIDE AND LOOK AT DIFFERENCES IN

3909
02:21:18,495 --> 02:21:19,697
HOW THEY'RE CAUGHT IN THE

3910
02:21:19,697 --> 02:21:21,532
DISEASE BY DOG COMPARISONS

3911
02:21:21,532 --> 02:21:31,909
BETWEEN THE VIRUSES. 

3912
02:21:32,576 --> 02:21:33,677
SO IN GENERAL, I'VE EXCITED TO

3913
02:21:33,677 --> 02:21:35,212
TELL YOU THE STORY ABOUT HOW

3914
02:21:35,212 --> 02:21:37,848
WE'VE BEEN TRYING TO MODEL THE

3915
02:21:37,848 --> 02:21:39,516
LONG ACUTE AND SARS-COV-2

3916
02:21:39,516 --> 02:21:39,883
INFECTION.

3917
02:21:39,883 --> 02:21:41,418
THIS PROJECT STARTED OUT A FEW

3918
02:21:41,418 --> 02:21:42,820
YEARS AGO, RIGHT WITH WHEN WE

3919
02:21:42,820 --> 02:21:44,321
WERE FIRST STARTING TO LEARN

3920
02:21:44,321 --> 02:21:45,089
ABOUT LONG COVID.

3921
02:21:45,089 --> 02:21:46,457
SO OUR FIRST ATTEMPT TO TRY CAN

3922
02:21:46,457 --> 02:21:49,393
MODEL THIS IN HAMSTERS WAS WE

3923
02:21:49,393 --> 02:21:51,328
REALLY NEED TO DO A SYSTEMIC

3924
02:21:51,328 --> 02:21:52,596
SCREEN, LOOKINGA THE ORGANS THAT

3925
02:21:52,596 --> 02:21:54,732
WERE IN THE AFFECTED HAMSTER,

3926
02:21:54,732 --> 02:21:55,899
AND REDUCING ANY PATHOLOGIES

3927
02:21:55,899 --> 02:21:57,368
THAT WERE ACUTE INFECTION TIME

3928
02:21:57,368 --> 02:21:58,936
POINTS AND FOLLOWING INFECTION,

3929
02:21:58,936 --> 02:22:01,338
THAT MIGHT MEDIATE THESE POST

3930
02:22:01,338 --> 02:22:02,339
ACUTE SEQUEL I INFECTION AND THE

3931
02:22:02,339 --> 02:22:04,541
WAY WE WANT TO IDENTIFY

3932
02:22:04,541 --> 02:22:05,743
SARS-COV-2 DOING IN A UNIQUE

3933
02:22:05,743 --> 02:22:07,911
WAY, IS WE WANT TO COMPETE IT

3934
02:22:07,911 --> 02:22:08,579
HEAD-TO-HEAD WITH ANOTHER VIRUS,

3935
02:22:08,579 --> 02:22:10,581
AND THIS IS WHERE THE FLU MODEL

3936
02:22:10,581 --> 02:22:12,149
COMES IN, SO THIS IS IN SOME

3937
02:22:12,149 --> 02:22:13,450
CASES BUT IT DOESN'T SEEM TO

3938
02:22:13,450 --> 02:22:15,419
OCCUR TO THE SAME EXTENT AT

3939
02:22:15,419 --> 02:22:17,254
LEAST TO THE SAME SEVERITY WE

3940
02:22:17,254 --> 02:22:19,757
SEE IN LONG COVID.

3941
02:22:19,757 --> 02:22:21,291
SO HERE WE FIRST INFECTED

3942
02:22:21,291 --> 02:22:24,261
HAMSTERS WITH FLU AGAIN, THIS IS

3943
02:22:24,261 --> 02:22:26,597
THE H1N1 FLIEN FLU STRAIN OR

3944
02:22:26,597 --> 02:22:28,298
SARS-COV-2, FOR THE WASHINGTON

3945
02:22:28,298 --> 02:22:28,532
STRAIN.

3946
02:22:28,532 --> 02:22:30,367
WE DID AT TIME LOOKING AT

3947
02:22:30,367 --> 02:22:32,369
REPLICATION DYNAMICS OF VIRUSES

3948
02:22:32,369 --> 02:22:34,171
IN THE LUNGS OVER TIME AND SEE

3949
02:22:34,171 --> 02:22:40,511
THAT THE FLU AND SARS-COV-2 HAVE

3950
02:22:40,511 --> 02:22:42,513
SIMILAR INFECTION KINETICS, BOTH

3951
02:22:42,513 --> 02:22:45,582
PEAK AT THE SAME TIME, AND THEY

3952
02:22:45,582 --> 02:22:47,885
CLEAR BETWEEN DAYS 5 AND 7,

3953
02:22:47,885 --> 02:22:49,353
COMPLETE BY 14, AND THIS

3954
02:22:49,353 --> 02:22:51,221
PRESENTED A NICE MODEL IN WHICH

3955
02:22:51,221 --> 02:22:53,223
WE CAN COMPARE THE 2 VIRUSES SO

3956
02:22:53,223 --> 02:22:55,893
OUR FIRST MAINLIOR SPRM IS WE

3957
02:22:55,893 --> 02:22:59,063
DID A LARGE LONGITUDINAL COHORT,

3958
02:22:59,063 --> 02:23:00,697
SARS-COV-2 INFLECTED, FLU INFECT

3959
02:23:00,697 --> 02:23:02,433
TD HAMSTERS AND THEN WE LET THEM

3960
02:23:02,433 --> 02:23:04,768
GO OUT TO 3 DAYS POST INFECTION,

3961
02:23:04,768 --> 02:23:06,737
AND 31 DAYS POST INFECTION

3962
02:23:06,737 --> 02:23:08,972
AGAIN, AT LEAST 3 WEEKS IT SEEMS

3963
02:23:08,972 --> 02:23:10,040
BEYOND VIRAL CLEARANCE TO SEE IF

3964
02:23:10,040 --> 02:23:11,909
WE CAN SEE WHAT'S GOING ON IN A

3965
02:23:11,909 --> 02:23:13,143
BUNCH OF DIFFERENT ORGANS THAT

3966
02:23:13,143 --> 02:23:15,846
MIGHT BE RELATED TO PERSISTENT

3967
02:23:15,846 --> 02:23:17,314
PATHOLOGY FROM THESE INFECTIONS.

3968
02:23:17,314 --> 02:23:19,650
SO AT THESE END POINTS WE TOOK

3969
02:23:19,650 --> 02:23:21,185
TISSUES, NERVOUS SYSTEM TISSUES

3970
02:23:21,185 --> 02:23:24,855
AND NONNERVOUS SYSTEM TISSUES SO

3971
02:23:24,855 --> 02:23:25,789
WE PARTNERED WITH

3972
02:23:25,789 --> 02:23:27,291
[INDISCERNIBLE] LAB AND LED BY

3973
02:23:27,291 --> 02:23:28,258
ALEX [INDISCERNIBLE].

3974
02:23:28,258 --> 02:23:30,561
THEY WERE NEUROTESTIFIES THAT

3975
02:23:30,561 --> 02:23:32,062
HELPED US DISSECT OUT FUNCTIONAL

3976
02:23:32,062 --> 02:23:33,697
BRAIN AREAS SO WE WERE ABLE TO

3977
02:23:33,697 --> 02:23:35,099
TAKE BRAIN AREAS THAT WERE

3978
02:23:35,099 --> 02:23:36,934
RELEVANT TO THE SYMPTOMOLOGY OF

3979
02:23:36,934 --> 02:23:38,635
LONG COVID AND WE'RE ABLE TO DO

3980
02:23:38,635 --> 02:23:40,104
SEQUENCING ON ALL OF THESE

3981
02:23:40,104 --> 02:23:40,838
DIFFERENT ORGANS AND TISSUE

3982
02:23:40,838 --> 02:23:43,407
AREAS AS WELL AS DO EFTHIMIOS ON

3983
02:23:43,407 --> 02:23:44,108
O LOGIC CHARACTERIZATION.

3984
02:23:44,108 --> 02:23:47,344
SO THERE WERE A LOT OF RESULTS,

3985
02:23:47,344 --> 02:23:48,812
FROM THIS KREEN.

3986
02:23:48,812 --> 02:23:50,781
AND I WILL KIND OF BREEZE

3987
02:23:50,781 --> 02:23:51,748
THROUGH THEM QUICKLY BECAUSE A

3988
02:23:51,748 --> 02:23:53,450
LOT OF THIS IS ALREADY PUBLISHED

3989
02:23:53,450 --> 02:23:56,286
BUT 1 OF THE PRIMARY FINDINGS IS

3990
02:23:56,286 --> 02:23:58,255
THAT WE SAW SARS-COV-2 AND FLU,

3991
02:23:58,255 --> 02:23:59,556
SEEM TO HAVE SARSIMILAR RESPONSE

3992
02:23:59,556 --> 02:24:00,824
IN ALL THE ORGANS THAT WOE

3993
02:24:00,824 --> 02:24:02,326
LOOKEDDA THE AND THIS WAS

3994
02:24:02,326 --> 02:24:04,194
CHARACTERIZED BY A MASSIVE

3995
02:24:04,194 --> 02:24:05,295
SYSTEMIC INFLAMMA ARE TOY

3996
02:24:05,295 --> 02:24:08,899
RESPONSE AND  ANTIVIRAL RESPONS.

3997
02:24:08,899 --> 02:24:12,102
SO HERE WE HAVE A HEAT MAP

3998
02:24:12,102 --> 02:24:14,171
SHOWING GENES SIMULATED IN

3999
02:24:14,171 --> 02:24:16,440
SARS-COV-2 AND FLU INFECTED

4000
02:24:16,440 --> 02:24:17,708
HAMSTERS, EVERYTHING IN RED IS

4001
02:24:17,708 --> 02:24:19,143
UPREGULATED SO YOU CAN

4002
02:24:19,143 --> 02:24:20,110
APPRECIATE THAT BETWEEN

4003
02:24:20,110 --> 02:24:21,578
SARS-COV-2 AND FLU, THESE ARE

4004
02:24:21,578 --> 02:24:23,247
UPREGULATED ACROSS THE BOARD AND

4005
02:24:23,247 --> 02:24:26,350
IT SEEMS LIKE THIS IS A SYSTEM

4006
02:24:26,350 --> 02:24:36,727
WIDE INFLAMMA ARE TOY

4007
02:24:47,037 --> 02:24:50,841
RESPONSE--AND WHAT WE ENDED UP

4008
02:24:50,841 --> 02:24:55,145
SEEING WAS WE SAW SMM NO

4009
02:24:55,145 --> 02:24:57,214
DIFFERENCE BETWEEN SARS-COV-2

4010
02:24:57,214 --> 02:25:01,285
AND FLU, AND REALLY THE ONLY

4011
02:25:01,285 --> 02:25:02,920
MAJOR DIFFERENCE WE SEEM TO SEE

4012
02:25:02,920 --> 02:25:06,657
IN THE VIRUSES IN THE OLFACTORY

4013
02:25:06,657 --> 02:25:08,592
BULBS OF HAMENTSTERS SO I SAID

4014
02:25:08,592 --> 02:25:10,661
THEY HAD MOSTLY RETURNED TO BASE

4015
02:25:10,661 --> 02:25:11,962
LINE AND THERE WAS 1 NOTABLE

4016
02:25:11,962 --> 02:25:13,297
EXCEPTION TO THAT AND THAT'S

4017
02:25:13,297 --> 02:25:14,631
THIS THE LAST COLUMN.

4018
02:25:14,631 --> 02:25:16,133
SO YOU'LL APPRECIATE THAT THE

4019
02:25:16,133 --> 02:25:18,035
IT'S STILL RED AT 31 DAYS POST

4020
02:25:18,035 --> 02:25:19,303
INFECTION.

4021
02:25:19,303 --> 02:25:20,137
SO THIS WAS BIZARRE FOR US

4022
02:25:20,137 --> 02:25:21,672
BECAUSE WE DIDN'T EXPECT TO FIND

4023
02:25:21,672 --> 02:25:22,739
THIS, THIS WAS 1 SINGLE AREA OF

4024
02:25:22,739 --> 02:25:27,010
THE BRAIN, WE DIDN'T SEE  

4025
02:25:27,010 --> 02:25:27,511
PERRISTENT INFLAMMATORY

4026
02:25:27,511 --> 02:25:29,446
RESPONSES AND IT WAS A SPECIFIC

4027
02:25:29,446 --> 02:25:30,747
PHENOMENA, SO A LOT OF OUR

4028
02:25:30,747 --> 02:25:31,715
RECENT WORK HAS BEEN TRYING TO

4029
02:25:31,715 --> 02:25:32,783
GO AFTER THIS AND FIGURE OUT

4030
02:25:32,783 --> 02:25:36,053
WHAT MIGHT BE DRIVING THIS

4031
02:25:36,053 --> 02:25:36,887
PERSISTENT INFLOOMATORY

4032
02:25:36,887 --> 02:25:39,056
RESPONSE, SO DR. PERLMAN'S TALK

4033
02:25:39,056 --> 02:25:40,490
WAS ON A NICE PRIMER FOR THIS

4034
02:25:40,490 --> 02:25:42,192
BUT 1 OF THE WAYS WE WANT TO DO

4035
02:25:42,192 --> 02:25:44,728
THIS WAS BY DOING A PRETTY

4036
02:25:44,728 --> 02:25:46,763
THOROUGH CHARKTIZATION OF HOW

4037
02:25:46,763 --> 02:25:48,265
SARS-COV-2 WAS AFFECTING THE

4038
02:25:48,265 --> 02:25:49,633
OLFACTORY SYSTEM, SO HERE BEFORE

4039
02:25:49,633 --> 02:25:51,001
JUMPING INTOAUR DATA I WANTED TO

4040
02:25:51,001 --> 02:25:55,872
GIVE A BRIEF PRIMER AND COPYING

4041
02:25:55,872 --> 02:25:57,307
DR. PERLMAN'S PRESENTATION ON

4042
02:25:57,307 --> 02:26:01,078
SIMILAR ANATOMY, SO HERE SHOWING

4043
02:26:01,078 --> 02:26:01,812
HISTOLOGY SLIDES, HAMSTER

4044
02:26:01,812 --> 02:26:03,447
OLFACTORY SYSTEM, THIS WAS TAKEN

4045
02:26:03,447 --> 02:26:06,183
FROM A CORONAL CUT FROM FAR DEEP

4046
02:26:06,183 --> 02:26:07,150
INTO THE HAMSTER SAMPLE AND A

4047
02:26:07,150 --> 02:26:09,253
BIT INTO THE CRANIAL CAVITY AND

4048
02:26:09,253 --> 02:26:11,688
YOU CAN SEE THE NAIS AT PASSAGES

4049
02:26:11,688 --> 02:26:13,257
HERE, AIR GOES THROUGH HERE AND

4050
02:26:13,257 --> 02:26:14,992
THESE ARE THE OLFACTORY BULBS IN

4051
02:26:14,992 --> 02:26:16,159
THE BRAIN.

4052
02:26:16,159 --> 02:26:18,428
O IT'S COMPRISED OF THE

4053
02:26:18,428 --> 02:26:21,298
OLFACTORY BULB AS WELL AS THE

4054
02:26:21,298 --> 02:26:23,200
EPITHELIUM, AND THIS IS IN THE

4055
02:26:23,200 --> 02:26:25,769
FRONT, THE CRANIAL CAVITY AND IT

4056
02:26:25,769 --> 02:26:26,737
PRIMARILY CONTROLS INITIAL

4057
02:26:26,737 --> 02:26:28,905
SENSATION OF SMELL AND IT IS

4058
02:26:28,905 --> 02:26:31,842
HEAVILY FUNCTIONING TO THE

4059
02:26:31,842 --> 02:26:33,877
OLFACTORY EPITHELIUM, THE

4060
02:26:33,877 --> 02:26:35,178
EPITHELIUM ITSELF IS IN THE BACK

4061
02:26:35,178 --> 02:26:36,913
AND TOP PART OF THE NOSE AND

4062
02:26:36,913 --> 02:26:39,783
IT'S AN EPITHELIAL LAYER WHERE

4063
02:26:39,783 --> 02:26:41,084
YOU HAVE THE NEURAL SENSORYS

4064
02:26:41,084 --> 02:26:43,053
HOUSED AND SO HERE WE SHOWING A

4065
02:26:43,053 --> 02:26:47,224
ZOOMED IN OF THE OLFACTORY AND

4066
02:26:47,224 --> 02:26:49,760
EPITHELIUM AND WE HAVE THEM

4067
02:26:49,760 --> 02:26:50,594
MARKED FOR SENSORY NEURONS AND

4068
02:26:50,594 --> 02:26:51,962
YOU CAN SEE THE SIMILAR

4069
02:26:51,962 --> 02:26:53,764
STRUCTURE TO WHAT WE SEE IN THE

4070
02:26:53,764 --> 02:26:55,465
CARTOON WHICH IS THE CELL BODIES

4071
02:26:55,465 --> 02:26:57,567
STACKED ON TOP OF EACH OTHER AND

4072
02:26:57,567 --> 02:26:58,602
THEN THE STRUCTURES PROTRUDING

4073
02:26:58,602 --> 02:27:00,203
OUT INTO THE NOSE AND THESE ARE

4074
02:27:00,203 --> 02:27:01,438
WHERE THE NEURONS ARE GOING TO

4075
02:27:01,438 --> 02:27:03,040
STICK OUT AND AS AIR AND FLEEING

4076
02:27:03,040 --> 02:27:04,808
BY, WHAT YOU INHALE, THEY WILL

4077
02:27:04,808 --> 02:27:08,745
CATCH THE MOLECULES AND SIGNAL

4078
02:27:08,745 --> 02:27:11,415
ACTION PROTENTIALS THAT WILL

4079
02:27:11,415 --> 02:27:13,183
INDICATE THE DETECTION OF SMELL.

4080
02:27:13,183 --> 02:27:14,885
SO THESE WILL PASS FROM THESE

4081
02:27:14,885 --> 02:27:16,353
NEURON CELL BODIES WHICH ARE

4082
02:27:16,353 --> 02:27:18,055
LOCATED IN THE EPITHELIUM

4083
02:27:18,055 --> 02:27:20,357
THROUGH AXONAL PROYEKSS WHICH

4084
02:27:20,357 --> 02:27:22,025
PROJECT OFF OF THE BASAL LATERAL

4085
02:27:22,025 --> 02:27:25,395
SIDE OF THE CELLS, THESE WILL

4086
02:27:25,395 --> 02:27:26,630
CLUSTER INTO LARGE NEURAL

4087
02:27:26,630 --> 02:27:28,031
BUNDLES AND THESE BUNDLES WILL

4088
02:27:28,031 --> 02:27:30,267
FLOW INTO THE OLFACTORY BULB AND

4089
02:27:30,267 --> 02:27:32,569
THERE THEY WILL SYNAPSE HIGHER

4090
02:27:32,569 --> 02:27:35,472
NEURONAL CELLS WITH THE AREAS

4091
02:27:35,472 --> 02:27:36,873
HERE CALLED GLUE MAR I HERE

4092
02:27:36,873 --> 02:27:38,542
EMPLOY AND LOOKING AT THE BULB

4093
02:27:38,542 --> 02:27:39,843
ITSELF, THIS IS PART OF THE

4094
02:27:39,843 --> 02:27:41,578
BRAIN, PART OF THE CENTRAL

4095
02:27:41,578 --> 02:27:43,613
NERVOUS SYSTEM,OOSE IMPORTANT TO

4096
02:27:43,613 --> 02:27:48,185
APPRECIATE THAT THE PORTION OF

4097
02:27:48,185 --> 02:27:49,419
THE BULB IS COMPRISED FROM THESE

4098
02:27:49,419 --> 02:27:50,487
NEURON ANDS THIS WAS INTERESTING

4099
02:27:50,487 --> 02:27:51,822
AND SOMETHING THAT WILL BECOME

4100
02:27:51,822 --> 02:27:57,194
IMPORTANT IN A BIT.

4101
02:27:57,194 --> 02:28:01,898
SO IT'S BEEN KNOWN THAT THIS

4102
02:28:01,898 --> 02:28:03,400
AFFECTS THE EPITHELIUM, AND THE

4103
02:28:03,400 --> 02:28:04,634
EFFECTS IS LOSS OF SMELL, SO WE

4104
02:28:04,634 --> 02:28:06,870
WANT TO DO THIS IN A HAMSTER.

4105
02:28:06,870 --> 02:28:10,707
SO WE INFECKED A BUNCH OF HAM

4106
02:28:10,707 --> 02:28:12,509
TERS NAISALLY, AND TOOK OLYMPIC

4107
02:28:12,509 --> 02:28:15,011
FACTOR EPITHELIUM AT 1, 3, 5, 7,

4108
02:28:15,011 --> 02:28:18,014
10, 30 AND 45 DAYS POST

4109
02:28:18,014 --> 02:28:20,117
INFECTION, AND WE DID PC Rs

4110
02:28:20,117 --> 02:28:21,752
AND WE LOOKED FOR SARS-COV-2

4111
02:28:21,752 --> 02:28:24,354
MATERIALS AND THIS IS LOOKING

4112
02:28:24,354 --> 02:28:26,123
FOR SUBGENOMIC AND TRANSCRIPT

4113
02:28:26,123 --> 02:28:27,424
PRODUCED WHEN SARS-COV-2 IS

4114
02:28:27,424 --> 02:28:29,626
REPLICATING AND AGAIN WE CAN SEE

4115
02:28:29,626 --> 02:28:31,027
THAT SARS-COV-2 IS REP

4116
02:28:31,027 --> 02:28:32,562
LITICATING NICELY AND WE CAN SEE

4117
02:28:32,562 --> 02:28:34,765
THE INCREASE AT 3 DAYS POST

4118
02:28:34,765 --> 02:28:36,066
INFECTION PEAK AND AGAIN

4119
02:28:36,066 --> 02:28:36,767
FOLLOWING SIMILAR DYNAMICS TO

4120
02:28:36,767 --> 02:28:40,937
WHAT WE SAW IN THE LUNG TISSUE.

4121
02:28:40,937 --> 02:28:43,240
NOTE ABLE WE WANT TO LACK AT AN

4122
02:28:43,240 --> 02:28:46,376
ANTIVIRAL RESPONSE AND DID A

4123
02:28:46,376 --> 02:28:48,378
SIMILAR QPC R AND IN THE

4124
02:28:48,378 --> 02:28:49,613
INTERFERON STIMULATED YEEN AND

4125
02:28:49,613 --> 02:28:51,281
WE SAW THAT STIMULATED YEEN

4126
02:28:51,281 --> 02:28:53,350
PRESENCE SEEMED TO MIRROR PRETTY

4127
02:28:53,350 --> 02:28:55,385
WELL WITH VIRAL PRESENCE AS WELL

4128
02:28:55,385 --> 02:28:56,686
AND PEEKING AT 3 DAYS POST

4129
02:28:56,686 --> 02:28:58,422
INTERACTION AND CLEANING AT

4130
02:28:58,422 --> 02:28:58,622
10-15.

4131
02:28:58,622 --> 02:29:01,024
SO WE ALSO BROUGHT UP A

4132
02:29:01,024 --> 02:29:02,092
SECONDARY LONGITUDINAL COHORT WE

4133
02:29:02,092 --> 02:29:03,527
USE TO DO HISTOLOGICAL STUDIES

4134
02:29:03,527 --> 02:29:04,628
WITH AND WE WANT TO SEE WHAT

4135
02:29:04,628 --> 02:29:07,531
THIS LOOKED LIKE IN THE

4136
02:29:07,531 --> 02:29:08,498
OLFACTORY EPITHEMUAL ITSELF, SO

4137
02:29:08,498 --> 02:29:11,268
FIRST WE PROBE FOR SARS-COV-2

4138
02:29:11,268 --> 02:29:12,636
INFECTION AND SHOWED INFECTION,

4139
02:29:12,636 --> 02:29:13,503
AND HOPEFULLY CAN YOU APPRECIATE

4140
02:29:13,503 --> 02:29:16,807
THAT IN RED AND GREEN, IN THE

4141
02:29:16,807 --> 02:29:18,675
INFECTED ANIMALOT RIGHT, TON OF

4142
02:29:18,675 --> 02:29:20,677
THE OLFACTORY EPITHELIUM IS

4143
02:29:20,677 --> 02:29:21,244
INFECTED BY SARS-COV-2.

4144
02:29:21,244 --> 02:29:24,614
SO THIS SEEMS TO BE A RAM PANT

4145
02:29:24,614 --> 02:29:25,615
INFECTION AFFECTING SEEMINGLY

4146
02:29:25,615 --> 02:29:27,350
THE MAJORITY OF THE TISSUE AT 3

4147
02:29:27,350 --> 02:29:29,219
DAYS POST INFECTION AT VIRAL

4148
02:29:29,219 --> 02:29:29,453
PEEK.

4149
02:29:29,453 --> 02:29:30,654
FURTHER MORE, WE WANT TO SEE

4150
02:29:30,654 --> 02:29:32,389
WHAT THIS INFLAMMA ARE TOY

4151
02:29:32,389 --> 02:29:33,824
RESPONSE LOOKED LIKE OUTSIDE OF

4152
02:29:33,824 --> 02:29:39,596
OUR QPC R AND HERE WE'RE

4153
02:29:39,596 --> 02:29:40,297
STAINING FOR [INDISCERNIBLE] AND

4154
02:29:40,297 --> 02:29:41,932
WHAT YOU CAN HOPEFULLY

4155
02:29:41,932 --> 02:29:43,867
APPRECIATE IS IT'S VERY RED AT 3

4156
02:29:43,867 --> 02:29:44,401
DAYS POST INFECTION.

4157
02:29:44,401 --> 02:29:47,337
SO THIS ISHT FERON RESPONSE IS

4158
02:29:47,337 --> 02:29:48,505
VERY PERSISTENT AND PREVALENT

4159
02:29:48,505 --> 02:29:49,773
THROUGHOUT THIS TISSUE.

4160
02:29:49,773 --> 02:29:53,009
SO OUR NEXT QUESTION THEN WAS,

4161
02:29:53,009 --> 02:29:54,611
SO WE--DURING OUR INFECTION

4162
02:29:54,611 --> 02:29:57,414
DIDN'T SEE THE OLFACTORY SENSORY

4163
02:29:57,414 --> 02:29:58,882
NEURONS INFECTED THEMSELVES.

4164
02:29:58,882 --> 02:30:00,283
THIS HAS BEEN SHOWN CONNIST

4165
02:30:00,283 --> 02:30:01,418
SEBTLY THROUGHOUT THE LITERATURE

4166
02:30:01,418 --> 02:30:03,687
BUT WITH ALL THIS INFECTION AND

4167
02:30:03,687 --> 02:30:04,654
ALL THIS ANTIVIRAL RESPONSE

4168
02:30:04,654 --> 02:30:06,957
HAPPENING INSIDE THE TISSUE, WE

4169
02:30:06,957 --> 02:30:08,658
ARE CURIOUS WHAT IS HAPPENING TO

4170
02:30:08,658 --> 02:30:10,961
THIS TISSUE EMPLOY SO HERE WE

4171
02:30:10,961 --> 02:30:14,197
STAIN PER PUNISHING DRMARKER IN

4172
02:30:14,197 --> 02:30:17,033
THE EPITHELIUM AND WE KEIN THESE

4173
02:30:17,033 --> 02:30:18,435
CELL BODIES, THESE STRUCTURES

4174
02:30:18,435 --> 02:30:20,437
BUT AS SOON AS YOU CAN GET TO

4175
02:30:20,437 --> 02:30:21,671
THE INFECTION AT 3 DAYS POST

4176
02:30:21,671 --> 02:30:22,639
INFECTION, YOU LOSE A LOT OF

4177
02:30:22,639 --> 02:30:24,541
THAT STRUCTURE AND THERE'S A

4178
02:30:24,541 --> 02:30:26,610
MASSIVE DISRUPTION, SO CAN YOU

4179
02:30:26,610 --> 02:30:27,677
SEE OLFACTORY SENSORY NEURONS

4180
02:30:27,677 --> 02:30:29,279
THERE, A LOT OF SLUFFING OFF

4181
02:30:29,279 --> 02:30:31,014
INTO THE NOSE, THE 1S THAT ARE

4182
02:30:31,014 --> 02:30:32,449
LEFT HAVE LOT THEIR SILLIARY

4183
02:30:32,449 --> 02:30:35,652
STRUCTURE AND THEY'RE NOT HAVING

4184
02:30:35,652 --> 02:30:35,952
FUN.

4185
02:30:35,952 --> 02:30:37,187
IS IT INTERESTINGLY WHENY WOO

4186
02:30:37,187 --> 02:30:39,556
LOOK LATER WE SEE THEM DISAPPEAR

4187
02:30:39,556 --> 02:30:39,856
ALTOGETHER.

4188
02:30:39,856 --> 02:30:41,658
SO AT 5 DAYS POST INFEC, A

4189
02:30:41,658 --> 02:30:43,393
SIGNIFICANT PORTION OF THE

4190
02:30:43,393 --> 02:30:44,661
EPITHELIUM WAS CLEAR OLFACTORY

4191
02:30:44,661 --> 02:30:46,730
SENSORY NEURONS AND THE 1S WE

4192
02:30:46,730 --> 02:30:48,131
DID SEE WERE OFTEN TIMES

4193
02:30:48,131 --> 02:30:49,733
SLUFFING OFF INTO THE NOSE AND

4194
02:30:49,733 --> 02:30:52,168
ONCE WE LOOK AT 10 DAYS POST

4195
02:30:52,168 --> 02:30:54,738
INFECTION, THE PRESENCE WAS JUST

4196
02:30:54,738 --> 02:30:55,705
COMPLETELY ALMOST ELIMINATED AND

4197
02:30:55,705 --> 02:30:57,474
WHILE THIS DID SEEM TO RECOVER

4198
02:30:57,474 --> 02:31:00,410
OVER TIME, AT 30 DAY POST

4199
02:31:00,410 --> 02:31:01,778
INFECTION, THE OLFACTORY

4200
02:31:01,778 --> 02:31:02,479
EPITHELIUM WAS SIGNIFICANTLY

4201
02:31:02,479 --> 02:31:04,581
THIN COMPARED TO WHAT WE SAW IN

4202
02:31:04,581 --> 02:31:06,116
OUR MOK INFECTED ANIMAL ANDS

4203
02:31:06,116 --> 02:31:07,817
THERE ARE DEFINITELY LESS

4204
02:31:07,817 --> 02:31:08,752
OLFACTORY SENSORY NEURONS.

4205
02:31:08,752 --> 02:31:10,153
SO HERE PUTTING SOME

4206
02:31:10,153 --> 02:31:13,223
QUANTITATIVE NUMBERS TO THIS,

4207
02:31:13,223 --> 02:31:15,392
LOOKS LIKE SOME OF THE DOTS ARE

4208
02:31:15,392 --> 02:31:16,459
NOT SHOWING CORRECTLY BUT YOU

4209
02:31:16,459 --> 02:31:18,094
CAN SEE IT THERE SO HERE WE

4210
02:31:18,094 --> 02:31:19,062
MEASURED THE THICKNESS PUTTING

4211
02:31:19,062 --> 02:31:22,399
NUMBERS TO WHAT WE JUST IN

4212
02:31:22,399 --> 02:31:23,867
HISTOLOGY AND HOPEFULLY YOU CAN

4213
02:31:23,867 --> 02:31:24,467
APPRECIATE THAT.

4214
02:31:24,467 --> 02:31:26,603
IT CAN PEEK AT 5 DAYS POST

4215
02:31:26,603 --> 02:31:27,904
INFECTION AND RECOVERS A BIT BY

4216
02:31:27,904 --> 02:31:29,205
30 DAYS POST INFECTION IT

4217
02:31:29,205 --> 02:31:31,341
DOESN'T GET BACK UP TO BASE LINE

4218
02:31:31,341 --> 02:31:31,575
LEVELS.

4219
02:31:31,575 --> 02:31:34,010
FURTHER MORWHEN WE LOOK AT

4220
02:31:34,010 --> 02:31:35,178
OLFACTORY NEURON, WE STARTED

4221
02:31:35,178 --> 02:31:38,014
COUNTING THE NUMBER OF FLUORONS

4222
02:31:38,014 --> 02:31:39,249
FOR MICROTISSUE, WE CAN SEE

4223
02:31:39,249 --> 02:31:41,718
AGAIN AN EVEN MORE DRAMATIC

4224
02:31:41,718 --> 02:31:43,453
EFFECT BY 30 DAYS POST INFECTION

4225
02:31:43,453 --> 02:31:45,121
EVEN THOUGH THEY STARTED COMING

4226
02:31:45,121 --> 02:31:46,489
BACK, THEY DIDN'T REALLY ACHIEVE

4227
02:31:46,489 --> 02:31:47,891
SIMILAR LEVELS TO WHAT WE SAW AT

4228
02:31:47,891 --> 02:31:48,992
BASE LINE.

4229
02:31:48,992 --> 02:31:50,260
SO, AGAIN, OUR NEXT QUESTION

4230
02:31:50,260 --> 02:31:52,262
THEN WAS IF THESE OLFACTORY

4231
02:31:52,262 --> 02:31:53,530
SENSORY FIEWRONS ARE DYING OR

4232
02:31:53,530 --> 02:31:56,166
BEING CLEAR INDEED SOME SENSE AS

4233
02:31:56,166 --> 02:31:58,668
A RESULOF SARS OVERLAPPING 2

4234
02:31:58,668 --> 02:32:00,170
INFECTION, AND THESE ARE NOT

4235
02:32:00,170 --> 02:32:01,871
NECESSARILY INFECTED WHAT'S

4236
02:32:01,871 --> 02:32:09,679
HAPPENING IN THE BULB AND

4237
02:32:09,679 --> 02:32:14,551
UPSTREAM, WHAT'S HAPPENING

4238
02:32:14,551 --> 02:32:17,621
TO--AND WHAT'S HAPPENING TO

4239
02:32:17,621 --> 02:32:19,022
THESE UPSTREAM CELLS AND ARE

4240
02:32:19,022 --> 02:32:20,323
THEY GOING TO CONTINUE FIRING

4241
02:32:20,323 --> 02:32:26,062
WHEN THEY'RE DEFERVE 8ED OF

4242
02:32:26,062 --> 02:32:26,896
THEIR SENSORY INPUT SO THE FIRST

4243
02:32:26,896 --> 02:32:29,833
THING WE WANT TO GO AFTER AND

4244
02:32:29,833 --> 02:32:39,576
WHAT'S HAPPENING UPSTREAM?

4245
02:32:39,576 --> 02:32:41,845
SO WE SO IT'S A NEURONAL GENE

4246
02:32:41,845 --> 02:32:44,114
AND WHEN JIEWRONS FIRE MORE THEY

4247
02:32:44,114 --> 02:32:46,650
PRODUCE MORE PH OS, WHEN THEY

4248
02:32:46,650 --> 02:32:47,517
FIRE LESS, THEY PRODUCE LESS

4249
02:32:47,517 --> 02:32:49,452
EMPLOY SO IT'S A GENERAL MARKER.

4250
02:32:49,452 --> 02:32:52,922
AND HOPEFULLY YOU CAN APPRECIATE

4251
02:32:52,922 --> 02:32:56,426
THAT AFTER SARS-COV-2 INFECTION,

4252
02:32:56,426 --> 02:32:58,061
IT GOES DOWN AND STAYS DOWN.

4253
02:32:58,061 --> 02:32:59,829
NEXT WE WANT TO DO IS PROVIDE

4254
02:32:59,829 --> 02:33:02,032
DEFINITION ON THIS SO WE WENT

4255
02:33:02,032 --> 02:33:04,200
INTO OUR RNA SEQUENCING DATA CAN

4256
02:33:04,200 --> 02:33:06,403
AND TRIED TO GENERATE ANY

4257
02:33:06,403 --> 02:33:08,571
OLFACTORY BULB SEQUENCING WE

4258
02:33:08,571 --> 02:33:11,441
HAVE ON FILE AND ABLE TO COMPILE

4259
02:33:11,441 --> 02:33:13,643
A SEQUENCING SET FOR OLFACTORY

4260
02:33:13,643 --> 02:33:16,179
BULBS WHERE WE HAVE THIS TISSUE

4261
02:33:16,179 --> 02:33:18,815
AT 1, 2, 3, 4, 14, 16, 31 DAYS

4262
02:33:18,815 --> 02:33:21,785
POST INFECTION SO THERE ARE A

4263
02:33:21,785 --> 02:33:22,719
COUPLE DIFFERENT INFECTIOUS

4264
02:33:22,719 --> 02:33:23,687
PFUs THAT ARE DIFFERENT

4265
02:33:23,687 --> 02:33:28,391
THROUGHOUT THIS  COHORT BUT THEY

4266
02:33:28,391 --> 02:33:29,893
ALL MODEL IS NICELY AND WE'RE

4267
02:33:29,893 --> 02:33:33,697
ALL IN A RANGE OF 100 TO 10,000

4268
02:33:33,697 --> 02:33:33,963
PFU.

4269
02:33:33,963 --> 02:33:36,032
AND SO WHEN WE LOOK FOR FOSTER

4270
02:33:36,032 --> 02:33:38,334
NURSED, WE SEE SIMILAR IN QPC R

4271
02:33:38,334 --> 02:33:39,936
WHICH IS DOWN REGULATED AND

4272
02:33:39,936 --> 02:33:41,604
SEEMS TO STAY DOWN REGULATED

4273
02:33:41,604 --> 02:33:45,709
THROUGH 30 DAYS POST INFECTION.

4274
02:33:45,709 --> 02:33:46,876
WHATEVER ELSE IS REGULATED WE

4275
02:33:46,876 --> 02:33:50,613
SAW A BUNCH OF OTHER IMMEDIATE

4276
02:33:50,613 --> 02:33:57,620
EARLY ACTIVITY SO THIS INCLUDES

4277
02:33:57,620 --> 02:33:59,756
ARK, AND FOS3, AND THIS GOES UP

4278
02:33:59,756 --> 02:34:00,957
AND DOWN WITH NEURONAL ACTIVITY

4279
02:34:00,957 --> 02:34:02,592
SO IT DOES SEEM THAT FACTORY

4280
02:34:02,592 --> 02:34:06,162
BULB AND SEEMS TO BE

4281
02:34:06,162 --> 02:34:06,996
PERSISTENTLY UPREGULATED

4282
02:34:06,996 --> 02:34:07,630
FOLLOWING SARS-COV-2 INFEC

4283
02:34:07,630 --> 02:34:08,998
EMPLOY HOWEVER, WITH THIS DATA

4284
02:34:08,998 --> 02:34:10,567
SET, WE'RE ALSO THEN CURIOUS,

4285
02:34:10,567 --> 02:34:13,169
WHAT ELSE IS HAPPENING IN THE

4286
02:34:13,169 --> 02:34:13,837
OLFACTORY BALB?

4287
02:34:13,837 --> 02:34:16,306
WE HAVE THE DATA SET, AND HERE

4288
02:34:16,306 --> 02:34:18,241
AGAIN WE SAW THE MAJOR

4289
02:34:18,241 --> 02:34:19,509
ONTOLOGIES THAT POPPED OUT ON

4290
02:34:19,509 --> 02:34:21,277
THE ANALYSIS FOR TYPE 1

4291
02:34:21,277 --> 02:34:22,579
INTERFERON AND IMMUNE RESPONSES,

4292
02:34:22,579 --> 02:34:25,248
SO HERE THIS IS KIND OF SHOWING

4293
02:34:25,248 --> 02:34:26,783
GENE ENRICHMENT ANALYSIS ON ALL

4294
02:34:26,783 --> 02:34:28,885
OF OUR DIFFERENT DATA SETS,

4295
02:34:28,885 --> 02:34:30,453
SHOWING DAYS POST INFECTION AND

4296
02:34:30,453 --> 02:34:32,188
OUR X-AXIS AND THE ENRICHMENT

4297
02:34:32,188 --> 02:34:34,758
CORE FOR THE ANALYSIS FOR THIS

4298
02:34:34,758 --> 02:34:39,562
ON THE Y-AXIS WITH THE BALLS AT

4299
02:34:39,562 --> 02:34:42,665
THE TOP HERE, THAT'S MY STUFF,

4300
02:34:42,665 --> 02:34:44,434
THAT'S FORTUNATE SHOWING

4301
02:34:44,434 --> 02:34:45,935
SNIFFING CANC AND APOLOGIES ON

4302
02:34:45,935 --> 02:34:48,605
THAT BUT IN THE TYPE 1

4303
02:34:48,605 --> 02:34:52,342
INTERFERENCE WE AWE IT

4304
02:34:52,342 --> 02:34:55,378
UPREGULATED DURING ACUTE

4305
02:34:55,378 --> 02:34:57,547
INFECTION AND HAVE A BUMP AT 14

4306
02:34:57,547 --> 02:34:58,248
DAYS INFECTION AND BEING

4307
02:34:58,248 --> 02:34:59,816
SIGNIFICANT AT LEAST THROUGH 1

4308
02:34:59,816 --> 02:35:00,583
MONTH POST INFECTION.

4309
02:35:00,583 --> 02:35:01,851
FURTHER MORE WHEN WE LOOK AT

4310
02:35:01,851 --> 02:35:04,220
OTHER ASSPECS OF THE IMINE

4311
02:35:04,220 --> 02:35:06,055
RESPONSE SUCH AS CHEMOKINE

4312
02:35:06,055 --> 02:35:07,524
ACTIVITY, WE SAW IT WHICH IS

4313
02:35:07,524 --> 02:35:10,660
THAT THESE MARKERS SEEM TO BE

4314
02:35:10,660 --> 02:35:11,828
UPREGULATED EVEN LATER FOLLOWING

4315
02:35:11,828 --> 02:35:13,429
INFECTION SO THERE'S A LATE

4316
02:35:13,429 --> 02:35:15,665
RISING ONTOLOGY THAT NOTABLILY

4317
02:35:15,665 --> 02:35:17,667
SEEMED TO START RISING AFTER 3

4318
02:35:17,667 --> 02:35:19,169
DAYS POST INFECTION, SO AFTER

4319
02:35:19,169 --> 02:35:20,970
THE PEAK OF VIRAL INFECTION, SO

4320
02:35:20,970 --> 02:35:22,605
THIS IS FOR CHEMOKINE ACTIVITY

4321
02:35:22,605 --> 02:35:25,975
INSIDE THE OLFACTORY.

4322
02:35:25,975 --> 02:35:27,610
WHEN WE'RE INTERESTED THEN IN

4323
02:35:27,610 --> 02:35:29,145
SEEING WHAT CELL TYPE MIGHT

4324
02:35:29,145 --> 02:35:31,781
DRIVE THIS ONTOLOGY, WE LOOK AT

4325
02:35:31,781 --> 02:35:32,749
THE GENE ENRICHMENT ANALYSIS FOR

4326
02:35:32,749 --> 02:35:35,652
THE CELL TYPES AND WE SAW THAT

4327
02:35:35,652 --> 02:35:37,420
MICROGLOIL CELLS WERE 1 OF THE

4328
02:35:37,420 --> 02:35:39,022
MAIN ONTOLOGIES THAT POPPED OUT

4329
02:35:39,022 --> 02:35:41,891
FOR DATA AND WE SEE ENRICHMENT

4330
02:35:41,891 --> 02:35:43,259
SCORES FOR MICROGLIAL PRESENCE

4331
02:35:43,259 --> 02:35:44,661
GOING UP, EVEN ACTUALLY

4332
02:35:44,661 --> 02:35:46,329
FOLLOWING THE PEAK OF INFECTION

4333
02:35:46,329 --> 02:35:47,163
AND REMAINING ELEVATED AND GOING

4334
02:35:47,163 --> 02:35:49,065
UP AND FURTHER PEEKING AT 14

4335
02:35:49,065 --> 02:35:50,366
DAYS POST INFECTION, SO AGAIN

4336
02:35:50,366 --> 02:35:53,970
THIS IS AFTER WE WOULD EXPECT

4337
02:35:53,970 --> 02:35:56,072
VIRAL CLEARANCE THIS HAVE GONE A

4338
02:35:56,072 --> 02:35:57,607
BIT INTRIGUING TO US.

4339
02:35:57,607 --> 02:35:58,942
SO WE NEXT WANTED TO SEE IT SO

4340
02:35:58,942 --> 02:36:00,710
WOE TURN TO OUR HISTOLOGICAL

4341
02:36:00,710 --> 02:36:05,415
COHORT AND WE STARTED STAINING

4342
02:36:05,415 --> 02:36:07,951
FOR MXA, IT A MARKER FOR MA

4343
02:36:07,951 --> 02:36:10,620
ROUGH ATOM PHAGE OR MICROGLIAL

4344
02:36:10,620 --> 02:36:11,621
CELL POPULATIONS AND APPRECIATE

4345
02:36:11,621 --> 02:36:12,989
THAT EVEN THOUGH IT'S UP AT 3

4346
02:36:12,989 --> 02:36:15,758
AND 5 DAYS POST INFECTION, IT

4347
02:36:15,758 --> 02:36:17,227
REMAINS ELEVATED OUT FOR 30 DAYS

4348
02:36:17,227 --> 02:36:18,394
POST INFECTION AND YOU CAN SEE

4349
02:36:18,394 --> 02:36:20,363
IT BLOTCHY AND ALMOST

4350
02:36:20,363 --> 02:36:21,865
EXCLUSIVELY MAINTAINED IN THIS

4351
02:36:21,865 --> 02:36:23,499
OUTSIDE AREA AROUND THE

4352
02:36:23,499 --> 02:36:24,634
OLFACTORY BULB, SO THE LOCAL

4353
02:36:24,634 --> 02:36:25,768
EYATION OF THIS SIGNAL WAS VERY

4354
02:36:25,768 --> 02:36:27,003
IMPORTANT TO US BECAUSE IF YOU

4355
02:36:27,003 --> 02:36:29,105
RECALL, THIS IS ALSO WHERE ALL

4356
02:36:29,105 --> 02:36:30,273
OF THESE OLFACTORY SENSORY

4357
02:36:30,273 --> 02:36:31,307
NEURONS FROM THE PERIPHERY ARE

4358
02:36:31,307 --> 02:36:31,841
COMING IN.

4359
02:36:31,841 --> 02:36:35,945
SO WHEN WE ALSO LOOKED AT IB1

4360
02:36:35,945 --> 02:36:37,413
SIGNATURES FOR THE INFILTRATION,

4361
02:36:37,413 --> 02:36:38,882
WE SAW THE SIGNATURE PEAKED AT

4362
02:36:38,882 --> 02:36:40,483
14 DAYS POST INFECTION AND

4363
02:36:40,483 --> 02:36:41,551
HOPEFULLY APPRECIATE AGAIN THAT

4364
02:36:41,551 --> 02:36:43,786
THERE ARE ALET BIT HARDER TO SEE

4365
02:36:43,786 --> 02:36:46,389
MORE GREEN DOTS AROUND THE

4366
02:36:46,389 --> 02:36:48,291
OUTSIDE HERE SO AGAIN IT LOOKS

4367
02:36:48,291 --> 02:36:49,926
LIKE THE MICROGLIAL CELLS OR

4368
02:36:49,926 --> 02:36:51,461
WHATEVER IS POSITIVE HERE ARE

4369
02:36:51,461 --> 02:36:53,096
MIGRATING TOWARDS THE OUTSIDE OF

4370
02:36:53,096 --> 02:36:54,030
THE OLFACTORY BULB AND SEEM TO

4371
02:36:54,030 --> 02:36:57,600
BE GOING THROUGH THE SAME PLACES

4372
02:36:57,600 --> 02:36:59,736
THAT THIS INTERFERON SIGNAL IS

4373
02:36:59,736 --> 02:37:00,169
PRESENT.

4374
02:37:00,169 --> 02:37:01,404
SO WE THEN QUANTIFIED IT AND WE

4375
02:37:01,404 --> 02:37:02,739
FOUND THAT WHEN YOU LOOK AT THE

4376
02:37:02,739 --> 02:37:05,408
OUTSIDE OF THE OLFACTORY BULB,

4377
02:37:05,408 --> 02:37:06,643
THE MICROGLIAL CELLS OR THE

4378
02:37:06,643 --> 02:37:08,011
POSITIVE CELLS SEEM TO BE THE 1S

4379
02:37:08,011 --> 02:37:09,746
THAT ARE PRODUCING THE MXAs,

4380
02:37:09,746 --> 02:37:11,180
THEY ARE IRPT FERON RESPONSIVE

4381
02:37:11,180 --> 02:37:12,715
AND THEY SEEM TO BE INTERFERON

4382
02:37:12,715 --> 02:37:14,017
RESPONSE AND I HAVE HELD THROUGH

4383
02:37:14,017 --> 02:37:16,552
30 DAYS POST INFECTION AND MORE

4384
02:37:16,552 --> 02:37:17,587
OVERWHELMINGLY WE LOOKED AT THE

4385
02:37:17,587 --> 02:37:20,123
INSIDE OF THE BULB AGAIN, AND WE

4386
02:37:20,123 --> 02:37:22,058
LOOK AT POSITIVE OR NEGATIVE FOR

4387
02:37:22,058 --> 02:37:23,092
THE OLFACTORY SENSORY NEURONS

4388
02:37:23,092 --> 02:37:24,928
THERE, WE FOUND THIS RESPONSE

4389
02:37:24,928 --> 02:37:26,229
ACTUALLY EXTENDED TO THE INSIDE

4390
02:37:26,229 --> 02:37:28,298
OF THE OLFACTORY BULB, AND YOU

4391
02:37:28,298 --> 02:37:29,332
SEE IMAGES OF THIS HERE, AND

4392
02:37:29,332 --> 02:37:31,401
THIS IS THE OUTSIDE OF THE

4393
02:37:31,401 --> 02:37:34,237
OLFACTORY BULB, WE SEE THESE

4394
02:37:34,237 --> 02:37:36,673
LARGE PLAQUES OF THE CELLS THAT

4395
02:37:36,673 --> 02:37:38,207
ARE POSITIVE FOR MXA, AND WITH

4396
02:37:38,207 --> 02:37:40,176
WHEN WE ELECTRIC AT THE INSIDE,

4397
02:37:40,176 --> 02:37:42,278
EVEN THOUGH THEY WERE MORE

4398
02:37:42,278 --> 02:37:43,913
DISPERGSED YOU CAN SEE THESE

4399
02:37:43,913 --> 02:37:46,549
CELLS ARE ALSO POSITIVE FOR MXA,

4400
02:37:46,549 --> 02:37:50,787
SO IT SEEMS LIKE THE INTERFERON

4401
02:37:50,787 --> 02:37:53,623
REPONS IS PREVALENT THROUGHOUT

4402
02:37:53,623 --> 02:37:53,890
THE BULB.

4403
02:37:53,890 --> 02:37:56,259
SO NEXT QUESTION, WHY ARE THEY

4404
02:37:56,259 --> 02:37:57,994
ACTIVATED IN WHY ARE THEY

4405
02:37:57,994 --> 02:37:59,228
PRODUCING TYPE 1 INTERFERON?

4406
02:37:59,228 --> 02:38:01,564
IS THIS A PERSISTENT INFECTION,

4407
02:38:01,564 --> 02:38:03,800
IS SARS-COV-2 GETTING INTO THE

4408
02:38:03,800 --> 02:38:06,469
OLFACTORY BULB, DOES IT AFFECT

4409
02:38:06,469 --> 02:38:08,104
THE OLFACTORY BULB IS IT A SIDE

4410
02:38:08,104 --> 02:38:10,306
EFFECT OF THE INFECTION IN SO

4411
02:38:10,306 --> 02:38:11,941
EVERY WAY WE COULD TELL IT WAS

4412
02:38:11,941 --> 02:38:15,345
NO, WE COULDN'T SEE ANY SIGNS OF

4413
02:38:15,345 --> 02:38:17,080
THE SARS-COV-2 PRESENCE, HERE

4414
02:38:17,080 --> 02:38:18,314
WE'RE STAINING FOR SARS-COV-2 S

4415
02:38:18,314 --> 02:38:20,817
AND N AND FOLLOWING ACUTE AND

4416
02:38:20,817 --> 02:38:22,385
FOLLOWING INFECTION WE COULDN'T

4417
02:38:22,385 --> 02:38:23,553
SEE ANY THERE.

4418
02:38:23,553 --> 02:38:25,021
SO OUR NEXT THOUGHT WAS LET'S

4419
02:38:25,021 --> 02:38:26,923
LOOK BACK TO THE SEQUENCING DATA

4420
02:38:26,923 --> 02:38:29,392
AND SEE IF WE CAN FIND MARKERS

4421
02:38:29,392 --> 02:38:30,126
OF MICROGLIAL ACTIVITY AND WE

4422
02:38:30,126 --> 02:38:33,062
LOOKED INTO THE LITERATURE TO

4423
02:38:33,062 --> 02:38:34,330
FIND OUT WHAT MICROGLIAL

4424
02:38:34,330 --> 02:38:36,532
ACTIVITY THERE WERE AND LOOKING

4425
02:38:36,532 --> 02:38:37,967
INTO THE ALZHEIMERS LITERATURE

4426
02:38:37,967 --> 02:38:40,603
AND WE ENDED UP SEEING THAT A

4427
02:38:40,603 --> 02:38:41,904
TEEP UPREGULATION FOR THAT

4428
02:38:41,904 --> 02:38:43,406
ENTIRE MONTH POST INFECTION WIND

4429
02:38:43,406 --> 02:38:46,209
O THAT WE'RE LOOKING AT OF

4430
02:38:46,209 --> 02:38:50,380
MICROGLIAL MARKERS THAT WERE

4431
02:38:50,380 --> 02:38:52,749
SPECIFIC FOR PH AGO-6 ACTIVITY

4432
02:38:52,749 --> 02:38:53,916
AND WHERE MICROGLIA CAN MEET

4433
02:38:53,916 --> 02:38:56,185
PARTS OF NEURONS TO HELP GUIDE

4434
02:38:56,185 --> 02:38:56,853
DEVELOPMENT AND INNERVATION.

4435
02:38:56,853 --> 02:38:59,989
SO HERE WE SAW UPREGULATION OF

4436
02:38:59,989 --> 02:39:02,759
THE COMPLEMENT C1 A AND 3, AND

4437
02:39:02,759 --> 02:39:04,394
THEIR REQUISITE RECEPTORS WHICH

4438
02:39:04,394 --> 02:39:08,197
ARE ALL USED TO MARK DEBRISS AND

4439
02:39:08,197 --> 02:39:10,299
OTHER SYNAPTIC PRUNING SITES IN

4440
02:39:10,299 --> 02:39:12,135
THE SYSTEM BY THE MICROGRIA.

4441
02:39:12,135 --> 02:39:15,138
AND WE AWE ADDITION, SUCH AS

4442
02:39:15,138 --> 02:39:17,407
TRAN 2 AND THE COMPONENT

4443
02:39:17,407 --> 02:39:18,274
SIGNALING COMPLEXES AND FURTHER

4444
02:39:18,274 --> 02:39:22,512
MOIRE WHEN WE LOOK AT GENE SET

4445
02:39:22,512 --> 02:39:23,312
ENRICHMENT ANALYSIS SIMILAR TO

4446
02:39:23,312 --> 02:39:26,149
WHAT WE HAD SEEN EARLIER, WE SAW

4447
02:39:26,149 --> 02:39:27,717
A SIMILAR LATE RISING PHENOTYPE,

4448
02:39:27,717 --> 02:39:30,286
WITH THE BRUINING THAT SEEMS TO

4449
02:39:30,286 --> 02:39:31,554
CORRELATE WITH THE MICROGLIAL

4450
02:39:31,554 --> 02:39:31,821
SIGNATURE.

4451
02:39:31,821 --> 02:39:34,757
SO I AT THIS POINT IT LOOKS LIKE

4452
02:39:34,757 --> 02:39:36,959
MICRODPLIA SEEM TO BE FLOCKING

4453
02:39:36,959 --> 02:39:39,395
TOWARDS THE OLYMPIC PACTRY BULB

4454
02:39:39,395 --> 02:39:42,231
AND UPREGULATING IT ON THE TYPE

4455
02:39:42,231 --> 02:39:42,899
1 IRPT FORON RESPONSIVE, HOWEVER

4456
02:39:42,899 --> 02:39:43,866
OUR NEXT QUESTION IS WHAT ARE

4457
02:39:43,866 --> 02:39:45,635
THEY GOING OUT TO BECAUSE WHAT

4458
02:39:45,635 --> 02:39:46,969
ARE THEY GOING TO EAT IN AND

4459
02:39:46,969 --> 02:39:48,571
BASED ON THE LOCALIZATION OF THE

4460
02:39:48,571 --> 02:39:49,972
SIGNAL LINE WHERE ALL THESE

4461
02:39:49,972 --> 02:39:50,840
THINGINGS WERE HAPPENING, OUR

4462
02:39:50,840 --> 02:39:55,244
FIRST THOUGHT WAS ARE THEY

4463
02:39:55,244 --> 02:39:58,147
ACTUALLY EATING ALL OF THESE

4464
02:39:58,147 --> 02:40:00,183
RESIDUALY DEBRIS FROM THE

4465
02:40:00,183 --> 02:40:00,883
NEURONS FOLLOWING SARS-COV-2

4466
02:40:00,883 --> 02:40:03,653
INFECTION, AND SO, WE WANT--FROM

4467
02:40:03,653 --> 02:40:04,754
OUR HISTOLOGY, COHORT, WE

4468
02:40:04,754 --> 02:40:07,290
QUANTIFIED THE IN. TENSITY OF

4469
02:40:07,290 --> 02:40:09,192
OMP, AGAIN MARKERS FOR OLFACTORY

4470
02:40:09,192 --> 02:40:10,226
SENSORY NEURON IN THE PATIENT IN

4471
02:40:10,226 --> 02:40:11,994
THIS TISSUE AT LATER TIME POINTS

4472
02:40:11,994 --> 02:40:14,597
POST INFECTION AND EVEN THOUGH

4473
02:40:14,597 --> 02:40:15,631
OLFACTORY SENSORY NEURONS SEEM

4474
02:40:15,631 --> 02:40:17,867
TO HAVE PEAK CLEARANCE AT AROUND

4475
02:40:17,867 --> 02:40:19,268
5 DAYS POST INFECTION AND THERE

4476
02:40:19,268 --> 02:40:22,171
SEEMED TO BE DELAYED CLEARANCE

4477
02:40:22,171 --> 02:40:23,873
OF THE OMP SIGNATURE INSIDE THE

4478
02:40:23,873 --> 02:40:25,341
OLFACTORY BULB SO TO US IT LOOKS

4479
02:40:25,341 --> 02:40:26,042
LOAMACYIC THESE MIGHT BE EATING

4480
02:40:26,042 --> 02:40:28,244
SOME OF THE DEBRIS FROM THE

4481
02:40:28,244 --> 02:40:36,385
OLFACTORY SENSORY, FROM ACUTE

4482
02:40:36,385 --> 02:40:36,586
INFEC.

4483
02:40:36,586 --> 02:40:37,920
SO OUR MODEL FOR WHAT'S GOING

4484
02:40:37,920 --> 02:40:39,989
ON, WE THINK THAT THEY'RE NOT

4485
02:40:39,989 --> 02:40:41,290
NECESSARILY INFACTED BUT DAMAGE

4486
02:40:41,290 --> 02:40:43,259
TO THE EPITHELIUM CAN CAUSE

4487
02:40:43,259 --> 02:40:44,794
THESE TO SLUFF OFF INTO THE NOSE

4488
02:40:44,794 --> 02:40:46,129
AND YOU GET SENSORY NEURON LOSS.

4489
02:40:46,129 --> 02:40:48,898
THIS LEADS TO THE FORMATION OF

4490
02:40:48,898 --> 02:40:50,533
SOME NEURONAL DEBRIS AS A RESULT

4491
02:40:50,533 --> 02:40:52,068
OF THIS INTERACTION AS WELL AS

4492
02:40:52,068 --> 02:40:53,503
THE STOP AS WELL AS THE

4493
02:40:53,503 --> 02:40:54,971
INHIBITION OF TIGER

4494
02:40:54,971 --> 02:40:55,705
DATABASEINALLING GOING TOWARDS

4495
02:40:55,705 --> 02:40:57,840
DEEPER AREAS OF THE OLFACTORY

4496
02:40:57,840 --> 02:41:00,143
BULB LEADING TO A DECREASE IN

4497
02:41:00,143 --> 02:41:01,577
NEURONAL FUNCTION IN THIS AREA,

4498
02:41:01,577 --> 02:41:05,548
FURTHER MORE THAT DEBRIS ISN'T

4499
02:41:05,548 --> 02:41:06,649
JUST DOING NOTHING, IT'S

4500
02:41:06,649 --> 02:41:08,818
RECRUITING WHAT APPEARS TO BE A

4501
02:41:08,818 --> 02:41:09,752
MACROPHAGE OR MICRODPLEEL

4502
02:41:09,752 --> 02:41:11,687
POPULATION THAT IS TYPE 1

4503
02:41:11,687 --> 02:41:12,688
INTERFERON RESPONSIVE AND THIS

4504
02:41:12,688 --> 02:41:14,757
EPPEDS UP DOING IS CAUSING THE

4505
02:41:14,757 --> 02:41:15,825
OLFACTORY BULBS TO BE

4506
02:41:15,825 --> 02:41:16,993
IBT--INTEGRATE FLAMED WITH A

4507
02:41:16,993 --> 02:41:17,860
TYPE 1 SIGNATURE FOR GREATER

4508
02:41:17,860 --> 02:41:24,500
THAN A MONTH FOLLOWING THE

4509
02:41:24,500 --> 02:41:24,767
INFECTION.

4510
02:41:24,767 --> 02:41:26,302
SO, EVEN THOUGH THIS IS THE IN

4511
02:41:26,302 --> 02:41:28,037
OLFACTORY BULB AND MOST OF THE

4512
02:41:28,037 --> 02:41:30,406
SMELL, THE OLFACTORY BULB ITSELF

4513
02:41:30,406 --> 02:41:32,508
IT HEAVILY CONNECTED TO THE SUCH

4514
02:41:32,508 --> 02:41:34,644
AS THE EMILY CIBOL SYSTEM,

4515
02:41:34,644 --> 02:41:36,279
MEMORY, AND BEHAVIOR AND A LOT

4516
02:41:36,279 --> 02:41:39,549
OF ACTUALLY HUMAN MRI STUDIES

4517
02:41:39,549 --> 02:41:41,817
HAVE SEEN THAT IN POST COVID

4518
02:41:41,817 --> 02:41:42,785
INDIVIDUALS WHEN YOU DO--WHEN

4519
02:41:42,785 --> 02:41:45,221
YOU LOOK AT THE BRAIN, YOU CAN

4520
02:41:45,221 --> 02:41:46,789
SEE GRAY MATTER CHANGES IN A LOT

4521
02:41:46,789 --> 02:41:48,758
OF AREAS THAT ARE FUNCTIONALLY

4522
02:41:48,758 --> 02:41:50,293
LINKED TO OLFACTORY BULB, THERE

4523
02:41:50,293 --> 02:41:52,195
IS A HYPOTH IS THAT 1 MIGHT BE

4524
02:41:52,195 --> 02:41:54,063
DRIVING THIS, FOR DEC OR

4525
02:41:54,063 --> 02:41:57,033
INFLAMMATORY PATHWAYS OR A LESS

4526
02:41:57,033 --> 02:41:58,801
OF SENSORY INPUT DUE TO

4527
02:41:58,801 --> 02:41:59,869
INHOSPITALITY, SO WE THINK THERE

4528
02:41:59,869 --> 02:42:01,304
IS A MECHANISM THAT MIGHT

4529
02:42:01,304 --> 02:42:03,206
PROVIDE AN EXPLANATION FOR WHY

4530
02:42:03,206 --> 02:42:04,574
THESE HAPPEN AND SARS-COV-2

4531
02:42:04,574 --> 02:42:08,744
INFECTION EVEN WITHOUT CHRONIC

4532
02:42:08,744 --> 02:42:09,378
OR PERSISTENT INFECTION.

4533
02:42:09,378 --> 02:42:11,247
SO IN CONCLUSION WE HAVE SHOWN A

4534
02:42:11,247 --> 02:42:12,682
FEW THINGS ABOUT LONG COVID BUT

4535
02:42:12,682 --> 02:42:14,317
KIND OF TAKING A STEP BACK AND

4536
02:42:14,317 --> 02:42:16,185
TALKING ABOUT THE HAMSTER MODEL

4537
02:42:16,185 --> 02:42:17,153
GENERALLY.

4538
02:42:17,153 --> 02:42:19,322
IT'S BEEN A REALLILY GREAT

4539
02:42:19,322 --> 02:42:20,790
PLATFORM FOR ACUTE SARS-COV-2

4540
02:42:20,790 --> 02:42:22,625
PATHOLOGY AND PARTICULARLY FOR

4541
02:42:22,625 --> 02:42:23,292
MODELING PATHOLOGY, HAMSTERS

4542
02:42:23,292 --> 02:42:24,660
LOSE A SENSE OF SMELL SO IT'S

4543
02:42:24,660 --> 02:42:27,029
BEEN GREAT TO USE THEM FOR

4544
02:42:27,029 --> 02:42:28,464
INVESTIGATOR OF ACUTE INFECTION,

4545
02:42:28,464 --> 02:42:29,699
FURTHER MORE SYSTEMIC INFLAMMA

4546
02:42:29,699 --> 02:42:32,101
ARE TOY RESPONSES HAVE BEEN

4547
02:42:32,101 --> 02:42:33,903
INSIGHTFUL FOR LEARNING ABOUT

4548
02:42:33,903 --> 02:42:35,605
HOW THE DISEASE REFLEBTS THE

4549
02:42:35,605 --> 02:42:36,939
ENTIRE BODY, THE TROAPISM IS

4550
02:42:36,939 --> 02:42:39,942
NICE FOR MODELING THE INFECTION,

4551
02:42:39,942 --> 02:42:40,876
HOWEVER, HAMSTERS AS HAS BEEN

4552
02:42:40,876 --> 02:42:42,211
SAID A FEW TYPES TODAY, THEY'RE

4553
02:42:42,211 --> 02:42:44,413
NOT MICE AND WE ARE EMILY THED

4554
02:42:44,413 --> 02:42:45,514
BY REEAMENTS SO WE DON'T HAVE

4555
02:42:45,514 --> 02:42:46,816
ALL THE ANTIBODY SAYS WE LIKE TO

4556
02:42:46,816 --> 02:42:49,552
HAVE, WE HAVE A LOT OF CELL TYPE

4557
02:42:49,552 --> 02:42:51,320
SPECIFIC GENETIC MOLL MODELS WE

4558
02:42:51,320 --> 02:42:53,422
LIKE TO HAVE IN MOUSE ELEMENTS

4559
02:42:53,422 --> 02:42:55,791
AND THEIR CONTINUES TO BE

4560
02:42:55,791 --> 02:42:56,659
DEVELOPING BIO-INFORMATICS

4561
02:42:56,659 --> 02:42:59,662
PIPELINES SO WE'RE LIMITED TO

4562
02:42:59,662 --> 02:43:00,329
OMICS TECHNOLOGIES AND EVEN

4563
02:43:00,329 --> 02:43:02,231
THOUGH IT IS A VALUABLE MODEL,

4564
02:43:02,231 --> 02:43:04,233
THERE IS ROOM TO GROW AND I

4565
02:43:04,233 --> 02:43:06,636
THINK IT'S WORTH IT.

4566
02:43:06,636 --> 02:43:10,506
WITH THAT THANKS TO THE LAB, AND

4567
02:43:10,506 --> 02:43:14,143
A WHOA LOT OF OTHER PEOPLE WHO

4568
02:43:14,143 --> 02:43:15,444
HELPED OUT IN CREATING THIS

4569
02:43:15,444 --> 02:43:15,678
PROJECT.

4570
02:43:15,678 --> 02:43:26,122
I CAN TAKE ANY QUESTIONS.

4571
02:43:28,024 --> 02:43:28,924
>> THANK YOU VERY MUCH
EMPLOY WE

4572
02:43:28,924 --> 02:43:34,196
HAVE  TIME FOR A FEW QUESTIONS.

4573
02:43:34,196 --> 02:43:34,664
SEEMA?

4574
02:43:34,664 --> 02:43:38,034
>> IN THE HAMSTER MODEL,
AFTER

4575
02:43:38,034 --> 02:43:48,511
30 DAYS,  WHAT IS THE--LIKE

4576
02:43:50,046 --> 02:43:51,247
RECURRENT INFECS IN HUMANS?

4577
02:43:51,247 --> 02:43:52,848
>> IT'S A IMRAIT QUESTION.

4578
02:43:52,848 --> 02:43:55,685
WE ACTUALLY HAVEN'T DONE

4579
02:43:55,685 --> 02:43:58,754
RECURRENT INFECTIONS THE CLOSEST

4580
02:43:58,754 --> 02:44:00,389
WE'VE DONE IS A POST DOC IN OUR

4581
02:44:00,389 --> 02:44:02,024
GROUP A YORE OR 2 AGO DID A

4582
02:44:02,024 --> 02:44:05,928
TODAY WHERE HE WAS LOOKING AT

4583
02:44:05,928 --> 02:44:07,897
KAN--KANA INFECTION WITH 1

4584
02:44:07,897 --> 02:44:09,765
STRAIN OF SARS-COV-2 LEAD TO

4585
02:44:09,765 --> 02:44:11,634
ANOTHER INFECTION OF SARS-COV-2

4586
02:44:11,634 --> 02:44:14,704
AND WE HAD SEEN YOU DO GET

4587
02:44:14,704 --> 02:44:18,908
ADEQUATE PROTECTION FROM PRIOR

4588
02:44:18,908 --> 02:44:20,009
VARIANT STRAINS WITHIN THE O

4589
02:44:20,009 --> 02:44:25,314
WILL FACTORY--AND WE CONTINUE TO

4590
02:44:25,314 --> 02:44:26,782
LOOK FOR DAMAGE AGAIN AT THAT

4591
02:44:26,782 --> 02:44:26,982
TIME.

4592
02:44:26,982 --> 02:44:28,884
>> I HAVE 1 QUESTION FOR
THE

4593
02:44:28,884 --> 02:44:31,354
KLEIN GROUP AT WASH-U HAD SHOWN

4594
02:44:31,354 --> 02:44:33,689
IN THE CONTENTS OF WEST NILE

4595
02:44:33,689 --> 02:44:35,558
VIRUS THAT INTERFERON-GAMMA CAN

4596
02:44:35,558 --> 02:44:38,761
LEAD TO MICROFLEEL ACTIVATION

4597
02:44:38,761 --> 02:44:40,029
LEADING TO NEURONAL SYNAPSE

4598
02:44:40,029 --> 02:44:40,296
PRUNING.

4599
02:44:40,296 --> 02:44:42,164
IN YOUR MODEL HAVE BEEN ABLE TO

4600
02:44:42,164 --> 02:44:44,266
DIFFERENTIATE THE IMPACT OF TYPE

4601
02:44:44,266 --> 02:44:46,836
1 VERSUS TYPE 2 INTERFERON, AND

4602
02:44:46,836 --> 02:44:47,937
ESSENTIALLY INDUCE ANTIVIRAL

4603
02:44:47,937 --> 02:44:49,238
YEENS, OR THINKING IT'S TIME 1

4604
02:44:49,238 --> 02:44:52,341
BUT IT CAN BE TYPE 2 IN A MODEL

4605
02:44:52,341 --> 02:44:54,744
SHE ALSO SHOWED A ROLE FOR

4606
02:44:54,744 --> 02:44:59,482
T-CELLS AS WELL, SECRETING

4607
02:44:59,482 --> 02:45:00,583
INTERFERON-GAMMA EMPLOY.

4608
02:45:00,583 --> 02:45:01,884
>> YEAH, GREAT QUESTION
AND IT'S

4609
02:45:01,884 --> 02:45:03,219
SOMETHING WE LOOKED AT FOR THE

4610
02:45:03,219 --> 02:45:04,653
T-CELL AND WE LOOKED FOR T-CELLS

4611
02:45:04,653 --> 02:45:06,522
AND WE THOUGHT WE WERE GOING TO

4612
02:45:06,522 --> 02:45:08,124
FIND T-CELLS AND WE HAVEN'T

4613
02:45:08,124 --> 02:45:12,495
FOUND THEM SOY DO SEE INCREASED

4614
02:45:12,495 --> 02:45:13,863
PRESENCE IN OLFACTORY EPITHELIUM

4615
02:45:13,863 --> 02:45:17,433
IMNLLY BUT THEY'RE NOT THERE IN

4616
02:45:17,433 --> 02:45:19,034
MASSIVE AMOUNTS ESPECIALLY IN

4617
02:45:19,034 --> 02:45:19,668
THE BULB ITSELF.

4618
02:45:19,668 --> 02:45:20,903
IT'S DRIVEN MORE LOCALLY.

4619
02:45:20,903 --> 02:45:23,139
WHEN WE LOOK CLOSELY, WE CAN

4620
02:45:23,139 --> 02:45:24,974
UPDATE THE HAMSTER HAN OITATION,

4621
02:45:24,974 --> 02:45:29,111
WE CAN SEE SOME TYPES OF TYPE 1

4622
02:45:29,111 --> 02:45:32,815
FIRNT FERON BEING EXPRESSED IT'S

4623
02:45:32,815 --> 02:45:34,984
LOW LEVELS, BUT WE SEE IT AT 10

4624
02:45:34,984 --> 02:45:36,152
AND 14 DAYS POST INFECTION AND

4625
02:45:36,152 --> 02:45:38,788
WE THINK ALL OF THAT'S LIKELY

4626
02:45:38,788 --> 02:45:40,389
HAPPENING LOCALLY, THERE'S ALSO

4627
02:45:40,389 --> 02:45:41,524
SOME TISSUE EXPWRIEWKS PATTERNS

4628
02:45:41,524 --> 02:45:43,292
WHICH I DIDN'T SHOW HERE WHICH

4629
02:45:43,292 --> 02:45:45,728
HAVE US THINKING THAT THE

4630
02:45:45,728 --> 02:45:46,695
INTERFERON ITSELF IS ACTUALLY

4631
02:45:46,695 --> 02:45:48,197
COMING FROM INSIDE THE OLFACTORY

4632
02:45:48,197 --> 02:45:49,832
BULB AND WITHOUT THE T-CELLS

4633
02:45:49,832 --> 02:45:51,500
THERE, WE'RE NOT SURE WE WOULD

4634
02:45:51,500 --> 02:45:52,802
BE PRODUCING THE FAMILIES GAMMA

4635
02:45:52,802 --> 02:45:54,737
ITSELF BUT WITH THAT WE ALSO

4636
02:45:54,737 --> 02:45:59,275
DON'T SEE A LOT OF ISSFERON

4637
02:45:59,275 --> 02:46:02,178
GAMMA SEQUENCING EITHER.

4638
02:46:02,178 --> 02:46:03,112
>> PETER?

4639
02:46:03,112 --> 02:46:08,284
>> SO WHAT ISOLATE OR
VARIANT DO

4640
02:46:08,284 --> 02:46:10,419
YOU THINK THIS WAS?

4641
02:46:10,419 --> 02:46:12,188
AND SO CERTAIN VARIANTS WITH

4642
02:46:12,188 --> 02:46:13,823
LOSS OF SMELL?

4643
02:46:13,823 --> 02:46:14,523
YOUR THOUGHTS ON THAT?

4644
02:46:14,523 --> 02:46:16,192
>> GREAT QUESTION AND 1 I
HAVE

4645
02:46:16,192 --> 02:46:18,594
BEEN THINKING ABOUT, MYSELF,

4646
02:46:18,594 --> 02:46:19,562
UNFORTUNATELY HAVEN'T DONE THOSE

4647
02:46:19,562 --> 02:46:21,430
STUDIES YET BUT IT'S ON THE

4648
02:46:21,430 --> 02:46:23,732
AGENDA FOR SURE, SO THIS WAS

4649
02:46:23,732 --> 02:46:24,767
DONE USING ANCESTRAL VARIANT,

4650
02:46:24,767 --> 02:46:26,435
THIS WAS THE WASHINGTON U STRAIN

4651
02:46:26,435 --> 02:46:27,770
FOR THE STUDIES BUT WE TARTED

4652
02:46:27,770 --> 02:46:28,737
WO,ING WITH,A DITIONAL TRAINS

4653
02:46:28,737 --> 02:46:29,939
AND 1 OF OUR FIRST THINGS WE

4654
02:46:29,939 --> 02:46:33,108
WANT TO DO IS TEST SMELL LOSS

4655
02:46:33,108 --> 02:46:34,643
FOR THOSE VARIANT ANDS DO A

4656
02:46:34,643 --> 02:46:38,380
COMPARISON AND SEE IF WE GET

4657
02:46:38,380 --> 02:46:39,615
THESE LONGITUDINAL AND

4658
02:46:39,615 --> 02:46:40,149
INFLAMMATORY PHENOMENON.

4659
02:46:40,149 --> 02:46:45,988
>> A LOT OF NICE DATA.

4660
02:46:45,988 --> 02:46:47,590
NYOU SHOWED EARLY STAGE ALMOST

4661
02:46:47,590 --> 02:46:49,358
[INDISCERNIBLE] EACH OTHER IN

4662
02:46:49,358 --> 02:46:51,060
TERMS OF GENETIC THAN THE

4663
02:46:51,060 --> 02:46:52,828
[INDISCERNIBLE] HAVE YOU DO ANY

4664
02:46:52,828 --> 02:46:55,664
CO INFECTION YET?

4665
02:46:55,664 --> 02:46:59,668
>> I HAVEN'T YET BUT IN
THE

4666
02:46:59,668 --> 02:47:00,469
[INDISCERNIBLE] LABORATORY BUT

4667
02:47:00,469 --> 02:47:02,705
THEY HAD DONE DAY 1 POST

4668
02:47:02,705 --> 02:47:04,006
INFECTION FLU FOLLOWED BY SARS

4669
02:47:04,006 --> 02:47:06,208
AND VICE VERSA AND SHOWED

4670
02:47:06,208 --> 02:47:07,276
PROTECTIVE EFFECTS FROM 1 TO THE

4671
02:47:07,276 --> 02:47:07,576
OTHER.

4672
02:47:07,576 --> 02:47:10,513
IF I REMEMBER CORRECTLY, PRIOR

4673
02:47:10,513 --> 02:47:12,448
EXISTING SARS INFECTION LIMITED

4674
02:47:12,448 --> 02:47:14,984
SPREAD OF FLU BUT I WOULD DOUBLE

4675
02:47:14,984 --> 02:47:17,086
CHECK THAT, I AM HAPPY TO TALK

4676
02:47:17,086 --> 02:47:18,521
AFTER TO GIVE YOU THAT PAPER.

4677
02:47:18,521 --> 02:47:23,659
>> THANK YOU VERY MUCH.

4678
02:47:23,659 --> 02:47:23,959
GREAT TALK.

4679
02:47:23,959 --> 02:47:26,862
>> AND OUR FINAL SPEAKER
OF THIS

4680
02:47:26,862 --> 02:47:28,464
SESSION IS SABRA KLEIN FROM

4681
02:47:28,464 --> 02:47:29,565
JOHNS HOPKINS UNIVERSITY AND SHE

4682
02:47:29,565 --> 02:47:31,166
WILL TALK ABOUT SEX DIFFERENCES

4683
02:47:31,166 --> 02:47:41,677
IN ANIMAL MODELS OF INFLUENZA

4684
02:47:42,811 --> 02:47:43,312
AND SARS-COV-2.

4685
02:47:43,312 --> 02:47:43,679
>> THANK YOU.

4686
02:47:43,679 --> 02:47:46,749
AND THANK YOU TO THE ORGANIZERS

4687
02:47:46,749 --> 02:47:47,449
FOR INCLUDING THIS TOPIC.

4688
02:47:47,449 --> 02:47:50,553
TODAY RATHER THAN GIVE A STORY

4689
02:47:50,553 --> 02:47:52,187
WITH A SINGLE VIRUS, I WILL GIVE

4690
02:47:52,187 --> 02:47:54,156
YOU A LOT OF VIGNETTES,

4691
02:47:54,156 --> 02:47:56,525
HOPEFULLY TO GIVE YOU THE MODELS

4692
02:47:56,525 --> 02:47:58,394
AVAILABLE AND THAT WE UTILIZED

4693
02:47:58,394 --> 02:48:00,729
TO ANSWER QUESTIONS ABOUT

4694
02:48:00,729 --> 02:48:07,202
DIFFERENCES BETWEEN MALES AND

4695
02:48:07,202 --> 02:48:09,071
FEMALES EMPLOY SO I THOUGHT WE

4696
02:48:09,071 --> 02:48:12,341
COULD START WITH WHAT SEX AS A

4697
02:48:12,341 --> 02:48:12,875
BIOLOGICAL VARIABLE MEANS.

4698
02:48:12,875 --> 02:48:14,877
BECAUSE I KNOW EACH OF YOU

4699
02:48:14,877 --> 02:48:17,012
WRITES THIS IN YOUR NIH GRANTS.

4700
02:48:17,012 --> 02:48:19,882
SO WHAT THIS IS REFERRING TO ARE

4701
02:48:19,882 --> 02:48:20,749
THE BIOLOGICAL DIFFERENCES

4702
02:48:20,749 --> 02:48:24,687
BETWEEN FEMALES AND MALES.

4703
02:48:24,687 --> 02:48:26,789
FEMALES HAVING 2 X CHROMOSOMES,

4704
02:48:26,789 --> 02:48:29,525
MALES HAVE AN X AND A Y, THERE

4705
02:48:29,525 --> 02:48:30,926
CAN BE DIFFERENCES IN SEXUAL

4706
02:48:30,926 --> 02:48:34,330
DEVELOPMENT THAT CAN LEAD TO

4707
02:48:34,330 --> 02:48:35,698
DIVERSITY IN SEX CHROMOSOME

4708
02:48:35,698 --> 02:48:37,766
COMPLEMENT AND I WILL TALK ABOUT

4709
02:48:37,766 --> 02:48:40,469
THAT SO I WILL HOLD YOU THERE.

4710
02:48:40,469 --> 02:48:43,205
BUT 1 THING THAT'S REALLY

4711
02:48:43,205 --> 02:48:45,674
IMPORTANT ON THE TINY

4712
02:48:45,674 --> 02:48:49,111
Y-CHROMOSOME IS A GENE CALLED

4713
02:48:49,111 --> 02:48:49,878
SRY.

4714
02:48:49,878 --> 02:48:53,616
AND WHAT SRY ENCODES FOR IS THE

4715
02:48:53,616 --> 02:48:54,483
DETERMINING IN FACTOR AND THAT

4716
02:48:54,483 --> 02:48:56,051
WILL BE IMPORTANT IN SOME OF OUR

4717
02:48:56,051 --> 02:48:56,885
DISCUSSIONS TODAY AS WELL.

4718
02:48:56,885 --> 02:48:59,588
SO I WILL ASK YOU TO HOLD ON TO

4719
02:48:59,588 --> 02:49:01,790
THIS. 

4720
02:49:01,790 --> 02:49:03,659
BUT 1 THING THAT TEST ESTIMATE

4721
02:49:03,659 --> 02:49:05,527
THAD DETERMINING FACTOR DOES IS

4722
02:49:05,527 --> 02:49:06,795
EARLY ON EMBRYONIC DEVELOPMENT

4723
02:49:06,795 --> 02:49:08,364
ALL OF US HUMANS AND MICE ALIKE

4724
02:49:08,364 --> 02:49:11,700
IS WE ALL START OUT WITH A

4725
02:49:11,700 --> 02:49:12,868
BI-POTENTIAL GONAD THAT CAN GO

4726
02:49:12,868 --> 02:49:16,739
AND DEVELOP EITHER WAY AND IN

4727
02:49:16,739 --> 02:49:18,707
THE PRESENCE OF CERTAIN SIGNALS

4728
02:49:18,707 --> 02:49:26,448
INCLUDING THIS  TESTIS THAT IT

4729
02:49:26,448 --> 02:49:32,054
DEVELOPS INTO A TESTES, BUT IN

4730
02:49:32,054 --> 02:49:34,623
THE ABSENCE OF SRY WE WILL GOET

4731
02:49:34,623 --> 02:49:35,557
THAT DEVELOPMENT AT TISSUE INTO

4732
02:49:35,557 --> 02:49:36,859
THE FETAL COMPARTMENT

4733
02:49:36,859 --> 02:49:37,793
MALPRODUCTIVE TRACT.

4734
02:49:37,793 --> 02:49:40,062
SO I WILL TALK TODAY ABOUT SEX

4735
02:49:40,062 --> 02:49:42,031
CHROME SOAPS, I WILL TALK TODAY

4736
02:49:42,031 --> 02:49:45,534
ABOUT SEX CHROMOSOME GENES BUT

4737
02:49:45,534 --> 02:49:48,170
I'M ALSO GOING TO TALK A BIT

4738
02:49:48,170 --> 02:49:50,272
TODAY ABOUT THE GONEADAL

4739
02:49:50,272 --> 02:49:53,042
STEROIDS THAT HAVE THE PRESENCE

4740
02:49:53,042 --> 02:49:55,577
OF OVARIES OR THE PRESENCE OF

4741
02:49:55,577 --> 02:49:56,145
TESTES.

4742
02:49:56,145 --> 02:49:58,981
SO THESE HORMONES THESE ARE

4743
02:49:58,981 --> 02:50:00,749
STEROID HORMONES WHEN WE THINK

4744
02:50:00,749 --> 02:50:03,552
ABOUT STEROIDS WE THINK ABOUT

4745
02:50:03,552 --> 02:50:05,554
THE TBLIEWK O CORTICOIDS AND HOW

4746
02:50:05,554 --> 02:50:07,056
THEY FUNCTION AND HOW THEY CAN

4747
02:50:07,056 --> 02:50:12,261
DO  THINGS LIKE BEAUTIFULLY

4748
02:50:12,261 --> 02:50:14,430
DAMPEN INFLAMMATION BUT TODAY I

4749
02:50:14,430 --> 02:50:17,366
WILL TALK ABOUT THESE GONADAL

4750
02:50:17,366 --> 02:50:18,801
STEROIDS, ANDROGEN ROUGH

4751
02:50:18,801 --> 02:50:21,370
ATOMIENS AND ESTROGENS HOW THESE

4752
02:50:21,370 --> 02:50:22,905
CAN BE IMMUNOMODULATORY.

4753
02:50:22,905 --> 02:50:29,478
AND PART OF HOW THEY'RE

4754
02:50:29,478 --> 02:50:30,379
IMMUNOMODULATORY, IS THAT EVERY

4755
02:50:30,379 --> 02:50:31,346
SINGLE STYLE WE HAVE LOOKEDDA

4756
02:50:31,346 --> 02:50:34,717
THE IN HUMAN AND THEY HAVE

4757
02:50:34,717 --> 02:50:37,519
RECEPTORS FOR THESE HORMONES.

4758
02:50:37,519 --> 02:50:38,921
SO THEY'RE LIP OPHILIC,

4759
02:50:38,921 --> 02:50:40,222
STEROIDS, THEY'RE RAPIDLY

4760
02:50:40,222 --> 02:50:41,824
CROSSING THE BILAYER WHERE THEY

4761
02:50:41,824 --> 02:50:45,627
COMBINE TO LAYERS LOCATED

4762
02:50:45,627 --> 02:50:47,329
INTRACELLULARLY TO HAVE

4763
02:50:47,329 --> 02:50:47,896
CANNONICLE GENOMIC EFFECTS.

4764
02:50:47,896 --> 02:50:51,266
SO I LIKE TO THINK ABOUT

4765
02:50:51,266 --> 02:50:53,769
SPHEROIDS AS TRANSCRIPTIONAL

4766
02:50:53,769 --> 02:50:54,870
REGULATES OF IMMUNE CELL

4767
02:50:54,870 --> 02:50:55,137
FUNCTION.

4768
02:50:55,137 --> 02:50:56,405
SO ULTIMATELY WHEN WE THINK

4769
02:50:56,405 --> 02:50:57,840
ABOUT VIRAL DECS WHICH IS WHY

4770
02:50:57,840 --> 02:50:59,675
WE'RE ALL HERE, TALKING ABOUT

4771
02:50:59,675 --> 02:51:07,649
MODELING THESE VIRAL DECS MY

4772
02:51:07,649 --> 02:51:09,585
GROUP AND OTHERS HAVE GENERALLY

4773
02:51:09,585 --> 02:51:11,687
SPEAKING THE GOOD, BAD AND UGLY

4774
02:51:11,687 --> 02:51:13,355
OF ALL THIS REGULATION EMPLOY SO

4775
02:51:13,355 --> 02:51:16,225
WHEN I'M OFTEN ASKED IN A

4776
02:51:16,225 --> 02:51:18,060
QUESTION AND ANSWER SESSION TO

4777
02:51:18,060 --> 02:51:19,695
DESCRIBE HOW FEMALES ARE BETTER

4778
02:51:19,695 --> 02:51:21,597
I WOULD NEVER SAY THAT FEMALES

4779
02:51:21,597 --> 02:51:22,965
ARE NECESSARILY BETTER THAN

4780
02:51:22,965 --> 02:51:24,867
MALES AND AS WE GO THROUGH OUR

4781
02:51:24,867 --> 02:51:27,169
DAT AWE WILL SEE THIS, IT'S THAT

4782
02:51:27,169 --> 02:51:28,937
THEY'RE DIFFERENT AND THERE CAN

4783
02:51:28,937 --> 02:51:34,143
BE PLUSES AND MINUSES TO AN

4784
02:51:34,143 --> 02:51:36,078
ABROAD BRUSH STROKE TYPE OF WAY,

4785
02:51:36,078 --> 02:51:37,613
GREATER IMMUNE RESPONSES IN

4786
02:51:37,613 --> 02:51:39,481
FEMALES, FEMALES ARE MORE LIKELY

4787
02:51:39,481 --> 02:51:41,216
TO DEVELOP IMMUNE MEDIATED

4788
02:51:41,216 --> 02:51:42,618
PATHOLOGY, BUT THERE ALSO MAY BE

4789
02:51:42,618 --> 02:51:44,052
MORE LIKELY TO CLEAR VIRUSES AND

4790
02:51:44,052 --> 02:51:46,789
I WILL SHOW YOU EVIDENCE OF THIS

4791
02:51:46,789 --> 02:51:49,491
TODAY, WHEREAS FOR MALES WE HAVE

4792
02:51:49,491 --> 02:51:50,993
AN INCREASED LIKELIHOOD OF I

4793
02:51:50,993 --> 02:51:53,061
HAVE ROLL PERSISTENCE AND ALSO

4794
02:51:53,061 --> 02:51:54,129
REDUCED VACCINE IMMUNITY, AGAIN,

4795
02:51:54,129 --> 02:52:00,202
I'M GOING TO REVIEW THAT WITH US

4796
02:52:00,202 --> 02:52:00,402
TODAY.

4797
02:52:00,402 --> 02:52:02,671
SO AS WE TALK ABOUT

4798
02:52:02,671 --> 02:52:04,173
PATHOGENESIS, WHICH IS AGAIN WHY

4799
02:52:04,173 --> 02:52:06,775
WE'RE HERE, WE'RE TALKING ABOUT

4800
02:52:06,775 --> 02:52:07,676
MODELING PATHOGENESIS, I OFTEN

4801
02:52:07,676 --> 02:52:08,877
THINK ABOUT SEX DIFFERENCES IN

4802
02:52:08,877 --> 02:52:13,482
TERMS OF THIS DEC RESPONSE

4803
02:52:13,482 --> 02:52:15,584
DAMAGE MODEL WHERE I THINK WE'RE

4804
02:52:15,584 --> 02:52:17,352
ALL VERY ACCUSTOMED TO THINKING

4805
02:52:17,352 --> 02:52:18,887
ABOUT OUR DAMAGE THAT CAN OCCUR

4806
02:52:18,887 --> 02:52:22,591
AS A RESULT OF THIS CASE VIRAL

4807
02:52:22,591 --> 02:52:24,193
INFECTION AS RANGING FROM A LOW

4808
02:52:24,193 --> 02:52:26,094
DEGREE OF DAMAGE TO A HIGH

4809
02:52:26,094 --> 02:52:29,965
DEIMREE OF DAMAGE AND IF WE PLOT

4810
02:52:29,965 --> 02:52:31,733
THIS, AGAINST AN IMMUNE RESPONSE

4811
02:52:31,733 --> 02:52:34,102
WHICH CAN RANGE FROM BEING WEAK

4812
02:52:34,102 --> 02:52:35,537
TO STRONG, HERE'S YOUR DISEASE

4813
02:52:35,537 --> 02:52:36,004
RESPONSE CURVE.

4814
02:52:36,004 --> 02:52:39,474
YOU CAN GET A HIGH DEGREE OF

4815
02:52:39,474 --> 02:52:40,108
DISEASE AND HOST TISSUE CULTURE

4816
02:52:40,108 --> 02:52:41,810
MEDIA WITH THE WEAK IMMUNE

4817
02:52:41,810 --> 02:52:44,546
RESPONSE THAT DOESN'T ALLOW FOR

4818
02:52:44,546 --> 02:52:46,081
CONTROL OF VIRUS REPLICATION BUT

4819
02:52:46,081 --> 02:52:50,185
IF WE  WE FOLLOW THIS ALL THE WY

4820
02:52:50,185 --> 02:52:52,120
AROUND WE CAN GET A HIGH DEGREE

4821
02:52:52,120 --> 02:52:55,591
OF DISEASE IF WE HAVE AN

4822
02:52:55,591 --> 02:52:56,325
OVEREXUBERANT IMMUNE RESPONSE

4823
02:52:56,325 --> 02:52:59,061
WHICH CAN LEAD TO IMMUNO

4824
02:52:59,061 --> 02:52:59,328
PATHOLOGY.

4825
02:52:59,328 --> 02:53:01,463
SO ALL I'VE DONE, I'M NOT

4826
02:53:01,463 --> 02:53:03,866
CREATIVE, I DREW A SIMPLE LINE

4827
02:53:03,866 --> 02:53:06,435
AND I'M HIGHWAY POGHTICIZING AND

4828
02:53:06,435 --> 02:53:07,502
WE WILL DISCUSS DATA FROM MY

4829
02:53:07,502 --> 02:53:08,937
GROUP ARE SUPPORTING THIS

4830
02:53:08,937 --> 02:53:10,572
HYPOTHESIS BUT THAT WE WOULD SEE

4831
02:53:10,572 --> 02:53:13,342
A MALE BIAS, MEANING MALES MAY

4832
02:53:13,342 --> 02:53:14,676
SUFFER A WORSE OUTCOME THAN

4833
02:53:14,676 --> 02:53:16,278
FEMALES IF DISEASE IS BEING

4834
02:53:16,278 --> 02:53:20,048
CAUSED BY AN INABILITY TO

4835
02:53:20,048 --> 02:53:21,183
CONTROL VIRUS WHEREAS WE MIGHT

4836
02:53:21,183 --> 02:53:23,852
PREDICT WE WOULD SEE A FEMALE

4837
02:53:23,852 --> 02:53:25,287
BIAS, MEANING FEMALES MAY SUFFER

4838
02:53:25,287 --> 02:53:27,489
A WORSE OUTCOME IN THAT DISEASE

4839
02:53:27,489 --> 02:53:30,025
IS BEING CAUSED BY AN

4840
02:53:30,025 --> 02:53:37,699
OVEREXUBERANT OR MAYBE A LONGER

4841
02:53:37,699 --> 02:53:38,533
LASTING IMMUNE RESPONSE.

4842
02:53:38,533 --> 02:53:40,035
SO 1 VIRUS WE HAVE NOT TALKED

4843
02:53:40,035 --> 02:53:41,770
ABOUT HERE, I WANT TO PUT THIS

4844
02:53:41,770 --> 02:53:47,676
OUT HERE AND AIMING FOR DIVERSIY

4845
02:53:47,676 --> 02:53:49,444
WITH BROAD BRUSH STROKES.

4846
02:53:49,444 --> 02:53:53,115
SO INFLUENZA B WE HAVE 2 STRAINS

4847
02:53:53,115 --> 02:53:54,416
THAT ARE INAUR QUADRIVALENT

4848
02:53:54,416 --> 02:53:54,650
VACCINE.

4849
02:53:54,650 --> 02:53:56,952
WE HAVE A B-VICTORIOUS STRAIN

4850
02:53:56,952 --> 02:53:59,154
AND A B-[INDISCERNIBLE] STRAIN.

4851
02:53:59,154 --> 02:54:01,890
WORKING WITH DANIEL PEREZ, HE

4852
02:54:01,890 --> 02:54:04,860
WORKED WITH REVERSE GENETIC ANDS

4853
02:54:04,860 --> 02:54:06,128
DEVELOPED DIFFERENT STRAINS THAT

4854
02:54:06,128 --> 02:54:09,031
HAVE A MUTATION IN PB2 THAT

4855
02:54:09,031 --> 02:54:12,167
ALLOW THESE VIRUSES TO

4856
02:54:12,167 --> 02:54:13,302
PRODUCTIVELY INFECT MICE.

4857
02:54:13,302 --> 02:54:16,171
OKAY, SO CLINICAL ISOLATES DO

4858
02:54:16,171 --> 02:54:16,571
NOT INFECT MICE.

4859
02:54:16,571 --> 02:54:20,175
SO WHAT I'M SHOWING YOU HERE ARE

4860
02:54:20,175 --> 02:54:21,710
DATA FROM THE B-VICTORIA, BUT WE

4861
02:54:21,710 --> 02:54:25,314
SEE A SIMILAR PATTERN WITH

4862
02:54:25,314 --> 02:54:25,747
B-YAMAGADA.

4863
02:54:25,747 --> 02:54:28,317
AND WHAT WE INITIALLY DID AND WE

4864
02:54:28,317 --> 02:54:30,819
TOOK OUR ADULT MICE, TYPICALLY

4865
02:54:30,819 --> 02:54:34,022
8-10 WEEKSA THE TIME WE BEGIN

4866
02:54:34,022 --> 02:54:37,092
THESE INFECTIONS AND WE INTRA

4867
02:54:37,092 --> 02:54:39,027
NAISALLY INFECTED MALES IN GREEN

4868
02:54:39,027 --> 02:54:40,395
AND FEMALES IN PURPLE AND WE

4869
02:54:40,395 --> 02:54:49,705
NOTE THAD  MALES GOT SICKER,

4870
02:54:49,705 --> 02:54:55,277
FEMALES DIDN'T GET SICK HARDLY

4871
02:54:55,277 --> 02:54:55,844
AT ULTIMATELY.

4872
02:54:55,844 --> 02:54:57,746
SO WE TOOK MICE THAT WERE

4873
02:54:57,746 --> 02:54:58,814
JUVENILE, THEY WERE 23 DAYS AND

4874
02:54:58,814 --> 02:55:01,683
JUST AFTER THEY WERE WEANED, WE

4875
02:55:01,683 --> 02:55:04,686
INFECTED THEM WITH FLU B, THE

4876
02:55:04,686 --> 02:55:06,021
HOLD, MALES GOT SICKER THAN

4877
02:55:06,021 --> 02:55:08,023
FEMALES AND WE'RE LOOKING AT

4878
02:55:08,023 --> 02:55:10,325
RECTAL TEMPERATURE, WE DO RECTAL

4879
02:55:10,325 --> 02:55:11,326
TEMPERATURE, CLINICAL MARKERS OF

4880
02:55:11,326 --> 02:55:12,561
DISEASE, WE DO BODY MASS SO YOU

4881
02:55:12,561 --> 02:55:20,068
WILL SEE THAT THROUGHOUT.

4882
02:55:20,068 --> 02:55:23,939
SO THEN WE TOOK AGED MICE, THESE

4883
02:55:23,939 --> 02:55:27,743
MICE WERE 17 MONTH AT THE TIME

4884
02:55:27,743 --> 02:55:29,277
WE DID THESE INFECTIONS AND CAN

4885
02:55:29,277 --> 02:55:31,013
YOU SEE DEFINITELY THEY GET

4886
02:55:31,013 --> 02:55:33,582
SICKER BUT MALES AGAIN GET SICK.

4887
02:55:33,582 --> 02:55:35,450
FEMALES REALLY DON'T EVEN AT 17

4888
02:55:35,450 --> 02:55:36,885
MONTHS OF AGE.

4889
02:55:36,885 --> 02:55:40,155
WHEN WE MEASURE VIRAL TITERS IN

4890
02:55:40,155 --> 02:55:41,089
THE LUNGS, AND WAWE FIND

4891
02:55:41,089 --> 02:55:43,091
DEPENDING ON THE AGES OF THESE

4892
02:55:43,091 --> 02:55:45,093
ANIMALS, WITH YOU'VE NILES,

4893
02:55:45,093 --> 02:55:46,495
CLEARING VIRUS FASTER THAN

4894
02:55:46,495 --> 02:55:51,633
EITHER ADULT OR OLDER ADULT, BUT

4895
02:55:51,633 --> 02:55:54,870
WHAT WE FIND DPREEN MALES,

4896
02:55:54,870 --> 02:55:57,406
PURPLE FEMALES, LOG SCALE MALES

4897
02:55:57,406 --> 02:56:01,143
HAVE HIGHER VIRAL TITERS THAN

4898
02:56:01,143 --> 02:56:02,444
FEMALES DURING PEAK VIRUS

4899
02:56:02,444 --> 02:56:03,945
REPLICATION EMPLOY SO AT YOU'VE

4900
02:56:03,945 --> 02:56:07,983
NILES WE SEE THIS 3 AND 5 IN

4901
02:56:07,983 --> 02:56:09,184
ADULTS AND BY 7 MALE VS NOT

4902
02:56:09,184 --> 02:56:10,919
CLEARED AND FOR THE OLDER

4903
02:56:10,919 --> 02:56:12,220
ANIMALS MALES STILL HAVEN'T

4904
02:56:12,220 --> 02:56:15,190
CLEARED BY 9 DAYS AFTER

4905
02:56:15,190 --> 02:56:19,227
INFECTION AND WE'VE SHOWN THAT

4906
02:56:19,227 --> 02:56:21,830
THIS GREATER VIRUS REPLICATION

4907
02:56:21,830 --> 02:56:23,598
IN MALES DRIVES TYPE 1

4908
02:56:23,598 --> 02:56:25,434
INTERFERON RESPONSES SO IF WE

4909
02:56:25,434 --> 02:56:28,470
TREAT THEM WITH TAMAVIR, WE CAN

4910
02:56:28,470 --> 02:56:29,538
ELIMINATE THE SEX DIFFERENCE

4911
02:56:29,538 --> 02:56:31,406
BECAUSE WE CAN MAKE MALES LOOK

4912
02:56:31,406 --> 02:56:33,141
LIKE FEMALES.

4913
02:56:33,141 --> 02:56:38,580
FEMALES THAT GET OSILTAMAVIR,

4914
02:56:38,580 --> 02:56:39,748
DON'T LOOK THAT DIFFERENT THAN

4915
02:56:39,748 --> 02:56:41,049
THOSE THAT DON'T GET IT BECAUSE

4916
02:56:41,049 --> 02:56:43,618
THEY ARE NOT GETTING SICK IN

4917
02:56:43,618 --> 02:56:43,952
THESE MODELS.

4918
02:56:43,952 --> 02:56:45,754
FOR BOTH OUR YOUNG ADULTS 8-10

4919
02:56:45,754 --> 02:56:47,556
WEEKS OF AGE AS WELL AS OLDER

4920
02:56:47,556 --> 02:56:58,066
ADULT AS THE 17 MONTHS OF AGE.

4921
02:57:00,602 --> 02:57:01,903
YES, WE MEASURE THESE IN THE

4922
02:57:01,903 --> 02:57:04,473
LAB, AND HERE TO SHOW WHAT WE

4923
02:57:04,473 --> 02:57:07,876
SEE IF YOU MEASURE TESTOSTERONE,

4924
02:57:07,876 --> 02:57:10,479
THEY HAVE SLOW CIRCULATING

4925
02:57:10,479 --> 02:57:11,113
CONCENTRATIONS OF TESTOSTERONE

4926
02:57:11,113 --> 02:57:13,281
IN ARK DULT HOOD, THAT GOES UP,

4927
02:57:13,281 --> 02:57:14,816
THAT INCREDIBLE DIVERSITY, THOSE

4928
02:57:14,816 --> 02:57:16,118
ARE THE DOMINANCE HIERARCHIES IN

4929
02:57:16,118 --> 02:57:17,619
THE CAGES WHICH I'M CERTAIN ALL

4930
02:57:17,619 --> 02:57:23,425
OF YOU HAVE OBSERVED SO HERE ARE

4931
02:57:23,425 --> 02:57:24,426
THE SUBORDINATE MALES.

4932
02:57:24,426 --> 02:57:29,965
AND THEN AGING WHILE MICE DON'T

4933
02:57:29,965 --> 02:57:32,300
GO THROUGH THE SAME MENOPAUSE IN

4934
02:57:32,300 --> 02:57:35,770
TERMS OF FEMALES THEY DO

4935
02:57:35,770 --> 02:57:36,371
EXPERIENCE REPRODUCTIVE

4936
02:57:36,371 --> 02:57:37,873
SENESCENCE, NOT EVEN OUR FEMALES

4937
02:57:37,873 --> 02:57:40,308
BUT OUR MALES WE SEE A DECLINE

4938
02:57:40,308 --> 02:57:42,677
IN ANDROGENS BUT EACH WITH THESE

4939
02:57:42,677 --> 02:57:44,112
CHANGES INSTERIES, I THINK IT'S

4940
02:57:44,112 --> 02:57:46,681
REALLY IMPORTANT TO NOTE, WE SEE

4941
02:57:46,681 --> 02:57:48,016
THE SEX DIFFERENCE ACROSS

4942
02:57:48,016 --> 02:57:49,518
DIVERSE AGES SO THIS STARTED TO

4943
02:57:49,518 --> 02:57:54,122
SUGGEST TO US THAT MAYBE WITH MY

4944
02:57:54,122 --> 02:57:56,625
ENDOCRINOLOGY BACKGROUND, MAYBE

4945
02:57:56,625 --> 02:57:58,026
THESE GONADAL STEROIDS WERE NOT

4946
02:57:58,026 --> 02:57:58,293
INVOFFED.

4947
02:57:58,293 --> 02:58:00,729
SO WE HAVE LOTS OF DIFFERENT

4948
02:58:00,729 --> 02:58:02,697
WAYS THAT WE CAN START TO TEASE

4949
02:58:02,697 --> 02:58:05,100
APART IF IT'S NOT HORMONES, THEN

4950
02:58:05,100 --> 02:58:08,470
WHAT IS IT?

4951
02:58:08,470 --> 02:58:11,239
AND SO, AS SOMEONE WHO'S ROLELY

4952
02:58:11,239 --> 02:58:12,841
INTERESTED IN SEX BASED

4953
02:58:12,841 --> 02:58:17,479
VIROLOGY, IF IT'S NOT GONADAL

4954
02:58:17,479 --> 02:58:20,448
STEROIDS, THEN MY BRAIN GOES TO

4955
02:58:20,448 --> 02:58:21,917
SEX HORMONES BECAUSE THAT'S THE

4956
02:58:21,917 --> 02:58:22,217
DIFFERENCE.

4957
02:58:22,217 --> 02:58:23,919
WE HAVE LOTS OF TRANSGENIC MICE

4958
02:58:23,919 --> 02:58:26,655
THAT ARE AVAILABLE THAT ARE BRED

4959
02:58:26,655 --> 02:58:30,025
IN MY LAB THAT ARE NOT SMECIALLY

4960
02:58:30,025 --> 02:58:32,928
AVAILABLE AND 1 OF THEM IS

4961
02:58:32,928 --> 02:58:34,029
CALLED THE FCG, SO IF I CAN

4962
02:58:34,029 --> 02:58:38,400
BRING YOU BACK TO MY FIRST SLIDE

4963
02:58:38,400 --> 02:58:42,437
AND THAT SRY GENE THAT ENCODES

4964
02:58:42,437 --> 02:58:43,838
FOR TESTES DETERMINING FACTOR

4965
02:58:43,838 --> 02:58:46,575
WHAT'S DONE IN THE MICE IS THE

4966
02:58:46,575 --> 02:58:50,111
SRY YEEN HAS BEEN DELETED TO THE

4967
02:58:50,111 --> 02:58:51,846
Y-CHROMOSOME AND TRANSLOCATED TO

4968
02:58:51,846 --> 02:58:54,382
CHROMOSOME 3 SO THAT IT CAN BE

4969
02:58:54,382 --> 02:58:55,650
AUTOSOMEALLY INHERITED EMPLOY SO

4970
02:58:55,650 --> 02:58:57,953
NOW YOU CAN HAVE XY MICE,

4971
02:58:57,953 --> 02:59:01,423
THERE'S OUR LITTLE Y, X, CAN YOU

4972
02:59:01,423 --> 02:59:03,458
HAVE XY-MICE BUT DON'T HAVE THE

4973
02:59:03,458 --> 02:59:07,495
SRY SO THAT BI ON POTENTIAL

4974
02:59:07,495 --> 02:59:09,130
GONAD DEVELOPS INTO OVARIES.

4975
02:59:09,130 --> 02:59:11,466
WE HAVE OVARIES THAT SECRETING

4976
02:59:11,466 --> 02:59:13,468
ESTROGEN, WE ALSO HAVE X-MICE

4977
02:59:13,468 --> 02:59:16,605
THAT INHERIT THE SRY, AND SO

4978
02:59:16,605 --> 02:59:18,807
DESPITE HAVING 2 X-CHROMOSOMES

4979
02:59:18,807 --> 02:59:22,544
THEY HAVE THAT TESTES

4980
02:59:22,544 --> 02:59:27,182
DETERMINING FACTOR SO THAT GONAD

4981
02:59:27,182 --> 02:59:32,454
DEVELOPS INTO TESTES, SO CAN YOU

4982
02:59:32,454 --> 02:59:34,389
GET XXY-MALES OR XY-FEMALES SO

4983
02:59:34,389 --> 02:59:38,860
HERE WE FIND HERE FEMALES IN

4984
02:59:38,860 --> 02:59:40,562
PURPLE, OUR XX-FEMALES,

4985
02:59:40,562 --> 02:59:44,599
XX-ANIMALS WITH OVARIES AND WE

4986
02:59:44,599 --> 02:59:47,469
FIND THAT XX-MAILS SO THEY HAVE

4987
02:59:47,469 --> 02:59:49,070
2 X-CHROMES BUT THEY HAVE TEEOF

4988
02:59:49,070 --> 02:59:51,840
THE EASE THEY LOOK

4989
02:59:51,840 --> 02:59:52,440
INDISTINGUISHABLE.

4990
02:59:52,440 --> 02:59:53,141
THEY ARE PROTECTED.

4991
02:59:53,141 --> 02:59:57,479
MALES THAT HAVE AN X AND A Y

4992
02:59:57,479 --> 02:59:59,781
CHROMOSOME COMPLEMENT AS WELL AS

4993
02:59:59,781 --> 03:00:01,650
FEMALES MEANING ANIMALS WITH

4994
03:00:01,650 --> 03:00:03,251
OVARIES WITH AN XY COMPLEMENT

4995
03:00:03,251 --> 03:00:05,220
THAIZ GET AS SICK AS THE

4996
03:00:05,220 --> 03:00:08,023
BIOLOGICAL MALE.

4997
03:00:08,023 --> 03:00:08,323
OKAY?

4998
03:00:08,323 --> 03:00:11,192
SUGGESTING THAT IT'S SEX

4999
03:00:11,192 --> 03:00:13,128
CHROMOSOME COMPLEMENT MORE THAN

5000
03:00:13,128 --> 03:00:14,195
SEX STEROIDS HORMONES THAT ARE

5001
03:00:14,195 --> 03:00:15,263
MODULATING THIS DIFFERENCE AND

5002
03:00:15,263 --> 03:00:17,132
YOU CAN SEE THIS HERE, BOTH IN

5003
03:00:17,132 --> 03:00:21,136
TERMS OF VIRAL TITERS AND

5004
03:00:21,136 --> 03:00:22,637
INTERFERON BETA PRODUCTION.

5005
03:00:22,637 --> 03:00:25,940
SO WE ALSO AND I HAVE JEN LU,

5006
03:00:25,940 --> 03:00:27,375
SHE'S A POST DOC IN MY GROUP,

5007
03:00:27,375 --> 03:00:30,045
SHE'S HERE WITH US, WE'VE DONE

5008
03:00:30,045 --> 03:00:31,146
WORK WITH SARS-COV-2 AS WELL.

5009
03:00:31,146 --> 03:00:32,314
WHAT I'M SHOWING YOU HERE ON

5010
03:00:32,314 --> 03:00:36,084
THIS SLIDE IS USING THE NEW

5011
03:00:36,084 --> 03:00:38,420
VARIANT SO THIS IS A CLINICAL

5012
03:00:38,420 --> 03:00:40,255
ISOLATE OF THE NEW VARIANT.

5013
03:00:40,255 --> 03:00:43,558
IT WAS DISCUSSED STANLEY

5014
03:00:43,558 --> 03:00:44,726
BEAUTIFULLY DISCUSSED THIS N501

5015
03:00:44,726 --> 03:00:46,528
Y-MUTATION AND WHY IT'S SO

5016
03:00:46,528 --> 03:00:48,830
IMPORTANT FOR ALLOWING THE VIRUS

5017
03:00:48,830 --> 03:00:52,834
TO BIND TO MOUSE ACE 2, SO IF WE

5018
03:00:52,834 --> 03:00:55,370
USE THIS VARIANT, WE'VE ALSO

5019
03:00:55,370 --> 03:00:58,573
USED THE MA-10 FROM RALPH BARIC,

5020
03:00:58,573 --> 03:01:02,177
AND WE ALSO PUBLISHED USING MALE

5021
03:01:02,177 --> 03:01:03,812
AND FEMALE HAMSTERS INFEC WIDE

5022
03:01:03,812 --> 03:01:06,881
THAT WUSH WASH 1.

5023
03:01:06,881 --> 03:01:09,050
OKAY, SO 3 DIFFERENT MODELS AND

5024
03:01:09,050 --> 03:01:11,252
WHAT WE CONSISTENTLY FIND IS

5025
03:01:11,252 --> 03:01:13,121
THAT DURING THIS ACUTE PHASE OF

5026
03:01:13,121 --> 03:01:15,123
INFECTION, MALES IN GREEN,

5027
03:01:15,123 --> 03:01:19,828
FEMALES IN PURPLE, MALES GET

5028
03:01:19,828 --> 03:01:20,628
SICKER THAN FEMALES.

5029
03:01:20,628 --> 03:01:22,997
BUT HERE WE CONSISTENTLY, WE SAW

5030
03:01:22,997 --> 03:01:24,265
THIS WITH HAMSTERS AND WE'RE

5031
03:01:24,265 --> 03:01:26,634
SEEING THIS AND I SHOULD STATE

5032
03:01:26,634 --> 03:01:29,637
THESE ARE C57 BLACK 6 MICE, WE

5033
03:01:29,637 --> 03:01:34,809
HAVE USED BOTHIAC SON AS WELL AS

5034
03:01:34,809 --> 03:01:36,111
CHARLES RIVERS SO BOTH Y&  C
R

5035
03:01:36,111 --> 03:01:37,979
IF WE'RE GOING TO GET REAL

5036
03:01:37,979 --> 03:01:40,248
TECHNICAL AND THESE ARE WHAT I

5037
03:01:40,248 --> 03:01:41,783
WOULD CALL MIDDLE AGE, I WOULD

5038
03:01:41,783 --> 03:01:43,952
SAY THESE ARE MATURE MICE.

5039
03:01:43,952 --> 03:01:47,155
THEY ARE 30 WEBBINGS OF AGE

5040
03:01:47,155 --> 03:01:49,190
WHICH REALLY DOES CORRESPOND

5041
03:01:49,190 --> 03:01:51,526
WITH PEOPLE ROUGHLY IN THEIR 30S

5042
03:01:51,526 --> 03:01:54,829
TO EARLY 40S ACCORDING TOIAC SON

5043
03:01:54,829 --> 03:01:55,029
LABS.

5044
03:01:55,029 --> 03:01:56,965
SO CAN YOU SEE WE DON'T SEE A

5045
03:01:56,965 --> 03:01:58,266
DIFFERENCE IN VIRAL TITERS SO

5046
03:01:58,266 --> 03:02:00,268
THIS IS SAYING TO US, THERE

5047
03:02:00,268 --> 03:02:01,870
ISN'T A SEX DIFFERENCE IN THESE

5048
03:02:01,870 --> 03:02:03,505
RESISTANCE TYPES OF MECHANISMS,

5049
03:02:03,505 --> 03:02:04,172
SO ALREADY A LITTLE BIT

5050
03:02:04,172 --> 03:02:12,347
DIFFERENT THAN WHAT I SHOWED YOU

5051
03:02:12,347 --> 03:02:12,947
FOR FLU B.

5052
03:02:12,947 --> 03:02:15,817
WE DO LOOK IN THE LUNGS AND WE

5053
03:02:15,817 --> 03:02:17,585
FIND FEMALES HAVE UPREGULATION

5054
03:02:17,585 --> 03:02:20,188
OF CYTOKINES AND CHEMOKINES, WE

5055
03:02:20,188 --> 03:02:21,689
ALSO FIND SEVERAL IMMUNE CELLS,

5056
03:02:21,689 --> 03:02:23,658
I REALIZE I ONLY PUT MACROPHAGES

5057
03:02:23,658 --> 03:02:25,560
ON HERE BUT WE ALSO SEE THIS FOR

5058
03:02:25,560 --> 03:02:28,296
CERTAIN T-CELL POPULATIONS WHICH

5059
03:02:28,296 --> 03:02:30,131
I WILL COME BACK TO IPT GREATER

5060
03:02:30,131 --> 03:02:32,000
CLUING CD4, POSITIVE T-CELLS ARE

5061
03:02:32,000 --> 03:02:33,768
GREATER IN FEMALES DURING THIS

5062
03:02:33,768 --> 03:02:37,071
ACUTE PHASE OF INFECTION.

5063
03:02:37,071 --> 03:02:40,742
IF I SHOWED YOU THAT JEN HAS

5064
03:02:40,742 --> 03:02:43,077
CARRIED ANIMALS OUT TO ROUGHLY

5065
03:02:43,077 --> 03:02:45,847
21, 28 DAYS, SHE MEASURES

5066
03:02:45,847 --> 03:02:48,383
ANTIBODY, FEMALES ALSO HAVE MORE

5067
03:02:48,383 --> 03:02:49,918
ANTIBODY THAN MALES.

5068
03:02:49,918 --> 03:02:51,186
SO FEMALES, THEY'RE BY AND LARGE

5069
03:02:51,186 --> 03:02:54,222
DOING A LITTLE BIT BETTER.

5070
03:02:54,222 --> 03:02:55,924
SARS-COV-2 IN THESE MICE, IT

5071
03:02:55,924 --> 03:02:57,459
CAUSES A MILD DISEASE NOT LIKE

5072
03:02:57,459 --> 03:02:59,360
WHAT WE SEE WITH THINGS LIKE

5073
03:02:59,360 --> 03:03:01,129
INFLUENZA A, SO EVEN THOUGH I'M

5074
03:03:01,129 --> 03:03:04,332
SHOWING YOU FEMALES HAVING

5075
03:03:04,332 --> 03:03:04,999
GREATER CYTOKINE CONCENTRATIONS,

5076
03:03:04,999 --> 03:03:07,936
THIS IS NOT TO THE DEGREE OF

5077
03:03:07,936 --> 03:03:10,004
CYTOKINE CHANGES THAT WE SEE IN

5078
03:03:10,004 --> 03:03:16,010
THE LUNGS OF FLU A INFECTED

5079
03:03:16,010 --> 03:03:16,478
MICE.

5080
03:03:16,478 --> 03:03:18,947
BUT AGAIN WE CAN TAKE THESE

5081
03:03:18,947 --> 03:03:19,948
DIFFERENT TRANSGENIC MICE, I'VE

5082
03:03:19,948 --> 03:03:21,716
ALREADY INTRODUCED YOU TO THE 5

5083
03:03:21,716 --> 03:03:24,219
CORE TYPE OF MICE, WE USE THOSE

5084
03:03:24,219 --> 03:03:27,956
TO EPISAIT SEX CHROMOSOMES FROM

5085
03:03:27,956 --> 03:03:30,258
SEX GONADAL HORMONES AND WE FIND

5086
03:03:30,258 --> 03:03:32,393
THAT FEMALES ARE THE CLOSED

5087
03:03:32,393 --> 03:03:41,302
PURPLE, MALES ARE THE CLOSED

5088
03:03:41,302 --> 03:03:46,007
GREEN AND AGAIN X-FEMALE, SO

5089
03:03:46,007 --> 03:03:47,876
XEXTINGUISHING-WITH OVARIES, XY

5090
03:03:47,876 --> 03:03:50,311
MALES SO XY WITH TESTES AND CAN

5091
03:03:50,311 --> 03:03:53,414
YOU SEE THAT XX MALES, IT'S A

5092
03:03:53,414 --> 03:03:57,151
BIT INTERMEDIATE BUT THEY DO

5093
03:03:57,151 --> 03:04:01,823
MUCH BETTER THAN XY MALES AND XY

5094
03:04:01,823 --> 03:04:05,260
FEMALES DO WORSE THAN XX FEMALES

5095
03:04:05,260 --> 03:04:07,529
SUGGESTING THAT THERE IS A SEX

5096
03:04:07,529 --> 03:04:08,596
CHROME CHROME COMPLEMENT EFFECT.

5097
03:04:08,596 --> 03:04:12,634
NOW WHAT WE CAN DO IF WE SEE A

5098
03:04:12,634 --> 03:04:13,268
SEX CHROMOSOME COMPLEMENT CENTER

5099
03:04:13,268 --> 03:04:14,002
FOR EXCELLENCE ON AGING, MUCH

5100
03:04:14,002 --> 03:04:16,404
LIKE WE SAW OBSERVED WITH FLU B,

5101
03:04:16,404 --> 03:04:19,941
WE CAN THEN WORK WITH A

5102
03:04:19,941 --> 03:04:22,277
DIFFERENT TYPE OF TRANSGENIC

5103
03:04:22,277 --> 03:04:24,445
MOUSE MODEL, THESE ARE REKERRED

5104
03:04:24,445 --> 03:04:26,648
TO AS STAR Y MICE WHERE THERE'S

5105
03:04:26,648 --> 03:04:28,516
BEEN A MUTATION IN THE AUTOSOMAL

5106
03:04:28,516 --> 03:04:31,986
REGION OF THE X-ROAMSOME, WHICH

5107
03:04:31,986 --> 03:04:36,524
ALLOWS FOR US TO LOOK AT

5108
03:04:36,524 --> 03:04:37,959
DIFFERENT DOSAGES OF THE

5109
03:04:37,959 --> 03:04:39,694
X CHROMOSOME IN THE PRESENCE OR

5110
03:04:39,694 --> 03:04:42,030
ABSENCE OF THE Y CHROMOSOME.

5111
03:04:42,030 --> 03:04:43,965
BECAUSE WE HAVE AN INHERENT

5112
03:04:43,965 --> 03:04:45,600
DIFFERENCE IF WE'RE TALKING

5113
03:04:45,600 --> 03:04:50,104
ABOUT THE POLES OF BIOLOGICAL

5114
03:04:50,104 --> 03:04:52,206
SEX, FEMALES HAVING 2 X

5115
03:04:52,206 --> 03:04:53,274
CHROMOSOMES, MALES ONLY HAVING

5116
03:04:53,274 --> 03:04:53,408
1.

5117
03:04:53,408 --> 03:04:56,978
AND WHILE THROUGH A PROCESS OF X

5118
03:04:56,978 --> 03:04:58,346
CHROMOSOME INACTIVATION, THAT

5119
03:04:58,346 --> 03:04:58,746
SHOULDN'T MATTER.

5120
03:04:58,746 --> 03:05:02,550
WE SHOULD ALL HAVE THE SAME

5121
03:05:02,550 --> 03:05:04,586
NUMBER OF [INDISCERNIBLE] OR THE

5122
03:05:04,586 --> 03:05:06,588
SAME EXPRESSION OF X-LINKED

5123
03:05:06,588 --> 03:05:07,889
YEENS BUT ROUGHLY 15% OF THE

5124
03:05:07,889 --> 03:05:12,794
GENES ON THE X-CHROMOSOME IN

5125
03:05:12,794 --> 03:05:14,729
HUMANS ESCAPE X INACTIVATION.

5126
03:05:14,729 --> 03:05:18,800
SO THERE ARE SEVERAL GENES IN

5127
03:05:18,800 --> 03:05:19,901
INCLUDING TOLL-LIKE RECEPTOR 7

5128
03:05:19,901 --> 03:05:23,705
THAT ARE ON THE CHROMOSOME THAT

5129
03:05:23,705 --> 03:05:25,707
ESCAPE X ACTIVATION AND CONNIST

5130
03:05:25,707 --> 03:05:27,208
ISENTLY SHOW GREATER EXPRESSION

5131
03:05:27,208 --> 03:05:28,643
IN FEMALES AS COMPARED WITH

5132
03:05:28,643 --> 03:05:28,876
MALES.

5133
03:05:28,876 --> 03:05:31,346
SO NOW WHAT WE CAN DO IS WE CAN

5134
03:05:31,346 --> 03:05:34,515
HAVE MICE THAT DO NOT HAVE THE

5135
03:05:34,515 --> 03:05:36,985
SRY, THAT HAVE EITHER 2 COPIES

5136
03:05:36,985 --> 03:05:39,320
OF AN X-CHROMOSOME OR 1 COPY OF

5137
03:05:39,320 --> 03:05:42,523
AN X-CHROMOSOME, SO NOW WE SRO X

5138
03:05:42,523 --> 03:05:44,392
X FEMALES, WE CAN HAVE X O

5139
03:05:44,392 --> 03:05:46,361
FEMALES SO THIS WOULD BE CONSIST

5140
03:05:46,361 --> 03:05:48,496
WENT A DIFFERENT IN SEXUAL

5141
03:05:48,496 --> 03:05:51,899
DEVELOPMENT RESULTING IN TURNER

5142
03:05:51,899 --> 03:05:52,567
SYNDROME IN HUMANS.

5143
03:05:52,567 --> 03:05:55,603
WE CAN HAVE MICE THAT HAVE AND

5144
03:05:55,603 --> 03:05:57,872
INHERIT THE SRY ON THEIR Y

5145
03:05:57,872 --> 03:05:59,974
CHROMOSOME THAT HAVE EITHER 1

5146
03:05:59,974 --> 03:06:01,943
COPY OF THE X CHROMOSOME OR 2

5147
03:06:01,943 --> 03:06:05,446
COPIES OF THE X CHROMOSOME SO

5148
03:06:05,446 --> 03:06:07,915
YOU CAN HAVE XY MALES OR

5149
03:06:07,915 --> 03:06:10,118
EXTINGUISHING XY MALES SO THIS

5150
03:06:10,118 --> 03:06:11,786
TERMS OF THINKING ABOUT CLINICAL

5151
03:06:11,786 --> 03:06:13,855
RELEVANCE WOULD BE CONSIST WENT

5152
03:06:13,855 --> 03:06:17,392
AN INDIVIDUAL WHO MIGHT HAVE

5153
03:06:17,392 --> 03:06:19,193
[INDISCERNIBLE] DISORDER AND SO

5154
03:06:19,193 --> 03:06:21,496
NOW WHEN WE INFECT THOSE MICE

5155
03:06:21,496 --> 03:06:23,631
WITH THE NEW VARIANT OF

5156
03:06:23,631 --> 03:06:25,066
SARS-COV-2, YOU CAN SEE THIS

5157
03:06:25,066 --> 03:06:27,335
CLEARLY, ANIMALS THAT HAVE 2

5158
03:06:27,335 --> 03:06:30,605
COPIES OF THE X CHROMOSOME ARE

5159
03:06:30,605 --> 03:06:34,042
PROTECTED AGAINST ACUTE

5160
03:06:34,042 --> 03:06:34,475
SARS-COV-2 DISEASE.

5161
03:06:34,475 --> 03:06:37,478
MALES HAVING A SINGLE COPY OF

5162
03:06:37,478 --> 03:06:39,113
THE X CHROMOSOME, FEMALES HAVING

5163
03:06:39,113 --> 03:06:41,616
A SINGLE COPY OF X CHROMOSOME

5164
03:06:41,616 --> 03:06:45,420
GET SICKER BUT I THINK IT'S VERY

5165
03:06:45,420 --> 03:06:46,954
INTERESTING THAT HAVING THE

5166
03:06:46,954 --> 03:06:48,756
SINGLE COPY OF THE X CHROMOSOME

5167
03:06:48,756 --> 03:06:51,993
IN THE PRESENCE OF Y MAKES

5168
03:06:51,993 --> 03:06:52,727
ANIMALS THE SICKEST SUGGIEST

5169
03:06:52,727 --> 03:06:54,762
THRG IS SOMETHING ABOUT THE

5170
03:06:54,762 --> 03:06:56,097
Y-CHROMOSOME WHICH IS MANY

5171
03:06:56,097 --> 03:06:57,632
REGULATORY GENES EMPLOY SO WHAT

5172
03:06:57,632 --> 03:07:00,168
DO YOU DO WHEN WE SEE THIS

5173
03:07:00,168 --> 03:07:01,269
EMPLOY WELL, WE CAN THEN GO AND

5174
03:07:01,269 --> 03:07:04,138
LOOK AT SOME OF THE YEENS THAT

5175
03:07:04,138 --> 03:07:07,241
MAY BE ESCAPING X INACTIVATION,

5176
03:07:07,241 --> 03:07:08,443
I MENTIONED TOLL-LIKE RECEPTOR

5177
03:07:08,443 --> 03:07:10,378
7, WE PUBLISHED A LOT ON THAT.

5178
03:07:10,378 --> 03:07:13,281
BUT THERE ARE ALSO OTHER YEENS

5179
03:07:13,281 --> 03:07:13,881
THAT UPGENERATED ETDICALLY

5180
03:07:13,881 --> 03:07:15,049
REGULATE CELL ACTIVITY THAT CAN

5181
03:07:15,049 --> 03:07:17,051
DIFFER BETWEEN THE SEXES AS A

5182
03:07:17,051 --> 03:07:19,821
RESULT OF HAVING 2 COPIES OF THE

5183
03:07:19,821 --> 03:07:24,325
X-CHROMOSOME, SO WE CAN LOOK AT

5184
03:07:24,325 --> 03:07:27,895
THOSE X-LINKED YEENS THING

5185
03:07:27,895 --> 03:07:29,764
LOOSIC KDM6 A, KDM5 C BOTH OF

5186
03:07:29,764 --> 03:07:34,135
WHICH ARE SHOWN HERE AND

5187
03:07:34,135 --> 03:07:36,104
CDPOSITIVE T-CELLS IN SARS-COV-2

5188
03:07:36,104 --> 03:07:38,339
INFECTED MICE, AND XXINDIVIDUALS

5189
03:07:38,339 --> 03:07:43,611
HAVE GREATER EXPRESSION OF THESE

5190
03:07:43,611 --> 03:07:46,447
EPIGENETIC REGULATING GENES IN

5191
03:07:46,447 --> 03:07:48,182
THEIR REGULATING T-CELLS, SO

5192
03:07:48,182 --> 03:07:49,450
THEN WE HAVE CONDITIONALLY KNOCK

5193
03:07:49,450 --> 03:07:52,820
THESE OUT OF SPECIFIC CELLS,

5194
03:07:52,820 --> 03:07:53,621
MAYBE NOSE INFLAMMATORY

5195
03:07:53,621 --> 03:07:56,057
MACROPHAGES AS AN EXAMPLE.

5196
03:07:56,057 --> 03:07:57,925
MAYBE CD4 POSITIVE T-CELLS TO

5197
03:07:57,925 --> 03:08:00,561
LOOK AND SEE ARE THESE

5198
03:08:00,561 --> 03:08:04,866
PARTICULAR X-LINKED YEENS

5199
03:08:04,866 --> 03:08:06,200
MEDIATING THE SEX DIFFERENCE WE

5200
03:08:06,200 --> 03:08:07,502
OBSERVE EMPLOY SOW FLEW A, I

5201
03:08:07,502 --> 03:08:08,936
WOULD BE REMISS IF I DIDN'T GO

5202
03:08:08,936 --> 03:08:10,505
BACK TO WHERE THIS ALL BEGAN FOR

5203
03:08:10,505 --> 03:08:10,772
ME.

5204
03:08:10,772 --> 03:08:12,707
WE HAVE SHOWN THAT WHETHER WE

5205
03:08:12,707 --> 03:08:18,479
WORK WITH PRA, WHETHER WE WORK

5206
03:08:18,479 --> 03:08:22,583
WITH ACOW 09, WHETHER WE WORK

5207
03:08:22,583 --> 03:08:26,888
WITH H3 N2 VIRUSES, WHAT WE FIND

5208
03:08:26,888 --> 03:08:29,690
WITH FLU A ARE THAT FEMALES GET

5209
03:08:29,690 --> 03:08:30,191
SICKER THAN MALES.

5210
03:08:30,191 --> 03:08:31,125
THEY LOSE MORE WEIGHT, IF YOU

5211
03:08:31,125 --> 03:08:32,093
DON'T LIKE WEIGHT AND YOU WANT

5212
03:08:32,093 --> 03:08:34,896
TO TALK ABOUT SOME OF THE MORE

5213
03:08:34,896 --> 03:08:36,030
CLINICALLY RELEVANT MEASURES

5214
03:08:36,030 --> 03:08:37,765
THAT STANLEY BROUGHT UP AND YOU

5215
03:08:37,765 --> 03:08:40,735
LOOK AT THAT DIFFUSION CAPACITY

5216
03:08:40,735 --> 03:08:42,503
THAT EXCHANGE OF OXYGEN ACROSS

5217
03:08:42,503 --> 03:08:44,572
THE LUNGS, HERE I'M SHOWING YOU

5218
03:08:44,572 --> 03:08:47,008
14 DAYS AFTER INFECTION EMPLOY

5219
03:08:47,008 --> 03:08:52,046
SO 14 DAYS, MALES IN GREEN,

5220
03:08:52,046 --> 03:08:52,780
THEY'VE RETURNED.

5221
03:08:52,780 --> 03:08:54,849
THEY'RE BETTER THAN BASE LINE

5222
03:08:54,849 --> 03:08:55,183
HEALTH.

5223
03:08:55,183 --> 03:08:56,317
FEMALES HAVE NOT YET RETURNED

5224
03:08:56,317 --> 03:08:57,552
BUT AGAIN, IF YOU DON'T LIKE

5225
03:08:57,552 --> 03:09:02,056
THAT, HERE, CAN YOU SEE THE

5226
03:09:02,056 --> 03:09:03,191
STIFFLED NICE, CAN YOU SEE WHAT

5227
03:09:03,191 --> 03:09:05,993
IT LOOKS LIKE IN TERMS OF THE

5228
03:09:05,993 --> 03:09:07,862
OXYGEN EXCHANGE, MALES ARE BACK

5229
03:09:07,862 --> 03:09:09,664
UP TO NORMAL BASE LINE HEALTH,

5230
03:09:09,664 --> 03:09:10,998
FEMALES ARE NOT.

5231
03:09:10,998 --> 03:09:15,069
THIS IS NOT DUE TO RESISTANCE

5232
03:09:15,069 --> 03:09:17,805
MECHANISMS, WE FOUND IN NAIVE

5233
03:09:17,805 --> 03:09:19,340
MICE MALE ANDS FEMALES HAVE

5234
03:09:19,340 --> 03:09:23,811
SIMILAR TITERS OF REPLICATING

5235
03:09:23,811 --> 03:09:26,347
THEM IN THE LUNGS, THEY HAVE A

5236
03:09:26,347 --> 03:09:29,483
LOT MORE INFLAMMATION, CYTOKINE,

5237
03:09:29,483 --> 03:09:31,052
THAT CYTOKINE STORM CONSISTENTLY

5238
03:09:31,052 --> 03:09:32,687
SHOWED MUCH GREATER IN FEMALES

5239
03:09:32,687 --> 03:09:34,188
AS COMPARED WITH MALES.

5240
03:09:34,188 --> 03:09:36,057
SO WHAT IS IT ABOUT MALES, WELL,

5241
03:09:36,057 --> 03:09:38,192
HERE IS WHERE I THINK ANDROGENS

5242
03:09:38,192 --> 03:09:40,361
TERN OUT TO BE REALLY GOOD.

5243
03:09:40,361 --> 03:09:42,230
I KNOW AGAIN, CLINICALLY WE

5244
03:09:42,230 --> 03:09:44,332
ALWAYS TALK ABOUT THESE DPLU CO

5245
03:09:44,332 --> 03:09:45,633
CORTICOIDS BUT I WANT TO

5246
03:09:45,633 --> 03:09:46,567
CONVINCE THAT YOU ANDROGEN ROUGH

5247
03:09:46,567 --> 03:09:51,005
ATOMIENS ALSO DO A BEAUTIFUL JOB

5248
03:09:51,005 --> 03:09:51,505
DAMPENING INFLAMMATION.

5249
03:09:51,505 --> 03:09:54,008
AND SO SOME OF THE OTHER MODELS

5250
03:09:54,008 --> 03:09:56,978
WE HAVE ARE TEASING APART SEX

5251
03:09:56,978 --> 03:10:00,414
DIFFERENCES SO WE CAN DO

5252
03:10:00,414 --> 03:10:01,249
SURGICAL INTERVENTIONS, WE CAN

5253
03:10:01,249 --> 03:10:03,551
TAKE OUT THE TESTES, SO BY

5254
03:10:03,551 --> 03:10:06,454
TAKING OUT THE EAST EASE WE'VE

5255
03:10:06,454 --> 03:10:07,989
REDUCED CIRCULATING ANDROGEN

5256
03:10:07,989 --> 03:10:08,689
CONCENTRATIONS TO NONDETECTIBLE

5257
03:10:08,689 --> 03:10:09,023
LEVELS.

5258
03:10:09,023 --> 03:10:11,959
WE WANT TO KNOW, IS IT THAT 1

5259
03:10:11,959 --> 03:10:12,226
HORMONE?

5260
03:10:12,226 --> 03:10:14,428
WELL WE CAN TAKE THOSE MICE AND

5261
03:10:14,428 --> 03:10:18,032
WE CAN GIVE AN IMPLANT, A TIME

5262
03:10:18,032 --> 03:10:20,134
RELEASED IMPLANT THAT'S GOING TO

5263
03:10:20,134 --> 03:10:24,372
SECRETE EXOGENOUS IN THIS CASE

5264
03:10:24,372 --> 03:10:25,072
TESTOSTERONE INTO CIRCULATION

5265
03:10:25,072 --> 03:10:28,075
AND WE FIND THAT MALES THAT THEN

5266
03:10:28,075 --> 03:10:30,478
GET INFECT WIDE AICAL 09, IF

5267
03:10:30,478 --> 03:10:31,879
THEY HAVE ENDOGENOUS OR

5268
03:10:31,879 --> 03:10:32,613
EXOGENOUS ANDROGEN ROUGH

5269
03:10:32,613 --> 03:10:33,981
ATOMIEN, THEY DON'T GET US SICK

5270
03:10:33,981 --> 03:10:36,083
AS MALES THAT HAVE NO

5271
03:10:36,083 --> 03:10:36,584
CIRCULATING ANDROGENS.

5272
03:10:36,584 --> 03:10:38,386
TO SHOW YOU THIS ISN'T SO MUCH

5273
03:10:38,386 --> 03:10:39,220
ABOUT RESISTANCE, BUT MAYBE IT'S

5274
03:10:39,220 --> 03:10:41,555
A BIT MORE ABOUT HOW WELL THEY

5275
03:10:41,555 --> 03:10:43,491
TOLERATE VIRUS, I'M SHOWING YOU

5276
03:10:43,491 --> 03:10:46,027
VIRAL LOADS, 7 DAYS, COMPARED

5277
03:10:46,027 --> 03:10:47,228
WITH BODY MASS AND SO WHAT I

5278
03:10:47,228 --> 03:10:50,464
WANT YOU TO LOOK AT IS THAT ALL

5279
03:10:50,464 --> 03:10:51,999
ANIMALS WHETHER THEY HAVE THEIR

5280
03:10:51,999 --> 03:10:54,235
TESTES OR NOT, WHETHER THEY HAVE

5281
03:10:54,235 --> 03:10:56,370
ANDROGENS OR NOT, THEY HAVE A

5282
03:10:56,370 --> 03:10:58,072
VERY SIMILAR VIRAL LOAD, BUT THE

5283
03:10:58,072 --> 03:11:00,141
IMPACT OF HAVING THAT VIRAL LOAD

5284
03:11:00,141 --> 03:11:01,609
ON DEC REALLY DIFFERS, AND YOU

5285
03:11:01,609 --> 03:11:04,645
CAN SEE THAT BY THE SLOPE OF

5286
03:11:04,645 --> 03:11:06,881
THESE LINES.

5287
03:11:06,881 --> 03:11:07,515
MALES HAVE TAKEN--THEY ANDROGEN

5288
03:11:07,515 --> 03:11:08,449
ROUGH ATOMIENS, THE SLOPE

5289
03:11:08,449 --> 03:11:09,850
DOESN'T JUST STEEP, THEY'RE NOT

5290
03:11:09,850 --> 03:11:11,886
GETTING AS SICK AT THAT VIRAL

5291
03:11:11,886 --> 03:11:13,387
LOAD LEVEL AS COMPARED WITH

5292
03:11:13,387 --> 03:11:21,195
MALES THAT DON'T HAVE  ANDROGEN.

5293
03:11:21,195 --> 03:11:23,064
AND WE CAN COMPARE MALES AND

5294
03:11:23,064 --> 03:11:26,367
FEMALES WHICH I'VE SHOWN YOU AND

5295
03:11:26,367 --> 03:11:29,570
HERE THE FEMALES, OPEN ORANGE,

5296
03:11:29,570 --> 03:11:31,439
MALES CLOSED BLUE, AND WE CAN

5297
03:11:31,439 --> 03:11:34,041
NOW GET FEMALES IN ANDROGEN,

5298
03:11:34,041 --> 03:11:40,514
THAL CASE WE CHOSE TO GIVE THEM

5299
03:11:40,514 --> 03:11:42,450
HIHYDROTESTOSTERONE, THE DIRTY

5300
03:11:42,450 --> 03:11:43,384
LITTLE SECRET ABOUT TESTOSTERONE

5301
03:11:43,384 --> 03:11:46,887
IS THAT IT CAN BE CONFIRMED BY A

5302
03:11:46,887 --> 03:11:48,155
ENZYME INTO AROPA TAISS--SYNTH

5303
03:11:48,155 --> 03:11:48,723
INTO ESTRADISCIPLINARY OLDER

5304
03:11:48,723 --> 03:11:50,758
PEOPLE SO A LOT OF THESE EFFECTS

5305
03:11:50,758 --> 03:11:53,494
THAT ARE OCCURRING IN MALES ARE

5306
03:11:53,494 --> 03:11:55,229
REALLY THROUGH BINDING AT TIMES

5307
03:11:55,229 --> 03:11:57,231
TO THE ESTRO GENRE SEPTORSOR,

5308
03:11:57,231 --> 03:11:58,199
AND BEING AROMAITIZED SO WE

5309
03:11:58,199 --> 03:12:02,570
DIDN'T WANT THAT SO WE TOOK A

5310
03:12:02,570 --> 03:12:03,604
NONAROMAITIZABLE ANDROGEN, CAVE

5311
03:12:03,604 --> 03:12:04,872
THAT TO FEMALES AND NOW YOU CAN

5312
03:12:04,872 --> 03:12:07,708
SEE WE CAN MAKE FEMALES LOOK

5313
03:12:07,708 --> 03:12:09,977
INDISTINGUISHABLE FROM MALES IF

5314
03:12:09,977 --> 03:12:11,912
WE GIVE THEM ANDROGENS.

5315
03:12:11,912 --> 03:12:13,080
THEY DON'T GET US THERE.

5316
03:12:13,080 --> 03:12:17,018
AND WE'VE GONE ON TO SHOW THAT

5317
03:12:17,018 --> 03:12:20,187
IT'S PARTIALLY BY DAMPENING A

5318
03:12:20,187 --> 03:12:20,955
LOT OF INFLAMMATORY IMMUNE

5319
03:12:20,955 --> 03:12:22,757
RESPONSES IN THE LUNGS IS HOW

5320
03:12:22,757 --> 03:12:23,491
THEY'RE PROTECTING VERY SIMILAR

5321
03:12:23,491 --> 03:12:29,730
TO HOW WE KNOW THAT THE

5322
03:12:29,730 --> 03:12:30,831
CORTICOIDS PROTECT.

5323
03:12:30,831 --> 03:12:37,738
SO IF EVERYBODY LIVES BECAUSE

5324
03:12:37,738 --> 03:12:38,706
WITH ACALO9 EVERYBODY LIVES AND

5325
03:12:38,706 --> 03:12:40,608
WE LOOK AT ADAPTIVE TIME POINTS

5326
03:12:40,608 --> 03:12:43,077
WE FIND THAT FEMALES HAVE

5327
03:12:43,077 --> 03:12:45,246
GREATER ADAPTIVE IMMUNITY, WE

5328
03:12:45,246 --> 03:12:47,581
LOOK AT ANTIBODY IN THEIR SERUM

5329
03:12:47,581 --> 03:12:49,083
OR LOOK LOCALLY, I DON'T EVEN

5330
03:12:49,083 --> 03:12:51,519
KNOW HOW TO GET BACK OR WE LOOK

5331
03:12:51,519 --> 03:12:54,722
LOCALLY IN THE BRONCO ALVEOLAR

5332
03:12:54,722 --> 03:12:57,992
LAVAGE, WE CAN LOOK IN THE LUNGS

5333
03:12:57,992 --> 03:12:59,393
FOR ANTIBODY SECRETING CELLS,

5334
03:12:59,393 --> 03:13:01,395
ALL DIFFERENT KINDS OF FLAVORS

5335
03:13:01,395 --> 03:13:04,165
OF T-CELLS AND WHAT WE FIND

5336
03:13:04,165 --> 03:13:06,100
FEMALES THE OPEN SYMBOLS, THE

5337
03:13:06,100 --> 03:13:08,502
MALES THE CLOSED, I WAS CHARGED

5338
03:13:08,502 --> 03:13:09,103
FOR COLOR.

5339
03:13:09,103 --> 03:13:10,838
FEMALES HAVE MORE OF THESE

5340
03:13:10,838 --> 03:13:14,408
CELLS, MORE OF THIS ANTIBODY.

5341
03:13:14,408 --> 03:13:16,077
SO WE CAN--THIS GOT US THINKING

5342
03:13:16,077 --> 03:13:23,217
ABOUT VACCINES AND SO IF WE WORK

5343
03:13:23,217 --> 03:13:24,218
WITH ENACTIVATED AICAL 09 DOING

5344
03:13:24,218 --> 03:13:26,020
A PRIME BOOST AND THEN LOOK AT

5345
03:13:26,020 --> 03:13:27,888
THE RESPONSES AND NOW I WANT TO

5346
03:13:27,888 --> 03:13:32,960
START TO BRING IN AGING.

5347
03:13:32,960 --> 03:13:34,862
STANLEY SPOKE ABOUT AGING WE

5348
03:13:34,862 --> 03:13:36,330
THINK ABOUT AGING BUT I THINK

5349
03:13:36,330 --> 03:13:36,997
ABOUT ANALLING DIFFERENTLY.

5350
03:13:36,997 --> 03:13:39,200
I THINK ABOUT IT AS A TIME AS

5351
03:13:39,200 --> 03:13:43,704
OUR HORMONES ARE STARTING TO

5352
03:13:43,704 --> 03:13:44,839
SERIOUSLY DEMINNISH.

5353
03:13:44,839 --> 03:13:46,273
AND SOPHISTICATED TO ME IT'S

5354
03:13:46,273 --> 03:13:50,377
ALMOST A NATURAL MODEL STUDYING

5355
03:13:50,377 --> 03:13:53,647
HOW CHANGES IN GONADAL HORMONES

5356
03:13:53,647 --> 03:13:55,483
MIGHT IMPACT VACCINE DOSED

5357
03:13:55,483 --> 03:13:55,749
IMMUNITY.

5358
03:13:55,749 --> 03:13:58,452
SO HERE ARE ARK DULLS 2-3 MOCKS

5359
03:13:58,452 --> 03:14:00,354
OF AGE, AT THE TIME WE'RE

5360
03:14:00,354 --> 03:14:01,188
VACCINATING AND COLLECTING

5361
03:14:01,188 --> 03:14:03,924
SAMPLES AND AGAIN OUR ADULTS ARE

5362
03:14:03,924 --> 03:14:05,459
17-18 BECAUSE OF THE DURATION OF

5363
03:14:05,459 --> 03:14:09,597
TIME IT TAKES WITH THESE VACCINE

5364
03:14:09,597 --> 03:14:12,199
MODELS SO THE YOUNG ADULTS ARE

5365
03:14:12,199 --> 03:14:13,934
DARKER GREEN AND PURPLE AS

5366
03:14:13,934 --> 03:14:16,804
COMPARED WITH THE AGE.

5367
03:14:16,804 --> 03:14:19,039
SO IF YOU LOOK IN THE DRAINING

5368
03:14:19,039 --> 03:14:20,808
EMILY NODES, ADULT FEMALES LET'S

5369
03:14:20,808 --> 03:14:22,910
JUST TART OFF, THEY JUST HAVE

5370
03:14:22,910 --> 03:14:25,112
MORE B-CELLS THAN THEIR MALE

5371
03:14:25,112 --> 03:14:25,613
COUNTERPARTS.

5372
03:14:25,613 --> 03:14:28,282
WE LOSE THAT WITH AGING.

5373
03:14:28,282 --> 03:14:30,951
WE CAN MEASURE GERMINAL TRUSTEES

5374
03:14:30,951 --> 03:14:34,121
B-CELLS, WE CAN MEASURE PLASMA

5375
03:14:34,121 --> 03:14:35,923
BLAST, ASULTAN MALS HAVE MORE OF

5376
03:14:35,923 --> 03:14:37,658
THESE CELLS THAN ADULT MALES AND

5377
03:14:37,658 --> 03:14:39,393
WE LOSE THAT WITH AGING.

5378
03:14:39,393 --> 03:14:41,595
IN FACT, CAN YOU SEE IT LOOKS

5379
03:14:41,595 --> 03:14:52,239
PRETTY BAD FOR BOTH AGED MALES

5380
03:14:52,239 --> 03:14:52,540
AND FEMALES.

5381
03:14:52,540 --> 03:14:54,175
NEUTRALIZING ANTIBODIES AND WE

5382
03:14:54,175 --> 03:14:55,743
LOSE THAT SEX DIFFERENCE IN THE

5383
03:14:55,743 --> 03:14:58,078
AGING WE'VE DON CYSTENTLY SHOWN

5384
03:14:58,078 --> 03:15:00,381
IS GRITTER FOR FEMALES AS

5385
03:15:00,381 --> 03:15:01,782
COMPARED WITH MALES SO IT'S

5386
03:15:01,782 --> 03:15:03,284
CORRELATIONAL BUT I HOPE CAN YOU

5387
03:15:03,284 --> 03:15:04,652
SEE IF WE MEASURE

5388
03:15:04,652 --> 03:15:05,286
ESTRADISCIPLINARY OLDER PEOPLE

5389
03:15:05,286 --> 03:15:07,221
IN ALL THESE ANIMALS YOU CAN SEE

5390
03:15:07,221 --> 03:15:08,589
THAT THE PEAK OF

5391
03:15:08,589 --> 03:15:09,490
ESTRADISCIPLINARY OLDER PEOPLE

5392
03:15:09,490 --> 03:15:11,292
CORRELATES WITH THE INCREASES IN

5393
03:15:11,292 --> 03:15:13,194
ALL OF THESE DIFFERENT CELL

5394
03:15:13,194 --> 03:15:14,495
TYPES IN THESE ANTIBODY

5395
03:15:14,495 --> 03:15:16,864
RESPONSES, IT'S NOT WHAT WE SEE

5396
03:15:16,864 --> 03:15:20,467
WHEN WE MEASURE ANDROGENS IN

5397
03:15:20,467 --> 03:15:20,935
THESE ANIMALS.

5398
03:15:20,935 --> 03:15:23,504
SO SOME OF THE WAYS WE CAN USE

5399
03:15:23,504 --> 03:15:25,139
HORMONES THERAPEUTICALLY, WE CAN

5400
03:15:25,139 --> 03:15:26,574
TAKE AGED ANIMALS LIKE AGED

5401
03:15:26,574 --> 03:15:28,008
FEMALES AND MAYBE IT'S MY AGE

5402
03:15:28,008 --> 03:15:29,109
THAT I'M STARTING TO REALLY

5403
03:15:29,109 --> 03:15:32,012
THINK ABOUT THESE THINGS AND CAN

5404
03:15:32,012 --> 03:15:35,249
JUST INSERT A LITTLE

5405
03:15:35,249 --> 03:15:36,383
ESTRADISCIPLINARY OLDER PEOPLE,

5406
03:15:36,383 --> 03:15:38,852
EXOGENOUSLY IN THOSE ANIMALS AND

5407
03:15:38,852 --> 03:15:40,387
ESTRADISCIPLINARY OLDER PEOPLE

5408
03:15:40,387 --> 03:15:42,022
IS ABBREVIATED E2, SO WHEN WE

5409
03:15:42,022 --> 03:15:43,424
COMPARE THAT WITH ARK DULT

5410
03:15:43,424 --> 03:15:45,859
FEMALES IN AGED FEMALES, AFTER

5411
03:15:45,859 --> 03:15:49,296
WE DO OUR PRIME BOOST

5412
03:15:49,296 --> 03:15:51,031
VACCINATION, AGED FEMALES HAVE

5413
03:15:51,031 --> 03:15:51,765
LOWER ANTIBODY RESPONSES, I'VE

5414
03:15:51,765 --> 03:15:53,167
ALREADY SHOWN YOU THIS, BUT IF

5415
03:15:53,167 --> 03:15:57,171
YOU GIVE AN AGED FEMALE,

5416
03:15:57,171 --> 03:15:59,273
ESTRADISCIPLINARY OLDER PEOPLE,

5417
03:15:59,273 --> 03:16:00,407
THE ANTIBODY RESPONSE LOOKS

5418
03:16:00,407 --> 03:16:01,909
INDISTINGUISHABLE FROM EITHER

5419
03:16:01,909 --> 03:16:05,412
ADULT FEMALES THAT HAVE

5420
03:16:05,412 --> 03:16:06,447
EXOGENOUS ESTRADIOL, OR FROM

5421
03:16:06,447 --> 03:16:07,915
FEMALES THAT HAVE CLINICAL

5422
03:16:07,915 --> 03:16:08,983
GENETICS DODGE NOWS ESTRADIOL,

5423
03:16:08,983 --> 03:16:12,253
AND AGAIN WE GET TO WORK WITH

5424
03:16:12,253 --> 03:16:14,788
ANDY PECOS, WITH ALL HIS GENETIC

5425
03:16:14,788 --> 03:16:16,023
REVERSE SYSTEMS, AND HE MONITORS

5426
03:16:16,023 --> 03:16:17,725
WHAT'S GOING ON OVER 32 THROUGH

5427
03:16:17,725 --> 03:16:21,795
THE SURVEILLANCE EFFORTS OF SEER

5428
03:16:21,795 --> 03:16:23,430
AND INSERTS MUTATIONS INTO

5429
03:16:23,430 --> 03:16:27,234
VIRUSES SO THAT WE'RE DRIFTING

5430
03:16:27,234 --> 03:16:28,836
AICAL 09, SO WE CAN WORK WITH

5431
03:16:28,836 --> 03:16:36,777
THE  VIRUSES TO THE MATCH, BUT

5432
03:16:36,777 --> 03:16:38,679
THEY DON'T EVEN GET SICK IF

5433
03:16:38,679 --> 03:16:41,081
THEY'VE BEEN VACCINATED, THE WAY

5434
03:16:41,081 --> 03:16:45,519
AGED FEMALES DO, THEY GET SICK,

5435
03:16:45,519 --> 03:16:47,354
BUT THEY DON'T DIE, AND THEY DO

5436
03:16:47,354 --> 03:16:48,422
GET SICK.

5437
03:16:48,422 --> 03:16:51,158
BUT IN AN AGED FEMALE, WHO GOT

5438
03:16:51,158 --> 03:16:54,528
THE ESTRADIOL, SHE LOOKS

5439
03:16:54,528 --> 03:16:59,333
INDISTINGUISHABLE FROM THE ADULT

5440
03:16:59,333 --> 03:16:59,600
FEMALES.

5441
03:16:59,600 --> 03:17:00,968
SO I THINK I WILL HAVE THIS BE

5442
03:17:00,968 --> 03:17:02,803
MY LAST AND WE CAN END AFTER

5443
03:17:02,803 --> 03:17:06,140
THIS BUT AGAIN GOING BACK TO

5444
03:17:06,140 --> 03:17:07,808
THOSE FCGMICE AS 4 CORE GENOTYPE

5445
03:17:07,808 --> 03:17:09,743
MICE, WHAT I WANT TO SHOW YOU IS

5446
03:17:09,743 --> 03:17:11,412
WE SEE SOMETHING VERY DIFFERENT

5447
03:17:11,412 --> 03:17:14,315
WITH VACCINE INDUCED IMMUNITY WE

5448
03:17:14,315 --> 03:17:15,983
DO WITH VIRAL PATHOGENESIS, IN

5449
03:17:15,983 --> 03:17:17,818
WHICH CASE IF WE TAKE THOSE 4

5450
03:17:17,818 --> 03:17:20,087
GENOTYPES WHAT WE FIND IS THAT

5451
03:17:20,087 --> 03:17:22,656
FEMALES, MEANING ANIMALS THAT

5452
03:17:22,656 --> 03:17:24,124
HAVE OVARIES REGARDLESS OF

5453
03:17:24,124 --> 03:17:28,195
WHETHER THEY HAVE AN XX OR XY

5454
03:17:28,195 --> 03:17:29,229
CHROMOSOME COMPLEMENT THEY MAKE

5455
03:17:29,229 --> 03:17:30,564
MORE ANTIBODY TO OUR VACCINE

5456
03:17:30,564 --> 03:17:33,434
THAT IS ANIMALS THAT HAVE TESTES

5457
03:17:33,434 --> 03:17:35,869
REGARDLESS OF THE SEX CHROMOSOME

5458
03:17:35,869 --> 03:17:37,771
COMPLEMENT AND THIS IS REFLECT

5459
03:17:37,771 --> 03:17:40,808
INDEED GERMINAL CENTER B-CELLS,

5460
03:17:40,808 --> 03:17:42,776
PLASMA BLASTS AND CHALLENGE WITH

5461
03:17:42,776 --> 03:17:44,745
THE DRIFTED VIRUS, THOSE ANIMALS

5462
03:17:44,745 --> 03:17:46,513
THAT HAVE MORE ANTIBODY, MORE

5463
03:17:46,513 --> 03:17:48,982
CELLS THEY CLEAR VIRUS BETTER

5464
03:17:48,982 --> 03:17:50,617
THAN ANIMALS THAT HAVE TESTES,

5465
03:17:50,617 --> 03:17:52,586
SO WHAT I THINK I'VE DONE, I'VE

5466
03:17:52,586 --> 03:17:57,591
SHOWN WE HAVE LOTS OF MODELS

5467
03:17:57,591 --> 03:18:00,060
THAT I THINK ARE CRITICAL IN

5468
03:18:00,060 --> 03:18:02,563
HIGHLIGHTING THE ROLE BIOLOGICAL

5469
03:18:02,563 --> 03:18:04,531
MODELS PLAYS, I THINK SEX IMPACS

5470
03:18:04,531 --> 03:18:06,967
OUR LIFE STRATEGIES, I THINK

5471
03:18:06,967 --> 03:18:09,503
IT'S EVOLUTIONARY AND REALLY

5472
03:18:09,503 --> 03:18:11,405
IMPACTS THIS NOTION OF

5473
03:18:11,405 --> 03:18:12,906
RESISTANCE VERSUS TOLERANCE, WE

5474
03:18:12,906 --> 03:18:14,808
HAVE TRANSGENIC MICE, WE HAVE

5475
03:18:14,808 --> 03:18:17,745
SURGICAL MODELS, AGING TO SHOW

5476
03:18:17,745 --> 03:18:19,847
YOU ROLE OF COMPLEMENT VERSUS

5477
03:18:19,847 --> 03:18:21,815
SEX STEROIDS OTHERS BOTH FOR

5478
03:18:21,815 --> 03:18:23,016
VIRAL PATHOGENESIS BUT ALSO IN

5479
03:18:23,016 --> 03:18:24,017
THE CONTEXT OF VACCINATION AND

5480
03:18:24,017 --> 03:18:34,461
SO WITH THAT I WILL END. 

5481
03:18:36,864 --> 03:18:37,498
THANK YOU.

5482
03:18:37,498 --> 03:18:38,866
>> SO FOR THE PANEL
DISCUSSION,

5483
03:18:38,866 --> 03:18:40,801
WE WILL LIKE TO ASK THE SPEAKERS

5484
03:18:40,801 --> 03:18:43,103
TO JOIN UP FRONT AND SO WE WILL

5485
03:18:43,103 --> 03:18:44,204
HAVE OPEN QUESTIONS FOR ALL

5486
03:18:44,204 --> 03:18:46,673
PANEL MEMBERS OR ANY TYPE OF

5487
03:18:46,673 --> 03:18:48,675
GENERALIZED QUESTION THAT WOULD

5488
03:18:48,675 --> 03:18:54,848
BE DIRECTED IN GENTLEMEN TO THE

5489
03:18:54,848 --> 03:18:55,215
PANEL.

5490
03:18:55,215 --> 03:18:55,949
>> GO FOR IT.

5491
03:18:55,949 --> 03:18:58,385
>> I HAVE 1 FOR SABRA, I
LOVE

5492
03:18:58,385 --> 03:19:01,488
IT, I LOVE ALL OF IT.

5493
03:19:01,488 --> 03:19:03,891
BUT I AM SO CURIOUS ABOUT SOME

5494
03:19:03,891 --> 03:19:04,792
OF THE OBSERVATIONS THAT MOVE

5495
03:19:04,792 --> 03:19:06,627
MADE IN ALL OF THESE VARIOUS

5496
03:19:06,627 --> 03:19:10,464
MODELS THAT YOU'VE USED, HOW IT

5497
03:19:10,464 --> 03:19:13,967
RELATES TO, YOU KNOW THINGS THAT

5498
03:19:13,967 --> 03:19:14,902
HAPPEN IN HUMANS ESPECIALLY WHAT

5499
03:19:14,902 --> 03:19:16,837
I BELIEVE LIKE THE END WITH THE

5500
03:19:16,837 --> 03:19:19,339
ADDITIONAL ESTRO GENERATED IN

5501
03:19:19,339 --> 03:19:21,108
THE AGED FEMALE, A LOT OF PEOPLE

5502
03:19:21,108 --> 03:19:22,609
TALKING ABOUT MENOPAUSE RIGHT

5503
03:19:22,609 --> 03:19:24,278
NOW WITH THE NEW HEALTH

5504
03:19:24,278 --> 03:19:25,012
INITIATIVES AND THINGS.

5505
03:19:25,012 --> 03:19:27,181
WHAT DOES THAT MEAN AND HOW

5506
03:19:27,181 --> 03:19:29,616
CAN--YOU KNOW HOW IS IT

5507
03:19:29,616 --> 03:19:29,983
RELATING?

5508
03:19:29,983 --> 03:19:33,787
NSO IF I START AT THE END WITH

5509
03:19:33,787 --> 03:19:35,422
VACCINES, MENOPAUSE, HORMONE

5510
03:19:35,422 --> 03:19:36,924
REPLACE AM THERAPY, THERE'S

5511
03:19:36,924 --> 03:19:42,729
REALLY, THERE HAS BEEN

5512
03:19:42,729 --> 03:19:43,997
ABSOLUTELY NOTHING DONE WITH

5513
03:19:43,997 --> 03:19:45,032
VACCINATION, SO THAT'S SOMETHING

5514
03:19:45,032 --> 03:19:49,036
THE DIRECTION AS I AGE THAT I'M

5515
03:19:49,036 --> 03:19:51,472
TAKING THE LAB BECAUSE I WANT TO

5516
03:19:51,472 --> 03:19:53,707
KNOW BUT I DO THINK, YOU KNOW

5517
03:19:53,707 --> 03:19:58,312
THESE MOUSE STUDIES ARE REALLY

5518
03:19:58,312 --> 03:20:01,748
SUGGESTIVE THAT THERE GOING TO

5519
03:20:01,748 --> 03:20:02,483
BE A DIFFERENCE.

5520
03:20:02,483 --> 03:20:04,852
THE OTHER THING, YOU KNOW THAT

5521
03:20:04,852 --> 03:20:07,421
WE'VE GOTTEN INTERESTED IN, YOU

5522
03:20:07,421 --> 03:20:11,024
KNOW WHEN WE REPLACE HORMONE IN

5523
03:20:11,024 --> 03:20:13,760
MICE THESE ARE TIME RELEASED

5524
03:20:13,760 --> 03:20:15,462
CAPSULES SO IT'S LIKE PUTTING

5525
03:20:15,462 --> 03:20:17,531
THEM ON HORMONE REPLACEMENT

5526
03:20:17,531 --> 03:20:18,398
THERAPY BUT SOMETHING WE'RE ALSO

5527
03:20:18,398 --> 03:20:21,134
VERY INTERESTED IN IS THINKING

5528
03:20:21,134 --> 03:20:22,703
ABOUT HORMONES AS ADJUVANTS.

5529
03:20:22,703 --> 03:20:24,705
LIKE DO YOU NEED A BOLUS AT THE

5530
03:20:24,705 --> 03:20:26,473
TIME OF VACCINATION AND COULD

5531
03:20:26,473 --> 03:20:29,810
THAT BE SUFFICIENT OR DO YOU

5532
03:20:29,810 --> 03:20:32,412
NEED THIS CONSTANT RELEASE OF

5533
03:20:32,412 --> 03:20:33,146
THE HORMONES?

5534
03:20:33,146 --> 03:20:37,351
SO THOSE ARE SOME OF THE THINGS

5535
03:20:37,351 --> 03:20:39,152
WE'RE THINKING.

5536
03:20:39,152 --> 03:20:43,223
>> OTHER QUESTIONS?

5537
03:20:43,223 --> 03:20:43,624
MICHELLE?

5538
03:20:43,624 --> 03:20:45,526
>> I WOULD LIKE TO ASK A
GENERAL

5539
03:20:45,526 --> 03:20:47,227
QUESTION OF THE PANEL.

5540
03:20:47,227 --> 03:20:51,765
SO WHEN YOU ARE PREPARING

5541
03:20:51,765 --> 03:20:52,966
VIRUSES, YOU'RE GROWING UP THEM

5542
03:20:52,966 --> 03:20:55,602
UP IN THE LAB OR SUBCULTURE OR

5543
03:20:55,602 --> 03:20:58,171
ANIMALS, AND YOU ARE INFECTING

5544
03:20:58,171 --> 03:21:00,040
DIFFERENT ANIMAL MODELS, IS THIS

5545
03:21:00,040 --> 03:21:02,342
STANDARDIZED AMONG THE VIRUSES

5546
03:21:02,342 --> 03:21:04,578
THAT YOU USE ACROSS LABS OR IS

5547
03:21:04,578 --> 03:21:06,747
EVERY LAB DOING THEIR OWN THING

5548
03:21:06,747 --> 03:21:09,283
AND ACTUALLY USING LOTS OF YOU

5549
03:21:09,283 --> 03:21:12,986
KNOW DIFFERENT LEVELS OF VIRUS

5550
03:21:12,986 --> 03:21:13,887
AND SO ON?

5551
03:21:13,887 --> 03:21:17,891
>> I CAN DEFINITELY SAY
THAT IN

5552
03:21:17,891 --> 03:21:18,759
CORONA VIROLOGY IT VARIES FROM

5553
03:21:18,759 --> 03:21:19,726
LAB TO LAB.

5554
03:21:19,726 --> 03:21:22,696
THERE WERE MASSIVE CONVERSATIONS

5555
03:21:22,696 --> 03:21:23,997
KIND OF ACROSS, ESTABLISHED NEW

5556
03:21:23,997 --> 03:21:24,598
INVESTIGATORS WHEN SARS 2 HIT

5557
03:21:24,598 --> 03:21:27,734
BECAUSE OF THE ISSUES OF THE

5558
03:21:27,734 --> 03:21:29,469
CLEAVAGE SITE AND HAVING A

5559
03:21:29,469 --> 03:21:30,771
STABLE VIRUS STOCK, SO THERE

5560
03:21:30,771 --> 03:21:32,172
WERE KIND OF YOU KNOW COMMON

5561
03:21:32,172 --> 03:21:33,907
CONDITIONS THAT WE WOULD ALSO

5562
03:21:33,907 --> 03:21:36,910
USE BEFORE LIKE GROW INVIRO

5563
03:21:36,910 --> 03:21:38,879
CELLS AND TAKE BEFORE YOU HAVE

5564
03:21:38,879 --> 03:21:40,180
COMPLETE CPC AND SERUM AND ALL

5565
03:21:40,180 --> 03:21:41,915
OF THAT BUT I DON'T THINK

5566
03:21:41,915 --> 03:21:43,784
THERE'S ANY SORT OF COMPLETE

5567
03:21:43,784 --> 03:21:47,621
TANNED ARDIZEATION ACROSS THE

5568
03:21:47,621 --> 03:21:47,988
FIELD.

5569
03:21:47,988 --> 03:21:49,356
YOU GET BETTER AT IT OVER TIME

5570
03:21:49,356 --> 03:21:55,295
AND PASS ON TIPS AND TRICKS BUT

5571
03:21:55,295 --> 03:21:55,762
ABSOLUTELY NOTHING.

5572
03:21:55,762 --> 03:21:58,432
>> I THINK THAT'S EXACTLY
THE

5573
03:21:58,432 --> 03:22:02,669
CASE ALSO WITH INFLUENZA, FOR

5574
03:22:02,669 --> 03:22:04,104
THOSE OF US WORKING IN THESE

5575
03:22:04,104 --> 03:22:06,406
AREAS, I DO THINK THAT WE

5576
03:22:06,406 --> 03:22:10,611
SEQUENCE WHAT WE'RE GROWING.

5577
03:22:10,611 --> 03:22:14,982
THERE IS--SO YOU'VE GOT SOME

5578
03:22:14,982 --> 03:22:15,682
INTERNAL STANDARDIZATION, SOME

5579
03:22:15,682 --> 03:22:18,085
OF THE WAYS THAT WE GO ABOUT

5580
03:22:18,085 --> 03:22:20,988
CREATE YOU KNOW THE SEED STOCKS,

5581
03:22:20,988 --> 03:22:26,093
VERSUS THE WORKING STOCKS ARE

5582
03:22:26,093 --> 03:22:28,495
VERY STANDARDIZED BUT NO, I

5583
03:22:28,495 --> 03:22:31,765
THINK WE TRY TO SEEK CONSISTENCY

5584
03:22:31,765 --> 03:22:39,206
WITHIN OUR LABS AND GOING BEYOND

5585
03:22:39,206 --> 03:22:40,941
AND AND GOING TO WHAT EVERYONE

5586
03:22:40,941 --> 03:22:42,843
ELSE IS CORKING WITH IS PROBABLY

5587
03:22:42,843 --> 03:22:44,077
A NEAR IMPOSSIBLE TASK.

5588
03:22:44,077 --> 03:22:46,113
NAT THE END THE DAY DOES THAT

5589
03:22:46,113 --> 03:22:47,614
AFFECT THE RESULTS AND THE WAY

5590
03:22:47,614 --> 03:22:52,152
YOU ARE ABLE TO COMPARE RESULTS

5591
03:22:52,152 --> 03:22:53,286
BETWEEN LABS.

5592
03:22:53,286 --> 03:22:55,622
>> YEAH, AS YOU KNOW ABOUT
THE

5593
03:22:55,622 --> 03:22:57,691
SAVE PROJECT WHICH KEY DID AS A

5594
03:22:57,691 --> 03:22:59,159
COMMUNITY FOR STUDYING

5595
03:22:59,159 --> 03:23:01,028
SARS-COV-2, THERE ARE STOCKS

5596
03:23:01,028 --> 03:23:02,796
SENT OUT TO EVERYBODY SO THAT IN

5597
03:23:02,796 --> 03:23:07,000
THEORY WE COULD ALL JUST GET 10

5598
03:23:07,000 --> 03:23:09,102
OR 15 DOSES OF VIRUS AND USE ALL

5599
03:23:09,102 --> 03:23:10,303
THAT FOR OUR PRPLTS AND I THINK

5600
03:23:10,303 --> 03:23:13,774
THAT WE SAW PRETTY GOOD

5601
03:23:13,774 --> 03:23:15,809
CONFORMITY OF RESULTS BECAUSE OF

5602
03:23:15,809 --> 03:23:20,380
THAT, BUT THERE'S ALSO OTHER

5603
03:23:20,380 --> 03:23:21,915
VARIABLES SUCH AS--EVEN IF 1

5604
03:23:21,915 --> 03:23:23,750
MOVED FROM 1ITATE TO

5605
03:23:23,750 --> 03:23:28,555
ANOTHERITATE, THERE'S OFTEN

5606
03:23:28,555 --> 03:23:30,557
CHANGES IN MICROBIOMES AND

5607
03:23:30,557 --> 03:23:32,626
ANIMAL FACILITIES AND THAT

5608
03:23:32,626 --> 03:23:33,894
CHANGES HOW INFECTIONS OCCUR

5609
03:23:33,894 --> 03:23:35,796
EVEN APPROXIMATE 1 USES THE

5610
03:23:35,796 --> 03:23:38,098
STOCKS IN MICE, SO I AGREE WITH

5611
03:23:38,098 --> 03:23:38,765
THE ANSWER, IT'S PRETTY

5612
03:23:38,765 --> 03:23:41,134
DIFFICULT TO DO IT, IT'S IDEAL

5613
03:23:41,134 --> 03:23:43,070
IF WE COULD BUT IT'S PRETTY

5614
03:23:43,070 --> 03:23:43,336
DIFFICULT.

5615
03:23:43,336 --> 03:23:47,441
>> BUT I THINK WE SAW THAT
AT

5616
03:23:47,441 --> 03:23:49,076
LEAST FOR THE SARS-COV-2 WORK

5617
03:23:49,076 --> 03:23:50,477
THAT SOMETIMES ACROSS VERY

5618
03:23:50,477 --> 03:23:51,912
DIFFERENT SPECIES, DIFFERENT

5619
03:23:51,912 --> 03:23:53,647
LABS ISSUES EVEN DIFFERENT

5620
03:23:53,647 --> 03:23:55,482
STRAINS OF VIRUS, WE START TO

5621
03:23:55,482 --> 03:23:57,784
SEE--IF WE TART TO SEE

5622
03:23:57,784 --> 03:24:00,287
CONVERGING EVIDENCE THAT WE CAN

5623
03:24:00,287 --> 03:24:03,290
SEE SOMETHING LIKE THE ANASMIA,

5624
03:24:03,290 --> 03:24:07,527
LIKE THE INFLAMMATION OF THE

5625
03:24:07,527 --> 03:24:08,428
OLFACTORY BULB, ACROSS, THEN

5626
03:24:08,428 --> 03:24:10,931
THIS I THINK TO ME, THAT'S

5627
03:24:10,931 --> 03:24:12,132
ALMOST MORE EXCITING CONVERGING

5628
03:24:12,132 --> 03:24:15,102
EVIDENT BECAUSE IT DOESN'T MEAN

5629
03:24:15,102 --> 03:24:17,003
THAT YOU KNOW YOU HAVE TO STAND

5630
03:24:17,003 --> 03:24:18,805
ON 1 FOOT, GROW THE VIRUS THIS

5631
03:24:18,805 --> 03:24:21,274
WAY, INFECT THE ANIMAL WITH ITS

5632
03:24:21,274 --> 03:24:23,410
HEAD TILTED ONLY THIS WAY IN

5633
03:24:23,410 --> 03:24:28,715
ORDER TO REPLICATE WHAT SOMEBODY

5634
03:24:28,715 --> 03:24:29,249
HAS DONE.

5635
03:24:29,249 --> 03:24:31,952
>> I THINK WITH THE DEEP

5636
03:24:31,952 --> 03:24:33,386
SEQUENCING WE'VE DONE IN THE

5637
03:24:33,386 --> 03:24:34,488
LABORATORY THAT'S BECOME MUCH

5638
03:24:34,488 --> 03:24:37,157
MORE PROMINENT THAN IT HAS IN

5639
03:24:37,157 --> 03:24:39,493
THE PAST WITH VIRUS STOCKS.

5640
03:24:39,493 --> 03:24:41,128
I THINK WE KNOW WHAT FREQUENCY

5641
03:24:41,128 --> 03:24:42,796
OF THAT MUTATION IS PRESENT

5642
03:24:42,796 --> 03:24:45,165
WITHIN OUR VIRUS STOCKS,

5643
03:24:45,165 --> 03:24:47,234
PRECOVID, I'M NOT SURE HOW MANY

5644
03:24:47,234 --> 03:24:50,036
OF US ACTUALLY DEEP SEQUENCED

5645
03:24:50,036 --> 03:24:52,906
OUR VIRUS STOCKS--

5646
03:24:52,906 --> 03:24:56,643
>> ONLY IF WE WERE
SHIPPING IT--

5647
03:24:56,643 --> 03:24:57,477
>> --IT PROVIDES VARIATION
TO

5648
03:24:57,477 --> 03:24:59,379
WHAT WE'RE SEEING IN THE VIRAL

5649
03:24:59,379 --> 03:25:02,883
STOCKS BETWEEN LAB RAARE TOYS AS

5650
03:25:02,883 --> 03:25:03,683
WELL.

5651
03:25:03,683 --> 03:25:04,618
--LABORATORIES AS WELL.

5652
03:25:04,618 --> 03:25:05,852
>> I WAS WONDERING HOW
MUCH ALL

5653
03:25:05,852 --> 03:25:08,955
OF YOU GUYS LOOK AT DIFFERENT

5654
03:25:08,955 --> 03:25:09,856
INOCULATION ROUTES AND

5655
03:25:09,856 --> 03:25:10,757
[INDISCERNIBLE] BECAUSE I THINK

5656
03:25:10,757 --> 03:25:13,994
EVERY SINGLE 1 OF YOU IS

5657
03:25:13,994 --> 03:25:15,629
ANYTHING IN THE INTRA NAISAL

5658
03:25:15,629 --> 03:25:17,164
ROUTE, DO YOU SEE TRY FULL

5659
03:25:17,164 --> 03:25:21,368
[INDISCERNIBLE], DO YOU SEE

5660
03:25:21,368 --> 03:25:21,968
DIFFERENT PATHOGENESIS AFTER

5661
03:25:21,968 --> 03:25:25,105
THAT DO YOU TRY TO INOCULATEAR O

5662
03:25:25,105 --> 03:25:26,540
SOLS OR IS THAT SOMETHING YOU'RE

5663
03:25:26,540 --> 03:25:28,074
NOT CAPABLE OF DOING.

5664
03:25:28,074 --> 03:25:29,876
>> WE'VE TRIED ESPECIALLY
WITH

5665
03:25:29,876 --> 03:25:31,444
THE HAMSTER FOR SARS OVERLAPPING

5666
03:25:31,444 --> 03:25:35,882
2 TRIED A BUNCH OF DIFFERENT

5667
03:25:35,882 --> 03:25:37,217
INOCULATION METHODS, EVERYBODY

5668
03:25:37,217 --> 03:25:39,052
TRIED EVERYTHING PRACTICES INTRA

5669
03:25:39,052 --> 03:25:41,855
NAISAL TO IV OR OCULAR

5670
03:25:41,855 --> 03:25:44,090
DRIPPINGS, NAIS AT PASSAGES WITH

5671
03:25:44,090 --> 03:25:46,593
DIFFERENT DOSES RANGING FROM 100

5672
03:25:46,593 --> 03:25:50,063
UP TO MILLIONS OF PFU AND IT WAS

5673
03:25:50,063 --> 03:25:51,364
SURPRISING HOW INCONSISTENT THE

5674
03:25:51,364 --> 03:25:53,266
RESULTS WERE SO IN THE LUNGS THE

5675
03:25:53,266 --> 03:25:55,101
VIRUS IS REP LITICATED GENERALLY

5676
03:25:55,101 --> 03:25:57,304
THE SAME LEVELS ACROSS ALL THESE

5677
03:25:57,304 --> 03:25:59,372
DIFFERENT CONTRACT TRANSMISSION,

5678
03:25:59,372 --> 03:26:02,576
GET SIMILAR, NOT ENTIRELY SURE

5679
03:26:02,576 --> 03:26:03,043
BECAUSE IT'S CONTRACT

5680
03:26:03,043 --> 03:26:04,511
TRANSMISSION AND HOW MUCH IS

5681
03:26:04,511 --> 03:26:05,345
COMMUNICATED WEAN THE DIFFERENT

5682
03:26:05,345 --> 03:26:07,714
ANIMALS BUT YOU SEE SIMILAR

5683
03:26:07,714 --> 03:26:08,281
VIRAL DYNAMICS.

5684
03:26:08,281 --> 03:26:10,917
THE ONLY THING THAT CHANGED IS

5685
03:26:10,917 --> 03:26:13,720
THE SUBTLE SHIFT IN THE KINETICS

5686
03:26:13,720 --> 03:26:15,956
WITH HIGHER DOSES, IT SEEMS LIKE

5687
03:26:15,956 --> 03:26:18,124
HIGHER ANTIGEN IN THE FRONT, BUT

5688
03:26:18,124 --> 03:26:21,828
SO YOU SEE A QUICKER TRIGGER SO

5689
03:26:21,828 --> 03:26:23,864
IT'S BEEN INTERESTING HOW

5690
03:26:23,864 --> 03:26:25,498
CONSISTENT THE INFECS ARE FOR

5691
03:26:25,498 --> 03:26:25,732
SARS.

5692
03:26:25,732 --> 03:26:27,634
INITIATIVES THE ONLY OTHER THING

5693
03:26:27,634 --> 03:26:30,437
I MIGHT ADD IN ARK DITION TO

5694
03:26:30,437 --> 03:26:31,638
INOCULATION ROUTES AND I

5695
03:26:31,638 --> 03:26:32,973
COMPLETELY AGREE AND WE'VE DONE

5696
03:26:32,973 --> 03:26:34,207
THAT WITH SEVERAL DIFFERENT

5697
03:26:34,207 --> 03:26:35,642
VIRUSES, I THINK ALL OF US WITH

5698
03:26:35,642 --> 03:26:37,611
WE'RE FIRST STARTING WITH A NEW

5699
03:26:37,611 --> 03:26:39,713
VIRUS, WE DEFINITELY DO LD50S

5700
03:26:39,713 --> 03:26:42,349
WITH OUR MICE AND ANYTHING BACK

5701
03:26:42,349 --> 03:26:46,453
TO THE QUESTION ABOUT, YOU KNOW

5702
03:26:46,453 --> 03:26:47,153
CONSISTENCY ACROSS LABS, 1

5703
03:26:47,153 --> 03:26:49,656
OBSERVATION THAT I'VE MADE AT

5704
03:26:49,656 --> 03:26:53,159
LEAST WITH FLU IS THAT LOOKING

5705
03:26:53,159 --> 03:26:59,599
AT THE MOUSE LD50 DOSE ALLOWS US

5706
03:26:59,599 --> 03:27:01,701
TO THEN DEAL WITH THAT MAYBE

5707
03:27:01,701 --> 03:27:05,238
THAT PR8 VIRUS IS A LITTLE MORE

5708
03:27:05,238 --> 03:27:06,273
PATHOGENIC IN THIS GROUP THAN

5709
03:27:06,273 --> 03:27:12,612
THIS GROUP BUT YOU CAN MATCH IT

5710
03:27:12,612 --> 03:27:13,914
ON THE MLD 50 AND WHEN YOU DO

5711
03:27:13,914 --> 03:27:16,016
THAT YOU SEE THAT YOUR DATA IS

5712
03:27:16,016 --> 03:27:18,218
CONSISTENT WITH DATA FROM A

5713
03:27:18,218 --> 03:27:19,519
COMPLETELY DIFFERENT LAB WHO

5714
03:27:19,519 --> 03:27:21,621
GREW THEIR PR8 STRAIN FROM

5715
03:27:21,621 --> 03:27:22,489
ANOTHER COMPLETELY DIFFERENT LAB

5716
03:27:22,489 --> 03:27:25,926
EMPLOY SO THOSE KINDS OF THINGS

5717
03:27:25,926 --> 03:27:26,893
I DO THINK HELP.

5718
03:27:26,893 --> 03:27:29,496
I THINK ALL FIELDS STILL DIFFER

5719
03:27:29,496 --> 03:27:32,599
IN HOW MUCH THAT'S A NORM, I

5720
03:27:32,599 --> 03:27:35,936
THINK FOR FLU, THAT'S DEFINITELY

5721
03:27:35,936 --> 03:27:36,403
A NORM.

5722
03:27:36,403 --> 03:27:38,305
YOU ASKED ABOUT VOLUME, I DON'T

5723
03:27:38,305 --> 03:27:41,274
THINK--I KNOW WE DO NOT PLAY

5724
03:27:41,274 --> 03:27:46,379
MUCH WITH DIFFERENT VOLUMES, FOR

5725
03:27:46,379 --> 03:27:48,348
THE INNOCULUM WE KEEP THAT

5726
03:27:48,348 --> 03:27:49,416
CONSISTENT BUT MAYBE CHANGE HOW

5727
03:27:49,416 --> 03:27:50,717
MUCH VIRUS IS GOING IN, BUT

5728
03:27:50,717 --> 03:27:52,185
AGAIN THAT ALSO DIFFERS

5729
03:27:52,185 --> 03:27:54,587
DEPENDING ON THE ROUTE.

5730
03:27:54,587 --> 03:27:57,324
NYEAH, I THINK A LOT OF IT IS

5731
03:27:57,324 --> 03:27:59,225
ALMOST PREDICTABLE SO IF YOU USE

5732
03:27:59,225 --> 03:28:02,862
A SMALLER VOLUME AND YOU DO AN

5733
03:28:02,862 --> 03:28:04,364
INTRA NAISAL INOCULATION YOU

5734
03:28:04,364 --> 03:28:06,366
WON'T COVER AS MUCH OF THE LUNGS

5735
03:28:06,366 --> 03:28:07,901
SO YOU GET A DIFFERENT RESULT.

5736
03:28:07,901 --> 03:28:10,370
IF YOU USE AEROSOL VIRUS, THE

5737
03:28:10,370 --> 03:28:11,204
CHALLENGE IS MAKING SURE YOU

5738
03:28:11,204 --> 03:28:12,939
HAVE THE SAME DOSE AS YOU WOULD

5739
03:28:12,939 --> 03:28:15,241
DELIVER DIRECTLY TO THE LUNGS

5740
03:28:15,241 --> 03:28:17,077
BUT INTRA NAISAL INOCULATION SO

5741
03:28:17,077 --> 03:28:18,712
WE'VE DONE DIFFERENCES IN

5742
03:28:18,712 --> 03:28:19,679
VOLUMES MOSTLY NOT FOR GOOD

5743
03:28:19,679 --> 03:28:21,181
REASONS BUT WE MADE MISTAKES AND

5744
03:28:21,181 --> 03:28:24,084
WE SAW DIFFERENCES THERE.

5745
03:28:24,084 --> 03:28:25,385
AEROSOL WE HAVEN'T TRIED BUT I'M

5746
03:28:25,385 --> 03:28:26,920
PRETTY SURE THAT IF YOU GET

5747
03:28:26,920 --> 03:28:32,258
ENOUGH VIRUS INTO THE LUNGS, OF

5748
03:28:32,258 --> 03:28:32,959
AN ANIMAL IT'S SUSCEPTIBLE,

5749
03:28:32,959 --> 03:28:34,260
BECAUSE THING WITH THE HAMSTER

5750
03:28:34,260 --> 03:28:35,662
SYSTEM THEY DON'T GET VERY SICK

5751
03:28:35,662 --> 03:28:37,263
RIGHT NETWORK THEY HAVE MODERATE

5752
03:28:37,263 --> 03:28:39,933
WEIGHT LOSS, THEY GET PEL

5753
03:28:39,933 --> 03:28:40,533
MONITORARY INFILTRATE AND

5754
03:28:40,533 --> 03:28:42,002
PNEUMONIA YOU ABOUT THEY ALWAYS

5755
03:28:42,002 --> 03:28:42,335
RECOVER.

5756
03:28:42,335 --> 03:28:43,536
>> WE HAVE GREAT
HISTOLOGY, I

5757
03:28:43,536 --> 03:28:44,371
REMEMBER FROM THE

5758
03:28:44,371 --> 03:28:46,106
BEGENERATEDDING WE HAD GREAT

5759
03:28:46,106 --> 03:28:47,774
HISTOLOGICAL CHANGES THAT WERE

5760
03:28:47,774 --> 03:28:49,175
USEFUL FOR FOLLOWING BUT THERE

5761
03:28:49,175 --> 03:28:50,377
YOU HAVE A BIGGER CHANGE THAN

5762
03:28:50,377 --> 03:28:51,511
WHAT YOU CAN GIVE BECAUSE YOU'RE

5763
03:28:51,511 --> 03:28:57,217
NOT GOING TO KILL THE ANIMALS.

5764
03:28:57,217 --> 03:28:59,152
>> I HAVE A QUESTION FOR
LISA

5765
03:28:59,152 --> 03:29:01,821
AND SORRY TO PUT YOU ON THE

5766
03:29:01,821 --> 03:29:03,223
SPOT, THE COLLABORATIVE CROSS

5767
03:29:03,223 --> 03:29:04,924
MOUSE MODEL HAS HELPED US BETTER

5768
03:29:04,924 --> 03:29:06,693
UNDERSTAND THE IMPACT OF MOUSE

5769
03:29:06,693 --> 03:29:10,830
GENETICS ON OUR PHENOTYPIC RATES

5770
03:29:10,830 --> 03:29:12,766
THAT 1 LOOKS AT BUT 1 OF THE

5771
03:29:12,766 --> 03:29:14,234
CHALLENGING PARTS OF THE

5772
03:29:14,234 --> 03:29:18,304
COLLABORATIVE PROCESS IS JUMPING

5773
03:29:18,304 --> 03:29:19,005
INTO USING THE COLLABORATIVE

5774
03:29:19,005 --> 03:29:23,710
CROSS AND THAT SEEMS TO BE A

5775
03:29:23,710 --> 03:29:33,086
BARRIER TO HAVE MUCH MORE WIDE

5776
03:29:33,086 --> 03:29:34,187
EXPRESS AND UNDERSTAND AND

5777
03:29:34,187 --> 03:29:35,588
UNDERSTANDING WHAT THE

5778
03:29:35,588 --> 03:29:39,092
PHENOTYPIC LOCI HOW THEY

5779
03:29:39,092 --> 03:29:41,461
CORRELATE CAN YOU SORT OF

5780
03:29:41,461 --> 03:29:43,463
PROVIDE MORE INSIGHT INTO HOW 1

5781
03:29:43,463 --> 03:29:44,998
CAN UTILIZE THAT MODEL,

5782
03:29:44,998 --> 03:29:48,768
WHATEVER, PATHOGEN WE MAY BE

5783
03:29:48,768 --> 03:29:49,335
INTERESTED IN?

5784
03:29:49,335 --> 03:29:50,870
>> YEAH, I WILL SAY
MESSIAH

5785
03:29:50,870 --> 03:29:52,472
EXPERIENCE WITH THE CC HAS BEEN

5786
03:29:52,472 --> 03:29:54,808
TARTING  ON SECOND BASE ALREADY

5787
03:29:54,808 --> 03:29:56,309
BECAUSE I'M LOCATED AT UNC WHERE

5788
03:29:56,309 --> 03:29:58,478
MOST OF THE MICE ARE AND A LOT

5789
03:29:58,478 --> 03:30:00,847
OF THE INVESTIGATORS WHO ARE

5790
03:30:00,847 --> 03:30:01,915
INVOLVED IN CREATING THIS

5791
03:30:01,915 --> 03:30:03,950
RESOURCE SO I DEFINITELY GAME IN

5792
03:30:03,950 --> 03:30:07,387
WITH A MASSIVE ADVANTAGE IN THAT

5793
03:30:07,387 --> 03:30:07,620
SENSE.

5794
03:30:07,620 --> 03:30:13,526
BUT THERE ARE A NUMBER OF MOUSE

5795
03:30:13,526 --> 03:30:15,862
GENETICISTS AT UNC, AND OCRANGE,

5796
03:30:15,862 --> 03:30:17,464
AND JACKSON HAS A LOT OF PEOPLE

5797
03:30:17,464 --> 03:30:19,365
WORKING WITH THEM AS WELL, AND

5798
03:30:19,365 --> 03:30:21,234
THEY ARE REALLY GOOD TO

5799
03:30:21,234 --> 03:30:22,702
COLLABORATE IN TERMS OF GENETICS

5800
03:30:22,702 --> 03:30:24,237
AND THE MODELING ASPECTS OF THAT

5801
03:30:24,237 --> 03:30:25,305
WHICH, YOU KNOW PEOPLE HAVE

5802
03:30:25,305 --> 03:30:27,407
TRIED TO TEACH ME HOW TO USE R

5803
03:30:27,407 --> 03:30:29,442
AND I CAN'T SAY IT'S BEEN

5804
03:30:29,442 --> 03:30:30,243
PARTICULARLY SUCCESSFUL, I HAVE

5805
03:30:30,243 --> 03:30:32,178
SPENT MY TIME LEARNING OTHER

5806
03:30:32,178 --> 03:30:35,248
THINGS, I WILLAD MITT, SO DOING

5807
03:30:35,248 --> 03:30:36,916
THE SCREENING INFECTING A LOT OF

5808
03:30:36,916 --> 03:30:38,585
MICE IS HONESTLY THE EASY PART.

5809
03:30:38,585 --> 03:30:40,153
CAN YOU GET GREAT PHENOTYPES AND

5810
03:30:40,153 --> 03:30:42,021
UNTIL YOU CAN CORRELATE WITH

5811
03:30:42,021 --> 03:30:44,491
WITH THE GENETICS AND DO THE

5812
03:30:44,491 --> 03:30:46,993
MODELING, YOU HAVE A PILE OF

5813
03:30:46,993 --> 03:30:49,863
DATA THAT CAN'T REALLY GO

5814
03:30:49,863 --> 03:30:51,831
ANYWHERE, SO, HAVING A PIPELINE

5815
03:30:51,831 --> 03:30:53,500
AND THERE'S FAIRLY STANDARDIZED

5816
03:30:53,500 --> 03:30:55,902
SCRIPTS IF YOU HAVE YOUR DATA

5817
03:30:55,902 --> 03:30:58,872
ORGANIZED PROPERLY THAT AREN'T

5818
03:30:58,872 --> 03:31:00,640
COMPLETELY PLUG AND PLAY BUT CAN

5819
03:31:00,640 --> 03:31:04,644
GET YOU TO QTLs PRETTY EASILY,

5820
03:31:04,644 --> 03:31:06,846
IN MY EXPERIENCE, THE BIGGEST

5821
03:31:06,846 --> 03:31:09,082
CHALLENGE HAS BEEN YOU HAVE A

5822
03:31:09,082 --> 03:31:11,084
QTR L, THIS REGION FROM

5823
03:31:11,084 --> 03:31:13,086
CHROMOSOME SENCH IS TIGHTLY

5824
03:31:13,086 --> 03:31:13,920
ASSOCIATED WITH THE PHENOTYPE OF

5825
03:31:13,920 --> 03:31:16,022
INTEREST AND HOW DO YOU GET TO A

5826
03:31:16,022 --> 03:31:17,991
CAUSATIVE YEEN AND HOW DO YOU

5827
03:31:17,991 --> 03:31:19,159
VALIDATE THAT SO A REAL

5828
03:31:19,159 --> 03:31:22,495
CHALLENGE FOR US HAS BEEN BOTH

5829
03:31:22,495 --> 03:31:23,429
IN GRANTSMANSHIP AND IN WRITING

5830
03:31:23,429 --> 03:31:24,531
PAPER ANDS HAVING PEOPLE WHO

5831
03:31:24,531 --> 03:31:26,566
WILL SUPPORT THE GENETIC SIDE

5832
03:31:26,566 --> 03:31:27,767
AND SUPPORT THE VIROLOGY SIDE,

5833
03:31:27,767 --> 03:31:30,336
AND RECOGNIZE THAT YOU MIGHT

5834
03:31:30,336 --> 03:31:33,039
HAVE AIAN LOT OF PRELIMINARY

5835
03:31:33,039 --> 03:31:34,941
DATA AND YOU MIGHT NOT HAVE A

5836
03:31:34,941 --> 03:31:37,777
COMPLETE STORY BUT IF A REVIEWER

5837
03:31:37,777 --> 03:31:38,611
COMPLETELY DISCOUNTS GENETICS

5838
03:31:38,611 --> 03:31:41,981
HALF OF IT, OR THE VIROLOGY HALF

5839
03:31:41,981 --> 03:31:43,516
OF IT AND BEING ABLE TO PUSH

5840
03:31:43,516 --> 03:31:44,851
THAT ACROSS THE FINISH LINE AND

5841
03:31:44,851 --> 03:31:45,985
GETTING PAPERS AND MORE MONEY TO

5842
03:31:45,985 --> 03:31:52,592
DO MORE WORK IS THE MOST

5843
03:31:52,592 --> 03:31:54,093
IMPORTANT PART.

5844
03:31:54,093 --> 03:31:55,428
>> UNT HAS DONE BASE LINE

5845
03:31:55,428 --> 03:31:56,930
MEASUREMENTS AS WELL AS

5846
03:31:56,930 --> 03:31:59,766
VALIDATED ANTIBODIES THAT 1 USES

5847
03:31:59,766 --> 03:32:00,200
FOR IMMUNE ANALYSIS.

5848
03:32:00,200 --> 03:32:02,168
IT'S A LOT OF THAT STUFF

5849
03:32:02,168 --> 03:32:03,937
PUBLICLY AVAILABLE, AND IF SO,

5850
03:32:03,937 --> 03:32:06,172
WHERE COULD 1 FIND IT IN.

5851
03:32:06,172 --> 03:32:13,713
>> A LOT OF IS SUPPOSED TO
BE

5852
03:32:13,713 --> 03:32:15,481
AVAILABLE ON JACK'S MOUSE FETAL

5853
03:32:15,481 --> 03:32:16,916
COMPARTMENT NOAM BUT I SHOULD

5854
03:32:16,916 --> 03:32:18,685
DOUBLE CHECK ON THAT.

5855
03:32:18,685 --> 03:32:20,787
ALTERNATIVELY AS YOU KNOW E-MAIL

5856
03:32:20,787 --> 03:32:24,557
MATTER FERRIS.

5857
03:32:24,557 --> 03:32:24,757
NYEAH.

5858
03:32:24,757 --> 03:32:25,558
--MARTY FERRIS.

5859
03:32:25,558 --> 03:32:27,827
>> WE HAVE A VIRTUAL
ATTENDEE

5860
03:32:27,827 --> 03:32:29,195
WITH THEIR HAND RAISED SO I WANT

5861
03:32:29,195 --> 03:32:32,765
TO CALL ON THEM.

5862
03:32:32,765 --> 03:32:36,436
KAY BARNS?

5863
03:32:36,436 --> 03:32:37,570
>> YEAH, HI, JUST
WONDERING WHAT

5864
03:32:37,570 --> 03:32:39,038
WAS YOUR VIEW ON THE USE OF

5865
03:32:39,038 --> 03:32:41,507
THOSE ANIMAL MODELS KNOWING THE

5866
03:32:41,507 --> 03:32:43,109
SEX DIFFERENCES IS QUITE EXTREME

5867
03:32:43,109 --> 03:32:47,680
OR THE USE OF THEM FOR

5868
03:32:47,680 --> 03:32:48,514
EVALUATING MEDICAL

5869
03:32:48,514 --> 03:32:49,182
COUNTERMEASURES, WOULD YOU

5870
03:32:49,182 --> 03:32:51,484
CONSIDER USING BOTH SEXES BUT

5871
03:32:51,484 --> 03:32:53,686
MAYBE HAVING BIGGER GROUPS TO

5872
03:32:53,686 --> 03:32:58,291
COUNT FOR THAT DIFFERENCE?

5873
03:32:58,291 --> 03:32:59,659
>> OKAY SO IF I'M
UNDERSTANDING

5874
03:32:59,659 --> 03:33:02,829
YOU CORRECTLY, YOU WANT TO KNOW

5875
03:33:02,829 --> 03:33:04,530
WHAT YOU OR ANYBODY AS AN

5876
03:33:04,530 --> 03:33:06,833
INVESTIGATOR SHOULD DO IF THERE

5877
03:33:06,833 --> 03:33:10,169
ARE THESE DIFFERENCES AND YOU'RE

5878
03:33:10,169 --> 03:33:11,604
BEING EXPECTED TO INCLUDE BOTH

5879
03:33:11,604 --> 03:33:14,340
BUT NOT THE KINDS OF MEMBERS

5880
03:33:14,340 --> 03:33:16,009
OBVIOUSLY THEY AM, I DO THINK

5881
03:33:16,009 --> 03:33:18,878
THAT'S A CHALLENGE AND I DO

5882
03:33:18,878 --> 03:33:19,712
THINK IT'S BEEN A PROBLEM WITH

5883
03:33:19,712 --> 03:33:23,082
THE 6 AS A BIOLOGICAL VARIABLE

5884
03:33:23,082 --> 03:33:23,383
REQUIREMENT.

5885
03:33:23,383 --> 03:33:27,220
BECAUSE I THINK IN SOME CASES IT

5886
03:33:27,220 --> 03:33:30,823
INCREASES HETEROGENEITY WHEN

5887
03:33:30,823 --> 03:33:31,557
YOU'RE LUMPING EVERYBODY

5888
03:33:31,557 --> 03:33:33,726
TOGETHER WHICH CAN NOT BE A GOOD

5889
03:33:33,726 --> 03:33:33,960
THING.

5890
03:33:33,960 --> 03:33:38,665
I THINK IN MANY CASES, WHAT I AM

5891
03:33:38,665 --> 03:33:42,168
SEEING IS JUST USING DATA SUCH

5892
03:33:42,168 --> 03:33:43,336
AS MINE THEN AS JUSTIFICATION

5893
03:33:43,336 --> 03:33:47,173
THAT IF YOU'RE STUDYING THE

5894
03:33:47,173 --> 03:33:48,107
PATHOGENESIS, FOR EXAMPLE, 3 B,

5895
03:33:48,107 --> 03:33:50,176
MAYBE IT IS BETTER TO GO AHEAD

5896
03:33:50,176 --> 03:33:51,744
AND USE MALE MICE BECAUSE THEY

5897
03:33:51,744 --> 03:33:55,114
GET SICK, AND YOU COULD STUDY IS

5898
03:33:55,114 --> 03:33:56,549
SEE BEAUTIFUL EFFECTS OF

5899
03:33:56,549 --> 03:34:01,554
DEFINITE ANTIVIRALS, IF YOU WERE

5900
03:34:01,554 --> 03:34:04,190
STUDYING ANTIVIRALS ON

5901
03:34:04,190 --> 03:34:05,058
EFFECTIVENESS ESPECIALLY NOVEL

5902
03:34:05,058 --> 03:34:06,893
ANTIVIRALS, I DON'T KNOW WHY YOU

5903
03:34:06,893 --> 03:34:08,594
WOULD GIVE THAT TO FEMALE MICE

5904
03:34:08,594 --> 03:34:09,962
WHEN THEY JUST DON'T GET SICK.

5905
03:34:09,962 --> 03:34:13,066
SO, YOU KNOW I THINK THERE ARE

5906
03:34:13,066 --> 03:34:14,934
RATIONAL WAYS TO UTILIZE WHAT WE

5907
03:34:14,934 --> 03:34:18,137
KNOW ABOUT SEX DIFFERENCES TO

5908
03:34:18,137 --> 03:34:20,406
THEN ASK WHAT QUESTION ARE YOU

5909
03:34:20,406 --> 03:34:23,042
ASKING AND COULD THAT BE

5910
03:34:23,042 --> 03:34:27,146
JUSTIFICATION FOR A SINGLE SEX

5911
03:34:27,146 --> 03:34:27,347
STUDY.

5912
03:34:27,347 --> 03:34:29,916
>> THANK YOU SO MUCH,
YEAH, I

5913
03:34:29,916 --> 03:34:30,817
AGREE.

5914
03:34:30,817 --> 03:34:33,886
IT'S A VERY BIG CHALLENGE, ISN'T

5915
03:34:33,886 --> 03:34:34,287
IT?

5916
03:34:34,287 --> 03:34:34,687
>> YEAH, IT IS.

5917
03:34:34,687 --> 03:34:37,724
>> SO TO FOLLOW UP ON
THAT, I

5918
03:34:37,724 --> 03:34:39,492
MAY HAVE MISSED THIS FROM YOUR

5919
03:34:39,492 --> 03:34:40,626
PRESENTATION, HOW MUCH HAS BEEN

5920
03:34:40,626 --> 03:34:42,161
DONE AT BASE LINE BETWEEN MALES

5921
03:34:42,161 --> 03:34:47,333
AND FEMALES IN TERMS OF INNATE

5922
03:34:47,333 --> 03:34:47,934
ANALYSIS, CYTOKINE ANALYSIS,

5923
03:34:47,934 --> 03:34:49,836
WHAT ARE DIFFERENCES INITIALLY

5924
03:34:49,836 --> 03:34:51,571
NNO, THAT'S SUCH A GOOD

5925
03:34:51,571 --> 03:34:51,938
QUESTION.

5926
03:34:51,938 --> 03:34:53,406
WE ABSOLUTELY ALWAYS DO THAT.

5927
03:34:53,406 --> 03:34:56,876
WE TEND TO NOT FIND A LOT OF

5928
03:34:56,876 --> 03:34:57,777
BASE LINE DIFFERENCES.

5929
03:34:57,777 --> 03:35:04,450
, YOU KNOW EITHER IN TERMS

5930
03:35:04,450 --> 03:35:06,986
OF'MUNE CELLS FROM FLOW

5931
03:35:06,986 --> 03:35:09,622
CYTOMETRY, OR PROTEIN CONTENT IN

5932
03:35:09,622 --> 03:35:11,190
THE LUNGS, CYTOKINES,

5933
03:35:11,190 --> 03:35:13,025
CHEMOKINES, THEY REALLY DO NOT

5934
03:35:13,025 --> 03:35:16,329
SEE A LOT OF BASE LINE

5935
03:35:16,329 --> 03:35:17,930
DIFFERENCES, SO, YOU KNOW I

5936
03:35:17,930 --> 03:35:20,299
THINK MUCH OF WHAT WE'RE SEEING

5937
03:35:20,299 --> 03:35:22,668
NOT SO DIFFERENT, I KNOW WE'RE

5938
03:35:22,668 --> 03:35:23,703
TALKING ABOUT RESPIRATORY

5939
03:35:23,703 --> 03:35:25,772
VIRUSES, BUT I MEAN, I COULD

5940
03:35:25,772 --> 03:35:27,907
REPLACE WHAT WE DO WITH

5941
03:35:27,907 --> 03:35:30,743
RESPIRATORY VIRUSES AND SHOW YOU

5942
03:35:30,743 --> 03:35:33,880
BEAUTIFUL WORK FROM OTHER

5943
03:35:33,880 --> 03:35:35,348
INVESTIGATORS WHO DO ALLERGY AND

5944
03:35:35,348 --> 03:35:37,083
ASTHMA MODELS AND I CAN SHOW YOU

5945
03:35:37,083 --> 03:35:38,351
THEY DON'T SEE BASE LINE

5946
03:35:38,351 --> 03:35:41,187
DIFFERENCES BUT THEY WILL GIVE

5947
03:35:41,187 --> 03:35:43,055
THEIR MICE THE HOUSE DUST MIGHTS

5948
03:35:43,055 --> 03:35:45,024
ALL OF A SUDDEN EVERYTHING THEY

5949
03:35:45,024 --> 03:35:47,660
SEE WITH FLU A, THEY SEE WHERE

5950
03:35:47,660 --> 03:35:51,330
FEMALES HAVE THIS OVER EXUBERANT

5951
03:35:51,330 --> 03:35:52,532
CYTOKINE RESPONSE, MORE TISSUE

5952
03:35:52,532 --> 03:35:54,033
DAMAGE, ET CETERA, SO IT'S

5953
03:35:54,033 --> 03:35:56,102
REALLY IN RESPONSE TO THE

5954
03:35:56,102 --> 03:35:57,069
STIMULUS, IT DOESN'T EVEN HAVE

5955
03:35:57,069 --> 03:36:03,943
TO BE A VIRUS.

5956
03:36:03,943 --> 03:36:04,377
>> STACEY?

5957
03:36:04,377 --> 03:36:06,579
>> SO THERE WAS AN
INTERESTING

5958
03:36:06,579 --> 03:36:08,881
PAPER IN OBESITY AND SEX BIAS

5959
03:36:08,881 --> 03:36:10,049
AND LOOKINGA THE ENDOTHELIAL

5960
03:36:10,049 --> 03:36:12,318
CELLS AND LAKE LOOKING AT BASE

5961
03:36:12,318 --> 03:36:14,587
LINE, THE DIFFERENCES BETWEEN

5962
03:36:14,587 --> 03:36:15,688
ENDOTHELIAL MALE AND FEMALE, IT

5963
03:36:15,688 --> 03:36:19,725
WAS IN THE RACE, IN THE CELLS

5964
03:36:19,725 --> 03:36:20,827
THEMSELVES THAT MALES JUST TEND

5965
03:36:20,827 --> 03:36:23,062
TOWARDS MORE OF A

5966
03:36:23,062 --> 03:36:24,430
PROINFLAMMATORY RESPONSE EVEN AT

5967
03:36:24,430 --> 03:36:26,866
THAT ENDOTHELIAL CELL LEVEL SO

5968
03:36:26,866 --> 03:36:29,669
THOUGHT THAT WAS FASCINATING

5969
03:36:29,669 --> 03:36:30,970
NSEEMA?

5970
03:36:30,970 --> 03:36:33,439
>> I WANTED TO--MY

5971
03:36:33,439 --> 03:36:34,640
INTERPRETATION OF THE QUESTION

5972
03:36:34,640 --> 03:36:35,908
WAS FOR LISA ABOUT THE

5973
03:36:35,908 --> 03:36:40,379
COLLABORATIVE CROSS AND THE

5974
03:36:40,379 --> 03:36:43,983
PHENOTYPES YOU SEE ARE YOU DOING

5975
03:36:43,983 --> 03:36:46,118
THEM IN BOTH GENDERS--BOTH

5976
03:36:46,118 --> 03:36:47,787
SEXES, RIGHT, I'M SORRY, NEED TO

5977
03:36:47,787 --> 03:36:51,324
BE BETTER WITH THAT, IN BOTH

5978
03:36:51,324 --> 03:36:53,726
SEXES IN ORDER TO ENSURE THEY

5979
03:36:53,726 --> 03:36:55,194
ARE REPRODUCIBLE AND SEX BIAS

5980
03:36:55,194 --> 03:36:55,695
THERE.

5981
03:36:55,695 --> 03:36:57,330
NYEAH, SO PAINFULLY WE ARE DOING

5982
03:36:57,330 --> 03:37:00,600
IT IN BOTH SEXES AND WE DO

5983
03:37:00,600 --> 03:37:04,971
SOMETIMES SEE SOME DIFFERENCES.

5984
03:37:04,971 --> 03:37:06,205
I WOULD RECOMMEND AGAINST SOME

5985
03:37:06,205 --> 03:37:09,141
OF THE MALE CC LINES IF

5986
03:37:09,141 --> 03:37:13,479
POSSIBLE, BUT WE ARE STUDYING

5987
03:37:13,479 --> 03:37:14,947
THEM FOR OUR APPROPRIATE

5988
03:37:14,947 --> 03:37:15,181
STUDIES.

5989
03:37:15,181 --> 03:37:18,117
>> AND NOT TO MAKE THIS'

5990
03:37:18,117 --> 03:37:19,385
REFERENDUM I SEE ON THING AS THE

5991
03:37:19,385 --> 03:37:21,020
STUDY SECTION BUT THIS IS MORE

5992
03:37:21,020 --> 03:37:23,456
OF A PROGRAM OFFICE IS THERE ANY

5993
03:37:23,456 --> 03:37:25,558
APPETITE AT NIH TO, I DON'T WANT

5994
03:37:25,558 --> 03:37:27,994
TO SAY LOOSEN SEX AS A

5995
03:37:27,994 --> 03:37:31,197
BIOLOGICAL VARIABLE BECAUSE I

5996
03:37:31,197 --> 03:37:32,331
THINK IT'S IMPORTANT WE CONSIDER

5997
03:37:32,331 --> 03:37:36,002
IT BUT I THINK SEEMA MADE POINTS

5998
03:37:36,002 --> 03:37:37,069
WHERE IT MIGHT BE APPROPRIATE TO

5999
03:37:37,069 --> 03:37:39,805
SELECT 1 OVER THE OTHER

6000
03:37:39,805 --> 03:37:41,007
BIOLOGICALLY THAT CAN I TELL YOU

6001
03:37:41,007 --> 03:37:43,075
BECAUSE OF THE WAY THE RULES ARE

6002
03:37:43,075 --> 03:37:44,477
WRITTEN, BECAUSE IT'S SO RIGID

6003
03:37:44,477 --> 03:37:47,246
EVEN IF YOU HAVE AN ABSOLUTELY

6004
03:37:47,246 --> 03:37:48,080
GOOD SCIENTIFIC RATIONAL, CAN

6005
03:37:48,080 --> 03:37:49,815
YOU GET DESTROYED BY THE STUDY.

6006
03:37:49,815 --> 03:37:51,250
IT'S HAM STRUNG, SOME STUDY OF

6007
03:37:51,250 --> 03:37:53,219
SEX AS A BIOLOGICAL BARRIER.

6008
03:37:53,219 --> 03:37:54,620
>> I FULLY AGREE WITH YOU

6009
03:37:54,620 --> 03:37:56,556
BECAUSE TOO QUICKLY I HAVE

6010
03:37:56,556 --> 03:37:58,758
PEOPLE GOING, OH IT DOESN'T

6011
03:37:58,758 --> 03:37:58,991
MATTER.

6012
03:37:58,991 --> 03:38:03,729
BUT YOU HAD ENDS OF 2, YOU KNOW?

6013
03:38:03,729 --> 03:38:05,731
SO I FULLY GET THAT, I THINK

6014
03:38:05,731 --> 03:38:07,400
WHAT'S HAPPENED IS IT'S GETTING

6015
03:38:07,400 --> 03:38:09,869
APPLIED AND THIS IS MUCH MORE

6016
03:38:09,869 --> 03:38:11,237
LESS ABOUT PROGRAM OFFICERS,

6017
03:38:11,237 --> 03:38:14,640
MORE ABOUT THE CENTER FOR

6018
03:38:14,640 --> 03:38:15,441
SCIENTIFIC REVIEW.

6019
03:38:15,441 --> 03:38:19,912
IT GETS APPLIED IN A VERY LAZY

6020
03:38:19,912 --> 03:38:21,614
WAY WHERE YOU KNOW, REALLY IF

6021
03:38:21,614 --> 03:38:25,117
YOU DO PROVIDE THE RATIONAL, YOU

6022
03:38:25,117 --> 03:38:26,752
KNOW I WILL JUST KEEP GOING BACK

6023
03:38:26,752 --> 03:38:28,421
TO FLU B, YOU KNOW THAT MALES

6024
03:38:28,421 --> 03:38:30,890
GET SO MUCH SICKER, YOU HAVE

6025
03:38:30,890 --> 03:38:32,525
DESIGNED ALL THESE REALLY COOL

6026
03:38:32,525 --> 03:38:34,260
NOVEL ANTIVIRALS THAT YOU WANT

6027
03:38:34,260 --> 03:38:38,931
TO TEST THAT WOULD BE FANTASTIC

6028
03:38:38,931 --> 03:38:42,201
RATIONAL, YOU KNOW IN I WILL

6029
03:38:42,201 --> 03:38:44,337
SAY, IT'S THE PROBLEM IS, YOU

6030
03:38:44,337 --> 03:38:46,572
JUST HAVE REVIEWERS SAYING, BOTH

6031
03:38:46,572 --> 03:38:49,308
THERE, YES, NO, IF THEY'RE BOTH

6032
03:38:49,308 --> 03:38:50,643
THERE, CHECK THE BOX, IF THEY'RE

6033
03:38:50,643 --> 03:38:50,876
NOT.

6034
03:38:50,876 --> 03:38:53,779
SO I DO AGREE WITH YOU, BUT I

6035
03:38:53,779 --> 03:38:56,182
DON'T SEE HOW IT'S CHANGING.

6036
03:38:56,182 --> 03:38:57,850
>> I WOULD AGREE, WE GOT
REAMED

6037
03:38:57,850 --> 03:38:58,918
ON A PREGNANCY GRANT BECAUSE

6038
03:38:58,918 --> 03:39:01,220
WE'RE NOT USING MALES, AND I'M

6039
03:39:01,220 --> 03:39:05,024
LOOK OKAY, BECAUSE THERE WAS A

6040
03:39:05,024 --> 03:39:06,325
LAZY REVIEWER AND NOBODY ON THE

6041
03:39:06,325 --> 03:39:07,860
STUDY SECTION CALLED THEM OUT

6042
03:39:07,860 --> 03:39:09,428
AND SAID HOW ARE YOU GOING TO DO

6043
03:39:09,428 --> 03:39:09,762
THAT?

6044
03:39:09,762 --> 03:39:13,099
SO I THINK THERE'S SOME GENERAL

6045
03:39:13,099 --> 03:39:14,100
REEDUCATION OF STUDY SECTIONS

6046
03:39:14,100 --> 03:39:17,737
THAT NEED TO HAPPEN AND IT'S

6047
03:39:17,737 --> 03:39:21,374
TRUE WHICH WE WON'T GET INTO,

6048
03:39:21,374 --> 03:39:24,477
WHERE GAIN OF FUNCTION, FOR A

6049
03:39:24,477 --> 03:39:28,080
REVIEWSHER, EVERYTHING'S GAIN OF

6050
03:39:28,080 --> 03:39:28,514
FUNCTION.

6051
03:39:28,514 --> 03:39:30,082
NOTHER QUESTIONS?

6052
03:39:30,082 --> 03:39:32,318
I HAVE 1 FOR JUSTIN.

6053
03:39:32,318 --> 03:39:34,887
IN YOUR WORK, LOOKING AT

6054
03:39:34,887 --> 03:39:36,188
MICRODPLEEL ACTIVATION,

6055
03:39:36,188 --> 03:39:37,857
OLFACTORY BULB IMPACS, THE

6056
03:39:37,857 --> 03:39:38,924
OMICRON VARIANTS IN HAMSTERS

6057
03:39:38,924 --> 03:39:40,426
DIFFERED IN THE WAY THEY

6058
03:39:40,426 --> 03:39:43,696
REPLICATE IN THE UPPER VERSUS

6059
03:39:43,696 --> 03:39:44,830
LOWER RESPIRATORY TRACT, HAVE

6060
03:39:44,830 --> 03:39:47,933
YOU SORT OF COMPARED DIFFERENT

6061
03:39:47,933 --> 03:39:51,303
VARIANTS IN THEIR IMPACT ON THE

6062
03:39:51,303 --> 03:39:52,104
UPPER RESPIRATORY TRACT.

6063
03:39:52,104 --> 03:39:54,373
>> WE HAVEN'T OURSELVES, I

6064
03:39:54,373 --> 03:39:55,241
THINK, [INDISCERNIBLE] LAB HAS

6065
03:39:55,241 --> 03:39:58,678
DONE A TON OF WORK I THINK ON

6066
03:39:58,678 --> 03:39:59,745
SPERKS LEECIALY LOWER

6067
03:39:59,745 --> 03:40:01,580
RESPIRATORY TRACT IN OMICRON

6068
03:40:01,580 --> 03:40:03,649
VARIANT WORK, SO I THINK I REF

6069
03:40:03,649 --> 03:40:05,217
FERENCED A LOT OF THEIR WORK IN

6070
03:40:05,217 --> 03:40:07,319
TERMS OF THE PERSISTENT

6071
03:40:07,319 --> 03:40:08,187
OLFACTORY PATHOLOGY, DEFINITELY

6072
03:40:08,187 --> 03:40:09,288
IS SOMETHING WE'RE INTERESTED

6073
03:40:09,288 --> 03:40:10,890
AND HAVEN'T DONE YET, ESPECIALLY

6074
03:40:10,890 --> 03:40:12,091
BECAUSE WE WOULD EXPECT BASED ON

6075
03:40:12,091 --> 03:40:13,793
AT LEAST SOME OF THE PRELIMINARY

6076
03:40:13,793 --> 03:40:14,960
DATA AND THE DATA THAT'S

6077
03:40:14,960 --> 03:40:17,296
AVAILABLE NOW WE MIGHT HAVE

6078
03:40:17,296 --> 03:40:18,464
HIGHER REPLICATION THAT THAN

6079
03:40:18,464 --> 03:40:20,433
THAT REAP YOJ WHICH MIGHT DRIVE

6080
03:40:20,433 --> 03:40:20,900
THIS PHENOMENON.

6081
03:40:20,900 --> 03:40:22,401
SO IT'S SOMETHING THAT WE'RE

6082
03:40:22,401 --> 03:40:23,669
DEFINITELY THINKING ABOUT AND

6083
03:40:23,669 --> 03:40:29,341
HOPING TO EXPAND INTO THAT AREA

6084
03:40:29,341 --> 03:40:29,975
FOR, FOR SURE.

6085
03:40:29,975 --> 03:40:31,610
AND JUST TO TIE IT TO THE

6086
03:40:31,610 --> 03:40:34,380
PREVIOUS DISCUSSION, HAVE YOU

6087
03:40:34,380 --> 03:40:35,881
LOOKED AT MALE-FEMALE IN HAM

6088
03:40:35,881 --> 03:40:36,582
TERS.

6089
03:40:36,582 --> 03:40:38,217
>> SO IF FEMALE HAMSTERS
THEY

6090
03:40:38,217 --> 03:40:39,985
GET TERRITORIAL SO WE CAN ONLY

6091
03:40:39,985 --> 03:40:41,120
SINGLE HOUSE THEM AT A TIME.

6092
03:40:41,120 --> 03:40:43,522
WE HAVE TRIED ON WORKING WITH

6093
03:40:43,522 --> 03:40:46,425
FEMALE HAMSTERS AND WE HELD

6094
03:40:46,425 --> 03:40:47,493
THEM, DOUBLE CAGED BECAUSE WE

6095
03:40:47,493 --> 03:40:50,296
THOUGHT IT WAS A TRIAL AND WE

6096
03:40:50,296 --> 03:40:51,597
ENDED UP HAVING TO POLIT THEM

6097
03:40:51,597 --> 03:40:54,834
FOR LIKE A WEEK.

6098
03:40:54,834 --> 03:40:57,970
SO WHAT WE HAVE DONE IS MOSTLY

6099
03:40:57,970 --> 03:41:00,206
FOCUS ON THE RESULTS OF HAMSTERS

6100
03:41:00,206 --> 03:41:01,807
ON THAT PILOT VALIDATION STUDY

6101
03:41:01,807 --> 03:41:04,477
AND WE'VE BEEN ABLE TO SEE THIS

6102
03:41:04,477 --> 03:41:06,445
PERSISTENT PHENOMENON IN THE

6103
03:41:06,445 --> 03:41:08,447
OLFACTORY BULBS BUT WE DO AT

6104
03:41:08,447 --> 03:41:13,619
LEAST FROM OUR PRELIMINARY DATA

6105
03:41:13,619 --> 03:41:13,853
SEE IT.

6106
03:41:13,853 --> 03:41:16,188
>>  I WILL ASK A NONSTUDY

6107
03:41:16,188 --> 03:41:16,589
SECTION QUESTION.

6108
03:41:16,589 --> 03:41:17,857
YOU KNOW, I STRUGGLE WITH THIS

6109
03:41:17,857 --> 03:41:20,593
TOO, HOW DO PEOPLE THINK ABOUT

6110
03:41:20,593 --> 03:41:23,262
TRYING TO MODEL A DISEASE THAT'S

6111
03:41:23,262 --> 03:41:24,463
ONLY OBSERVED IN A SMALL

6112
03:41:24,463 --> 03:41:26,732
FRACTION OF HUMANS THAT MAY HAVE

6113
03:41:26,732 --> 03:41:27,933
AN IDIO PATHIC COMPONENT BUT

6114
03:41:27,933 --> 03:41:29,802
HAPPENS IN A HUNDRED% OF THE

6115
03:41:29,802 --> 03:41:31,137
ANIMAL MODEL BUT IT'S IMPORTANT

6116
03:41:31,137 --> 03:41:32,505
TO FIND MODELS FOR THIS THING

6117
03:41:32,505 --> 03:41:37,777
BUT WHAT DOES IT MEAN WHEN 5% OF

6118
03:41:37,777 --> 03:41:40,079
HUMANS GET ANASMEI AND BUT A

6119
03:41:40,079 --> 03:41:41,213
HUNDRED PERCENT IN IN HAMSTERS

6120
03:41:41,213 --> 03:41:43,315
AND HOW DO WE THINK ABOUT THAT?

6121
03:41:43,315 --> 03:41:44,116
>> THAT'S SOMETHING WE
STRUGGLE

6122
03:41:44,116 --> 03:41:45,785
WITH BECAUSE WE WANT OUR ANIMAL

6123
03:41:45,785 --> 03:41:47,953
MODEL TO BE AS REPRESENTATIVE AS

6124
03:41:47,953 --> 03:41:49,388
POSSIBLE BUT PEOPLE WILL SAY I

6125
03:41:49,388 --> 03:41:52,258
FOUND THIS INTERESTING ASPECT OF

6126
03:41:52,258 --> 03:41:55,027
WHERE A VIRUS WAS LOCATED IN AN

6127
03:41:55,027 --> 03:41:55,961
AUTOPSIES, WHY CAN'T YOU SHOW

6128
03:41:55,961 --> 03:41:58,197
THIS OR LIKE YOU SAID WHY DO ALL

6129
03:41:58,197 --> 03:41:59,498
YOUR HAN ANIMAL VS THIS WHEN ALL

6130
03:41:59,498 --> 03:42:01,634
NOT ALL PEOPLE DO I THINK PART

6131
03:42:01,634 --> 03:42:03,035
OF THAT STEMS FROM LIKE WHEN

6132
03:42:03,035 --> 03:42:04,370
WE'RE DEVELOPING THESE MODELS

6133
03:42:04,370 --> 03:42:06,572
WE'RE USUALLY GOING FOR PRETTY

6134
03:42:06,572 --> 03:42:08,474
ROBUST DISEASE BECAUSE WE WANT

6135
03:42:08,474 --> 03:42:10,176
IT TO BE RELIABLE AND WE WANT IT

6136
03:42:10,176 --> 03:42:16,816
TO BE EASILY MEASURED AND THE

6137
03:42:16,816 --> 03:42:18,517
LIKE ARDS DEVELOPMENT VERSION OF

6138
03:42:18,517 --> 03:42:19,351
COVID IS SOMEWHAT MORE

6139
03:42:19,351 --> 03:42:21,086
INTERESTING TO STUDY JUST

6140
03:42:21,086 --> 03:42:22,454
BIOLOGICALLY THAN THE COMMON

6141
03:42:22,454 --> 03:42:27,660
COLD VERSION OF COVID IS.

6142
03:42:27,660 --> 03:42:30,296
SO I THINK IF WE BACKED OFF ON

6143
03:42:30,296 --> 03:42:31,630
DOSES AND MUCH LESS IN THE WAY

6144
03:42:31,630 --> 03:42:32,998
OF SIM TOMS WE PROBABLY WOULD

6145
03:42:32,998 --> 03:42:34,466
HAVE TAKEN--THEY TYPE OF

6146
03:42:34,466 --> 03:42:36,502
VARIABLE RESPONSE WHICH IS

6147
03:42:36,502 --> 03:42:38,604
HORRIBLE FOR GENERATING FIGURES

6148
03:42:38,604 --> 03:42:41,140
AND SAYING SOMETHING IS

6149
03:42:41,140 --> 03:42:42,174
STATISTICALLY SIGNIFICANT BUT

6150
03:42:42,174 --> 03:42:48,080
MUCH MORE REPRESENTATIVE OF WHAT

6151
03:42:48,080 --> 03:42:48,547
HAPPENS IN PEOPLE.

6152
03:42:48,547 --> 03:42:52,918
>> I WAS JUST ANYTHING TO
ADD TO

6153
03:42:52,918 --> 03:42:54,753
THAT, IN THE FIRST TALK,

6154
03:42:54,753 --> 03:42:56,288
STACEY'S TALK, ALL THE VARIABLES

6155
03:42:56,288 --> 03:42:57,590
THAT 1 COULD THINK ABOUT,

6156
03:42:57,590 --> 03:43:00,626
WHETHER IT'S MALE, FEMALE,

6157
03:43:00,626 --> 03:43:02,361
OBESITY, OTHER UNDERLYING

6158
03:43:02,361 --> 03:43:04,430
CONDITIONS HOW DOES 1 ACTUALLY

6159
03:43:04,430 --> 03:43:05,598
CHOOSE AN ANIMAL MODEL THAT

6160
03:43:05,598 --> 03:43:06,932
COMES NEAR FOCUSED ON MIMICKING

6161
03:43:06,932 --> 03:43:07,967
WHAT HAPPENS IN PEOPLE BECAUSE

6162
03:43:07,967 --> 03:43:10,569
ALL THE SINGLE VARIABLES, EVEN

6163
03:43:10,569 --> 03:43:12,404
THE COLLABORATIVE, OOGHTS A

6164
03:43:12,404 --> 03:43:14,740
SINGLE VARIABLE MICE OR HOWED IN

6165
03:43:14,740 --> 03:43:16,876
CONDITIONS MOST OF THE TIME WHEN

6166
03:43:16,876 --> 03:43:18,811
THEY DON'T GET EXPOSED TO OTHER

6167
03:43:18,811 --> 03:43:22,615
PATHOGENS SO THIS IS REALLY--I

6168
03:43:22,615 --> 03:43:24,350
COULDN'T THINK OF A WAY TO DO

6169
03:43:24,350 --> 03:43:25,684
IT, IT SEEMS OVERWHELMING IN YOU

6170
03:43:25,684 --> 03:43:28,754
TRY TO INCLUDE EVERYTHING.

6171
03:43:28,754 --> 03:43:31,824
>> I HAVE ANOTHER QUESTION
ON

6172
03:43:31,824 --> 03:43:33,392
THE SEX DIFFERENCE

6173
03:43:33,392 --> 03:43:39,064
[INDISCERNIBLE] FOR YOU.

6174
03:43:39,064 --> 03:43:40,699
YEAH, SO THERE IS MOW BASE LINE

6175
03:43:40,699 --> 03:43:41,767
DIFFERENCE BETWEEN MALES OR

6176
03:43:41,767 --> 03:43:44,536
FEMALES BUT AFTER INFECTION OR

6177
03:43:44,536 --> 03:43:46,171
CHALLENGE, MIGHT BE SOMETHING

6178
03:43:46,171 --> 03:43:46,438
DIFFERENT.

6179
03:43:46,438 --> 03:43:53,312
SO THEN DO WE KNOW WHETHER THE

6180
03:43:53,312 --> 03:43:54,580
IMMUNITY, WHICH TARGET BECOME

6181
03:43:54,580 --> 03:43:55,180
DIFFERENT?

6182
03:43:55,180 --> 03:43:58,617
WE HAVE SO MANY DIFFERENT MOUSE,

6183
03:43:58,617 --> 03:44:01,320
TRAITS HAVE YOU ANY OF THEM

6184
03:44:01,320 --> 03:44:01,854
[INDISCERNIBLE]?

6185
03:44:01,854 --> 03:44:03,088
>> YEAH, I THINK IT
DEPENDS ON

6186
03:44:03,088 --> 03:44:04,089
THE QUESTION YOU'RE ASKING AND

6187
03:44:04,089 --> 03:44:08,827
THE TIME POINTS THAT YOU LOOK AT

6188
03:44:08,827 --> 03:44:09,962
AS TO WHETHER THESE DIFFERENCES

6189
03:44:09,962 --> 03:44:11,864
AND YOU KNOW YOU COULD SAY, THE

6190
03:44:11,864 --> 03:44:16,135
SEX DIFFERENCE BUT I THINK IT'S

6191
03:44:16,135 --> 03:44:17,970
EVEN TRUE WITH AGE DIFFERENCE

6192
03:44:17,970 --> 03:44:19,204
CAN IMPACT BOTH THE INNATE AND

6193
03:44:19,204 --> 03:44:22,942
THE ASBESTOS DATA PROTECTIONIVE

6194
03:44:22,942 --> 03:44:24,209
IMMUNE RESPONSES.

6195
03:44:24,209 --> 03:44:26,211
AND THERE'S AMPLE DATA ON THE

6196
03:44:26,211 --> 03:44:31,250
LITERATURE ON THAT.

6197
03:44:31,250 --> 03:44:33,986
THANK YOU. 

6198
03:44:33,986 --> 03:44:38,590
NANY OTHER QUESTIONS? 

6199
03:44:38,590 --> 03:44:38,958
ONLINE? 

6200
03:44:38,958 --> 03:44:39,525
NONE?

6201
03:44:39,525 --> 03:44:42,127
ALL RIGHT, I THINK WE WILL END

6202
03:44:42,127 --> 03:44:42,661
THERE.

6203
03:44:42,661 --> 03:44:46,932
THANK OUR PANELISTS FOR YOUR

6204
03:44:46,932 --> 03:44:47,132
TIME.

6205
03:44:47,132 --> 03:44:51,645
I THINK NOW IS LUNCH.

6206
03:44:51,645 --> 03:44:54,047
>> WE'LL GET STARTED IN
THE NEXT

6207
03:44:54,047 --> 03:44:54,681
SESSION, DEFINING IMMUNE

6208
03:44:54,681 --> 03:44:56,983
RESPONSES IN ANIMAL MODELS OF

6209
03:44:56,983 --> 03:44:58,852
RESPIRATORY VIRUS INFECTION.

6210
03:44:58,852 --> 03:45:03,890
PARTICULARLY I'M DELIGHTED TO

6211
03:45:03,890 --> 03:45:06,760
INVITE RYAN LANGLOIS TO SPEAK,

6212
03:45:06,760 --> 03:45:10,030
AT THE UNIVERSITY OF IOWA I WAS

6213
03:45:10,030 --> 03:45:11,798
HIS FIRST MENTOR, I DON'T KNOW

6214
03:45:11,798 --> 03:45:14,468
IN THE LAST CENTURY TIME.

6215
03:45:14,468 --> 03:45:16,136
>> CHAIRED MY THESIS
COMMITTEE

6216
03:45:16,136 --> 03:45:16,503
AS WELL.

6217
03:45:16,503 --> 03:45:19,239
THIS IS HIS FAULT IF IT GOES

6218
03:45:19,239 --> 03:45:19,673
WRONG.

6219
03:45:19,673 --> 03:45:22,409
>> THE TITLE IS DIRTY
MICE,

6220
03:45:22,409 --> 03:45:24,678
BETTER REKA PIP LATE VACCINE

6221
03:45:24,678 --> 03:45:26,913
RESPONSES OBSERVED IN HUMANS.

6222
03:45:26,913 --> 03:45:27,948
>> THANK YOU VERY MUCH.

6223
03:45:27,948 --> 03:45:29,783
THANK YOU FOR THE INTRODUCTION.

6224
03:45:29,783 --> 03:45:33,019
WE'LL TALK ABOUT A MODEL THAT

6225
03:45:33,019 --> 03:45:37,824
MAKES ONE ATTEMPT TO NORMALIZE

6226
03:45:37,824 --> 03:45:40,460
ONE CRITIQUE OF SMALL ANIMAL

6227
03:45:40,460 --> 03:45:42,329
STUDIES, THAT THEY ARE LIVING IN

6228
03:45:42,329 --> 03:45:43,296
CLEAN HOUSING, DON'T EXPERIENCE

6229
03:45:43,296 --> 03:45:44,764
A NUMBER OF INFECTIONS THAT WE

6230
03:45:44,764 --> 03:45:45,632
ALL EXPERIENCE.

6231
03:45:45,632 --> 03:45:46,933
THIS IS JUST A MODEL.

6232
03:45:46,933 --> 03:45:57,477
I'M TRYING TO TARGET ONE OF THE

6233
03:45:57,677 --> 03:45:59,145
POTENTIAL CAVEATS THIS IS THE

6234
03:45:59,145 --> 03:45:59,779
MODEL.

6235
03:45:59,779 --> 03:46:06,319
HE WENT TO THE PET STORE, GET

6236
03:46:06,319 --> 03:46:12,192
MICE, FILLS WITH PATHOGENS,

6237
03:46:12,192 --> 03:46:14,961
VIRUSES, FUNGI, BACTERIA, A

6238
03:46:14,961 --> 03:46:16,263
WEALTH OF INFECTIONS THAT OTHER

6239
03:46:16,263 --> 03:46:18,198
ANIMALS EXPERIENCE FREE LIVING

6240
03:46:18,198 --> 03:46:19,299
IN THE WILD.

6241
03:46:19,299 --> 03:46:20,867
YOU CO-HOUSE PET STORE MICE.

6242
03:46:20,867 --> 03:46:22,168
I'LL TALK ABOUT A SLIGHT TWIST

6243
03:46:22,168 --> 03:46:23,570
ON THE SYSTEM.

6244
03:46:23,570 --> 03:46:28,909
CO-HOUSE THESE PET STORE MICE,

6245
03:46:28,909 --> 03:46:31,711
GENETICALLY DIVERSE, WITH

6246
03:46:31,711 --> 03:46:32,746
LABORATORY MICE, GENETICALLY

6247
03:46:32,746 --> 03:46:35,582
IDENTICAL, YOU CAN SORT OF

6248
03:46:35,582 --> 03:46:38,552
RETAIN MOUSE GENETICS, A LOT OF

6249
03:46:38,552 --> 03:46:41,855
MOUSE GENETIC TOOLS.

6250
03:46:41,855 --> 03:46:42,622
A COLLABORATIVE CROSS,

6251
03:46:42,622 --> 03:46:43,423
COMPOUNDING DIVERSITY WOULD BE

6252
03:46:43,423 --> 03:46:45,225
FUN BUT THIS IS GENETICALLY

6253
03:46:45,225 --> 03:46:46,660
IDENTICAL MICE.

6254
03:46:46,660 --> 03:46:48,094
WE CO-HOUSE THEM FOR 60 DAYS.

6255
03:46:48,094 --> 03:46:49,796
THIS GIVES ENOUGH TIME FOR THESE

6256
03:46:49,796 --> 03:46:51,998
MICE TO GET ACUTE AND CHRONIC

6257
03:46:51,998 --> 03:46:53,633
INFECTIONS, THEY WILL RESOLVE

6258
03:46:53,633 --> 03:46:56,703
THE ACUTE INFECTIONS BY THIS

6259
03:46:56,703 --> 03:46:57,003
TIME POINT.

6260
03:46:57,003 --> 03:46:58,338
THEY WILL HAVE RETURNED TO WHAT

6261
03:46:58,338 --> 03:47:02,075
THE NEW NORMAL IS, NEW BASELINE,

6262
03:47:02,075 --> 03:47:07,981
WITH A COMPLEX IMMUNE HISTORY

6263
03:47:07,981 --> 03:47:09,182
AND INFECTION EXPERIENCE

6264
03:47:09,182 --> 03:47:09,583
HISTORY.

6265
03:47:09,583 --> 03:47:11,585
THIS IS SOME DATA WHERE I'M

6266
03:47:11,585 --> 03:47:14,321
GOING TO TRY TO CONVINCE YOU WE

6267
03:47:14,321 --> 03:47:15,188
LIKE TO EMBRACE THE

6268
03:47:15,188 --> 03:47:17,724
HETEROGENEITY OF THE MODEL

6269
03:47:17,724 --> 03:47:18,858
SYSTEM, OTHERWISE YOU'LL GO

6270
03:47:18,858 --> 03:47:19,092
INSANE.

6271
03:47:19,092 --> 03:47:22,329
THIS IS OLDER DATA NOW.

6272
03:47:22,329 --> 03:47:23,530
WE'VE BEEN CONSTANTLY UPDATES, I

6273
03:47:23,530 --> 03:47:25,665
SHOULD MAKE SURE I GET THAT DATA

6274
03:47:25,665 --> 03:47:26,466
TABULATED SOMETIME.

6275
03:47:26,466 --> 03:47:30,971
THIS IS LOOKING AT CO-HOUSING,

6276
03:47:30,971 --> 03:47:31,871
WE MEASURE CDTA CELL ACTIVATION

6277
03:47:31,871 --> 03:47:35,742
IN THE BLOOD, IF THE MICE

6278
03:47:35,742 --> 03:47:39,245
WRITTEN EXPECTED, IF THERE WERE

6279
03:47:39,245 --> 03:47:43,883
CHANGES  BASEALLY TO THE IMMUNE

6280
03:47:43,883 --> 03:47:44,884
SYSTEM.

6281
03:47:44,884 --> 03:47:46,686
AFTER 60 DAYS OF CO-HOUSING THIS

6282
03:47:46,686 --> 03:47:49,222
IS WHAT IT LOOKS LIKE, FROM EACH

6283
03:47:49,222 --> 03:47:50,423
STACK AT DIFFERENT DATE,

6284
03:47:50,423 --> 03:47:51,958
DIFFERENT EXPERIMENT, DIFFERENT

6285
03:47:51,958 --> 03:47:55,028
MOUSE FROM THE PET STORE.

6286
03:47:55,028 --> 03:47:57,430
WE HAD TO TAKE A BREAK DUE TO

6287
03:47:57,430 --> 03:47:58,198
ANOTHER VIRUS CIRCULATING AROUND

6288
03:47:58,198 --> 03:47:59,199
THIS TIME.

6289
03:47:59,199 --> 03:48:03,403
WE CAN SEE WE COME BACK, THE

6290
03:48:03,403 --> 03:48:06,506
PHENOTYPES ARE STILL CONSISTENT.

6291
03:48:06,506 --> 03:48:07,240
THIS MULTI-DIMENSIONAL SCALING

6292
03:48:07,240 --> 03:48:09,142
ANALYSIS ON THE RIGHT I'M

6293
03:48:09,142 --> 03:48:10,176
SHOWING YOU DIFFERENT

6294
03:48:10,176 --> 03:48:11,511
COMBINATIONS OF PATHOGENS THEY

6295
03:48:11,511 --> 03:48:12,879
HAVE BY SEROLOGY.

6296
03:48:12,879 --> 03:48:15,815
EACH CLUSTER IS A UNIQUE

6297
03:48:15,815 --> 03:48:16,716
PATHOGEN COMBINATION.

6298
03:48:16,716 --> 03:48:20,120
AND OVERLAID ON TOP OF THAT IS

6299
03:48:20,120 --> 03:48:23,189
THE PERCENT OF HEAT MAP OF THE

6300
03:48:23,189 --> 03:48:24,391
CD8 T-CELL ACTIVATION.

6301
03:48:24,391 --> 03:48:26,126
THERE AREN'T ANY REALLY MAJOR

6302
03:48:26,126 --> 03:48:27,861
HOT SPOTS, RIGHT?

6303
03:48:27,861 --> 03:48:29,195
A PARTICULAR PATHOGEN

6304
03:48:29,195 --> 03:48:30,997
COMBINATION IS THE MAJOR DRIVER

6305
03:48:30,997 --> 03:48:36,836
OF T CELL  T-CELL ACTIVATION.

6306
03:48:36,836 --> 03:48:39,506
THIS IS OVER 700 MICE WHICH

6307
03:48:39,506 --> 03:48:41,374
YIELDED 150 UNIQUE PATHOGEN

6308
03:48:41,374 --> 03:48:43,109
COMBINATIONS.

6309
03:48:43,109 --> 03:48:48,581
WE NOW HAVE OVER 1600 MICE, MUCH

6310
03:48:48,581 --> 03:48:49,649
LARGER SET OF PATHOGENS, DOESN'T

6311
03:48:49,649 --> 03:48:52,452
MATTER WHAT THE INDIVIDUAL

6312
03:48:52,452 --> 03:48:55,588
PATHOGENS ARE, HAVING A COMPLEX

6313
03:48:55,588 --> 03:48:57,590
PATHOGEN EXPOSURE HISTORY

6314
03:48:57,590 --> 03:48:59,893
BASEALLY CHANGES YOUR IMMUNE

6315
03:48:59,893 --> 03:49:00,193
SYSTEM.

6316
03:49:00,193 --> 03:49:01,461
WE DID THIS FACTOR ANALYSIS OF

6317
03:49:01,461 --> 03:49:02,495
MIXED DATA.

6318
03:49:02,495 --> 03:49:05,498
THIS IS BASICALLY TAKING EACH OF

6319
03:49:05,498 --> 03:49:06,332
THESE POTENTIAL PATHOGENS

6320
03:49:06,332 --> 03:49:08,201
INDIVIDUALLY AND ASKING HOW THEY

6321
03:49:08,201 --> 03:49:09,269
IMPACT THE PHENOTYPE WE'RE

6322
03:49:09,269 --> 03:49:11,337
INTERESTED IN, WHICH WAS THE

6323
03:49:11,337 --> 03:49:12,572
CD44 EXPRESSION.

6324
03:49:12,572 --> 03:49:14,641
IF IT HAD ZERO IMPACT, THIS

6325
03:49:14,641 --> 03:49:16,710
WOULD LIVE ON THE ORDINAL HERE.

6326
03:49:16,710 --> 03:49:19,245
IF IT HAD A LARGE IMPACT WOULD

6327
03:49:19,245 --> 03:49:21,147
EXIST WAY OUT HERE.

6328
03:49:21,147 --> 03:49:22,615
WHAT YOU CAN APPRECIATE PATHOGEN

6329
03:49:22,615 --> 03:49:24,084
COMBINATION IS CLOSE TO THE

6330
03:49:24,084 --> 03:49:26,686
BASELINE HERE, SO THE PATHOGEN

6331
03:49:26,686 --> 03:49:28,221
COMBINATIONS DON'T REALLY DRIVE

6332
03:49:28,221 --> 03:49:33,927
CHANGES, IT'S JUST HAVING SOME

6333
03:49:33,927 --> 03:49:34,694
PATHOGEN EXPOSURE THAT MATTERS.

6334
03:49:34,694 --> 03:49:36,463
BECAUSE SEX AS A BIOLOGICAL

6335
03:49:36,463 --> 03:49:37,230
VARIABLE HAS HEAVILY DISCUSSED

6336
03:49:37,230 --> 03:49:38,531
SO FAR I WANT TO THROW THIS

6337
03:49:38,531 --> 03:49:41,367
PIECE OF DATA IN HERE TOO.

6338
03:49:41,367 --> 03:49:43,770
SO, ONE CAVEAT TO THIS MODEL

6339
03:49:43,770 --> 03:49:44,671
SYSTEM BECAUSE WE'RE CO-HOUSING

6340
03:49:44,671 --> 03:49:47,474
ANIMALS WE HAVE TO ONLY CO-HOUSE

6341
03:49:47,474 --> 03:49:48,141
FEMALES.

6342
03:49:48,141 --> 03:49:49,576
OTHERWISE THE MALES WILL FIGHT

6343
03:49:49,576 --> 03:49:51,211
AND FOR OBVIOUS REASONS WE CAN'T

6344
03:49:51,211 --> 03:49:52,545
TAKE A MALE PET STORE WITH

6345
03:49:52,545 --> 03:49:53,513
FEMALE MICE.

6346
03:49:53,513 --> 03:49:55,315
SO TO GET AROUND THAT POTENTIAL

6347
03:49:55,315 --> 03:50:00,754
CAVEAT WHAT WE CAN DO IS TAKE

6348
03:50:00,754 --> 03:50:02,856
FOMITES FROM PET STORE MICE,

6349
03:50:02,856 --> 03:50:06,359
BEDDING IS FILLED WITH PET STORE

6350
03:50:06,359 --> 03:50:07,761
MOUSE FECES, URINE, FUR, OTHER

6351
03:50:07,761 --> 03:50:12,098
THINGS, TRANSFER THAT OVER. 

6352
03:50:12,098 --> 03:50:13,867
THIS IS THE FOMITE TRANSMISSION.

6353
03:50:13,867 --> 03:50:15,101
THERE ARE SOME DIFFERENCES,

6354
03:50:15,101 --> 03:50:16,202
DIVERSITY ISN'T QUITE AS LARGE.

6355
03:50:16,202 --> 03:50:18,471
BUT WHAT I'M NOT SHOWING HERE IS

6356
03:50:18,471 --> 03:50:20,006
IF WE LOOK AT T-CELL ACTIVATION

6357
03:50:20,006 --> 03:50:22,342
IT'S STILL THE CAME.

6358
03:50:22,342 --> 03:50:25,945
IN TERMS OF ACTIVATING T-CELL

6359
03:50:25,945 --> 03:50:27,247
RESPONSE AND BASAL CHANGES THERE

6360
03:50:27,247 --> 03:50:30,850
WAS NO DIFFERENCE IN FOMITES.

6361
03:50:30,850 --> 03:50:31,985
FOR SIMPLICITIES WE'RE SWITCHING

6362
03:50:31,985 --> 03:50:34,220
TO FOMITES FOR A LARGE NUMBER OF

6363
03:50:34,220 --> 03:50:35,121
OUR EXPERIMENTS.

6364
03:50:35,121 --> 03:50:37,390
IT HELPS ADDRESS SEX AS A

6365
03:50:37,390 --> 03:50:38,291
BIOLOGICAL VARIABLE WHICH STUDY

6366
03:50:38,291 --> 03:50:40,593
SECTION CARES A LOT ABOUT.

6367
03:50:40,593 --> 03:50:40,794
OKAY.

6368
03:50:40,794 --> 03:50:42,362
THE OTHER THING I WANTED TO

6369
03:50:42,362 --> 03:50:43,863
POINT OUT FROM THE MODEL SYSTEM

6370
03:50:43,863 --> 03:50:45,732
AS A VIROLOGIST, I CARE ABOUT

6371
03:50:45,732 --> 03:50:47,734
THE VIRUSES HERE, THERE'S A LOT

6372
03:50:47,734 --> 03:50:49,702
OF NOVEL AND UNDER OR

6373
03:50:49,702 --> 03:50:50,570
UNAPPRECIATED VIRUSES FROM MICE.

6374
03:50:50,570 --> 03:50:52,806
THERE'S A LOT OF OBVIOUSLY

6375
03:50:52,806 --> 03:50:54,174
PATHOGENS THAT ARE NATURAL IN

6376
03:50:54,174 --> 03:50:59,078
MICE THAT WE DON'T SEE IN OUR

6377
03:50:59,078 --> 03:51:00,013
TRADITIONAL SPF PANELS DEVELOPED

6378
03:51:00,013 --> 03:51:01,047
BY JACKSON AND CHARLES RIVER.

6379
03:51:01,047 --> 03:51:02,482
I'M SHOWING YOU SOME VIRUSES

6380
03:51:02,482 --> 03:51:08,188
THAT YOU DON'T NORMALLY SORT OF

6381
03:51:08,188 --> 03:51:09,455
SEE.

6382
03:51:09,455 --> 03:51:12,992
THE NOROVIRUS, NHV, COMMON,

6383
03:51:12,992 --> 03:51:13,226
CLASSIC.

6384
03:51:13,226 --> 03:51:14,627
IN THIS ANALYSIS, THIS IS A

6385
03:51:14,627 --> 03:51:17,030
DIFFERENT WAY TO LOOK AT DATA,

6386
03:51:17,030 --> 03:51:19,699
SO IF THE PET STORE MOUSE HAD

6387
03:51:19,699 --> 03:51:21,734
THAT PATHOGEN, THIS IS ALSO FROM

6388
03:51:21,734 --> 03:51:24,237
ABOUT A THOUSAND MICE, IF THE

6389
03:51:24,237 --> 03:51:30,176
PET STORE MOUSE HAD THE PATHOGEN

6390
03:51:30,176 --> 03:51:31,811
EVERY TIME IT WOULD BE 100%.

6391
03:51:31,811 --> 03:51:34,147
THE HEAT MAP IS HOW FREQUENT DID

6392
03:51:34,147 --> 03:51:35,548
IT TRANSMIT WHEN PRESENT.

6393
03:51:35,548 --> 03:51:39,052
WHAT YOU CAN SEE ASTRO VIRUS 2

6394
03:51:39,052 --> 03:51:41,788
IS OUR WINNER HERE, IN EVERY

6395
03:51:41,788 --> 03:51:43,890
SINGLE PET STORE MOUSE,

6396
03:51:43,890 --> 03:51:44,824
TRANSMISSION EFFICIENCY IS

6397
03:51:44,824 --> 03:51:46,526
ALMOST 100%.

6398
03:51:46,526 --> 03:51:49,996
SOME OTHER VIRUSES HAVE VARYING

6399
03:51:49,996 --> 03:51:50,763
DEGREES.

6400
03:51:50,763 --> 03:51:52,131
BUT SOMETHING I WANT TO POINT

6401
03:51:52,131 --> 03:51:53,433
OUT THAT'S IMPORTANT, FOR

6402
03:51:53,433 --> 03:51:56,002
EXAMPLE, IN THIS ORIGINAL

6403
03:51:56,002 --> 03:51:58,004
ANALYSIS IN THIS PAPER, WE AT

6404
03:51:58,004 --> 03:51:59,939
THE FAMILY LEVEL MISSED SOME

6405
03:51:59,939 --> 03:52:02,942
VIRUSES, LOOKING DEEPER WE FIND

6406
03:52:02,942 --> 03:52:05,745
A ENVELOPE ALPHA CORONAVIRUS

6407
03:52:05,745 --> 03:52:09,048
QUITE FREQUENTLY IN THE PET

6408
03:52:09,048 --> 03:52:10,550
STORE MOUSE AND NOVEL

6409
03:52:10,550 --> 03:52:11,417
CORONAVIRUS DISTANTLY RELATED TO

6410
03:52:11,417 --> 03:52:13,052
THIS COVID REQUIRES HERE.

6411
03:52:13,052 --> 03:52:13,786
EVEN MORE IMPORTANTLY EVERYTHING

6412
03:52:13,786 --> 03:52:17,023
HERE WITH A STAR IS NOT SCREENED

6413
03:52:17,023 --> 03:52:19,492
BY ANY COMMERCIAL AVAILABLE KIT

6414
03:52:19,492 --> 03:52:23,162
THAT IS USED TO LOOK AT

6415
03:52:23,162 --> 03:52:24,464
SPF-NESS, FOR LACK OF BETTER

6416
03:52:24,464 --> 03:52:24,664
TERM.

6417
03:52:24,664 --> 03:52:26,900
A LOT OF THESE THINGS ARE

6418
03:52:26,900 --> 03:52:27,967
PRESENT IN OUR DIRTY MOUSE

6419
03:52:27,967 --> 03:52:28,301
MODEL.

6420
03:52:28,301 --> 03:52:30,837
I CAN TELL YOU, I WON'T NAME THE

6421
03:52:30,837 --> 03:52:33,506
VENDOR HERE, BUT VERY FREQUENTLY

6422
03:52:33,506 --> 03:52:37,277
IN SPF MICE WE PURCHASED WE FIND

6423
03:52:37,277 --> 03:52:38,378
ASTRO VIRUS 1 QUITE FREQUENTLY.

6424
03:52:38,378 --> 03:52:41,447
THERE'S A LOT OF THINGS STILL

6425
03:52:41,447 --> 03:52:42,749
GOING ON THAT COULD BE MISSED

6426
03:52:42,749 --> 03:52:43,950
BECAUSE THEY ARE NOT BEING

6427
03:52:43,950 --> 03:52:45,818
LOOKED FOR.

6428
03:52:45,818 --> 03:52:48,755
SO OUR LAB HAS DEVELOPED

6429
03:52:48,755 --> 03:52:52,992
SCREENING SYSTEMS, PCR PRIMERS

6430
03:52:52,992 --> 03:52:55,228
AND ELISAS FOR ALL OF THESE.

6431
03:52:55,228 --> 03:52:56,562
EXAMPLE OF HETEROGENEITY, WE GET

6432
03:52:56,562 --> 03:52:57,764
THE PET STORE MICE, WE DON'T

6433
03:52:57,764 --> 03:53:00,066
KNOW WHAT STAGE OF THE INFECTION

6434
03:53:00,066 --> 03:53:05,004
THEY ARE IN, ARE THEY IN ACUTE

6435
03:53:05,004 --> 03:53:10,176
INFECTION, CHRONIC STAGE.

6436
03:53:10,176 --> 03:53:12,445
THIS IS THE MARINE KO BU VIRUS.

6437
03:53:12,445 --> 03:53:14,213
WE GET PET STORE MICE, RESTED

6438
03:53:14,213 --> 03:53:15,848
THEM, BLED THEM EVERY WEEK.

6439
03:53:15,848 --> 03:53:19,185
AT WEEK ZERO THIS ANIMAL HERE

6440
03:53:19,185 --> 03:53:20,520
THAT WAS POSITIVE, SUSPECT

6441
03:53:20,520 --> 03:53:22,322
RATHER, ALL THESE WERE NEGATIVE.

6442
03:53:22,322 --> 03:53:26,059
WE LOOK AT 14 DAYS LATER SOME

6443
03:53:26,059 --> 03:53:27,226
ANIMALS DID SEROCONVERT,

6444
03:53:27,226 --> 03:53:29,629
SUGGESTING THEY WERE IN THE

6445
03:53:29,629 --> 03:53:37,070
ACUTE PHASE OF INFECTION

6446
03:53:37,070 --> 03:53:37,470
PRE-CONVALESCENS.

6447
03:53:37,470 --> 03:53:39,238
MANY MORE CONVERTED.

6448
03:53:39,238 --> 03:53:40,807
WE'RE PROVIDING OUR SPF MICE

6449
03:53:40,807 --> 03:53:44,410
WITH BOTH ACUTE AND CHRONIC

6450
03:53:44,410 --> 03:53:46,913
INFECTION.

6451
03:53:46,913 --> 03:53:51,584
OUR GOAL IS TO USE THIS MODEL TO

6452
03:53:51,584 --> 03:53:52,418
BETTER RECAPITULATE HUMAN IMMUNE

6453
03:53:52,418 --> 03:53:53,786
RESPONSES FROM HUMANS WHO SEE

6454
03:53:53,786 --> 03:53:55,188
LOTS OF INFECTIONS OVER THE

6455
03:53:55,188 --> 03:53:56,055
COURSE OF THEIR LIFE.

6456
03:53:56,055 --> 03:53:57,423
THIS IS WHAT THIS LOOKS LIKE.

6457
03:53:57,423 --> 03:54:00,059
I SHOWED YOU THIS IN THE FIRST

6458
03:54:00,059 --> 03:54:00,259
SLIDE.

6459
03:54:00,259 --> 03:54:03,463
WE CAN GIVE THEM A VACCINE.

6460
03:54:03,463 --> 03:54:05,398
WHEN WE'VE DONE THIS WE GAVE AN

6461
03:54:05,398 --> 03:54:07,967
INFLUENZA VACCINE, AND THIS IS A

6462
03:54:07,967 --> 03:54:09,602
SEASONAL FLU VACCINE THAT WE

6463
03:54:09,602 --> 03:54:11,170
BOUGHT FROM A COMPANY THAT IS

6464
03:54:11,170 --> 03:54:11,804
USED IN HUMANS.

6465
03:54:11,804 --> 03:54:14,307
WE GAVE IT TO MICE.

6466
03:54:14,307 --> 03:54:16,743
WE TOOK OUT THE PBMCs AND

6467
03:54:16,743 --> 03:54:18,044
MEASURED VACCINE RESPONSE OF

6468
03:54:18,044 --> 03:54:21,514
GENES, DID A GENE SET ENRICHMENT

6469
03:54:21,514 --> 03:54:23,316
ANALYSIS TO COMPARE RESPONSES IN

6470
03:54:23,316 --> 03:54:24,717
MICE, RESPONSES OBSERVED IN

6471
03:54:24,717 --> 03:54:26,552
CLINICAL TRIALS FROM HUMANS

6472
03:54:26,552 --> 03:54:28,654
WHERE PBMCs WERE ALSO TAKEN

6473
03:54:28,654 --> 03:54:30,590
AND DEEP SEQUENCED.

6474
03:54:30,590 --> 03:54:31,924
I HOPE YOU CAN APPRECIATE IF

6475
03:54:31,924 --> 03:54:34,227
YOU'RE FAMILIAR WITH THE GRAPHS

6476
03:54:34,227 --> 03:54:36,596
THIS CURVE IS SHOWING YOU A HIGH

6477
03:54:36,596 --> 03:54:37,830
SET OF ENRICHMENTS TO VACCINE

6478
03:54:37,830 --> 03:54:39,065
RESPONSE IN HUMANS IN THE DIRTY

6479
03:54:39,065 --> 03:54:40,900
MICE, SO THIS IS REALLY GREAT,

6480
03:54:40,900 --> 03:54:41,834
RIGHT?

6481
03:54:41,834 --> 03:54:42,969
THIS IS PRETTY PHENOMENAL

6482
03:54:42,969 --> 03:54:44,370
ENRICHMENT IN FACT.

6483
03:54:44,370 --> 03:54:47,140
AND THIS IS SORT OF

6484
03:54:47,140 --> 03:54:49,409
ANTI-ENRICHMENT, VERY LITTLE TO

6485
03:54:49,409 --> 03:54:52,779
NO ENRICHMENT IN THE SPF MICE.

6486
03:54:52,779 --> 03:54:54,514
SPF MICE ARE NOT RECAPITULATING

6487
03:54:54,514 --> 03:54:55,681
THE VACCINE RESPONSIVE GENES IN

6488
03:54:55,681 --> 03:54:58,251
HUMANS BUT THE DIRTY MICE ARE.

6489
03:54:58,251 --> 03:55:00,253
RIGHT AT THE BASELINE YOU'RE

6490
03:55:00,253 --> 03:55:01,454
HAVING APPLES TO ORANGES

6491
03:55:01,454 --> 03:55:03,122
COMPARISONS IF YOU'RE MODELING

6492
03:55:03,122 --> 03:55:05,725
VACCINE RESPONSES AND SPF MICE,

6493
03:55:05,725 --> 03:55:06,459
BECAUSE YOU'RE NOT MODELING

6494
03:55:06,459 --> 03:55:08,394
TRANSCRIPTIONAL CHANGES THAT

6495
03:55:08,394 --> 03:55:12,965
HAPPEN IN A HUMAN.

6496
03:55:12,965 --> 03:55:15,601
SO THAT IMPACTS THE END RESULTS

6497
03:55:15,601 --> 03:55:16,269
WHICH YOU CARE ABOUT, CORRELATE

6498
03:55:16,269 --> 03:55:17,937
OF PROTECTION.

6499
03:55:17,937 --> 03:55:21,174
IN THIS CASE I'LL SHOW ANTIBODY

6500
03:55:21,174 --> 03:55:21,441
RESPONSES.

6501
03:55:21,441 --> 03:55:23,276
HERE WE'RE LOOKING AT THE

6502
03:55:23,276 --> 03:55:24,577
ANTIBODY RESPONSE AGAINST THE

6503
03:55:24,577 --> 03:55:24,811
VACCINE.

6504
03:55:24,811 --> 03:55:25,812
AND SO WHAT YOU CAN APPRECIATE

6505
03:55:25,812 --> 03:55:27,313
IS THAT THERE ARE SOME

6506
03:55:27,313 --> 03:55:30,650
DIFFERENCES THAT YOU OBSERVED

6507
03:55:30,650 --> 03:55:31,350
HERE, RIGHT?

6508
03:55:31,350 --> 03:55:31,584
SORRY.

6509
03:55:31,584 --> 03:55:37,290
WHERE IF YOU LOOK AT SPF MICE,

6510
03:55:37,290 --> 03:55:40,126
YOU HAVE -- SORRY, I'LL COME UP

6511
03:55:40,126 --> 03:55:42,328
HERE, LOOKING AT SPF MICE HAVE A

6512
03:55:42,328 --> 03:55:44,363
STRONGER ANTIBODY RESPONSE.

6513
03:55:44,363 --> 03:55:46,766
AND THAT CORRELATES TO BETTER

6514
03:55:46,766 --> 03:55:47,400
PROTECTION, AND THE PROTECTION

6515
03:55:47,400 --> 03:55:49,836
IS WORSE IN THE DIRTY MICE.

6516
03:55:49,836 --> 03:55:52,972
SO IT IS EASIER TO PROTECT AN

6517
03:55:52,972 --> 03:55:54,674
SPF MICE WITH INFLUENZA VACCINE

6518
03:55:54,674 --> 03:55:56,142
THAN TO PROTECT A DIRTY MOUSE.

6519
03:55:56,142 --> 03:55:58,311
SO YOU GET THIS SORT OF

6520
03:55:58,311 --> 03:56:00,146
UNNATURAL LEVEL OF IMMUNITY WHEN

6521
03:56:00,146 --> 03:56:04,217
YOU'RE VACCINATING AN SPF ANIMAL

6522
03:56:04,217 --> 03:56:05,985
COMPARED TO DIRTY ANIMAL.

6523
03:56:05,985 --> 03:56:10,022
AND SO WITH MY ESTEEM COLLEAGUE

6524
03:56:10,022 --> 03:56:12,258
OVER HERE, WE WANTED TO

6525
03:56:12,258 --> 03:56:13,526
RECAPITULATE THIS WITH ANOTHER

6526
03:56:13,526 --> 03:56:16,629
VACCINE MODALITY SO THE PREVIOUS

6527
03:56:16,629 --> 03:56:18,264
VACCINE WAS THE KILLED INFLUENZA

6528
03:56:18,264 --> 03:56:19,799
VACCINE, SPLIT KILLED VACCINE,

6529
03:56:19,799 --> 03:56:27,206
THIS IS THE SARS-COV-2 VACCINE. 

6530
03:56:27,206 --> 03:56:32,545
SO WE VACCINATED ANIMALS, MEHUL

6531
03:56:32,545 --> 03:56:33,312
AND JENS ANALYZED SERUM

6532
03:56:33,312 --> 03:56:33,646
RESPONSE.

6533
03:56:33,646 --> 03:56:35,248
YOU GET A MUCH STRONGER RESPONSE

6534
03:56:35,248 --> 03:56:37,250
EVEN INITIALLY TO THE PRIME, A

6535
03:56:37,250 --> 03:56:38,251
WHOPPING RESPONSE COMPARED TO

6536
03:56:38,251 --> 03:56:39,118
THE PRIME.

6537
03:56:39,118 --> 03:56:41,854
AND YOU EVEN GET A BETTER BOOST

6538
03:56:41,854 --> 03:56:43,422
WHEN YOU BOOST.

6539
03:56:43,422 --> 03:56:44,657
HERE, THE BOOST IS REALLY

6540
03:56:44,657 --> 03:56:45,825
REQUIRED IN DIRTY MICE.

6541
03:56:45,825 --> 03:56:47,527
I THINK THIS REALLY NICELY

6542
03:56:47,527 --> 03:56:49,395
DEMONSTRATES WHAT WE OBSERVED IN

6543
03:56:49,395 --> 03:56:51,731
HUMANS WHERE HUMANS DID NEED

6544
03:56:51,731 --> 03:56:53,399
THAT BOOST FOR mRNA VACCINES

6545
03:56:53,399 --> 03:56:54,934
TO REACH PEAK OPTIMAL LEVEL.

6546
03:56:54,934 --> 03:56:57,503
YOU GET QUITE A GOOD RESPONSE TO

6547
03:56:57,503 --> 03:56:59,372
THE PRIMARY IN SPF MICE.

6548
03:56:59,372 --> 03:57:00,706
SO DIRTY MICE NEED THIS BOOST

6549
03:57:00,706 --> 03:57:02,041
JUST LIKE THE HUMANS DO.

6550
03:57:02,041 --> 03:57:09,415
SO I THINK THIS IS REALLY A

6551
03:57:09,415 --> 03:57:12,919
HELPFUL MODEL AND I HOPE WOULD

6552
03:57:12,919 --> 03:57:15,254
IMPROVE mRNA VACCINES, NOW YOU

6553
03:57:15,254 --> 03:57:16,455
CAN MAKE MODIFICATIONS TO TURN

6554
03:57:16,455 --> 03:57:19,759
THIS TO LOOK MORE LIKE THIS, TO

6555
03:57:19,759 --> 03:57:20,493
IMPROVE THE IMMUNOGENICITY, THE

6556
03:57:20,493 --> 03:57:21,961
STRENGTH OF THE VACCINE

6557
03:57:21,961 --> 03:57:22,228
RESPONSE.

6558
03:57:22,228 --> 03:57:23,930
THAT'S ONE HOPE OF HAVING A

6559
03:57:23,930 --> 03:57:29,068
MODEL SYSTEM THAT BETTER

6560
03:57:29,068 --> 03:57:31,037
RECAPITULATES PEOPLE.

6561
03:57:31,037 --> 03:57:31,871
ANOTHER COMPONENT BETTER

6562
03:57:31,871 --> 03:57:34,173
RECAPITULATED IN DIRTY MICE IS

6563
03:57:34,173 --> 03:57:34,473
DURABILITY.

6564
03:57:34,473 --> 03:57:36,142
OFTEN ESPECIALLY IN THE FLU

6565
03:57:36,142 --> 03:57:39,545
WORLD YOU VACCINATE MICE WITH

6566
03:57:39,545 --> 03:57:41,380
FLU MODALITIES ALMOST SEE NO

6567
03:57:41,380 --> 03:57:43,816
DIMINUTION OF VACCINE RESPONSE.

6568
03:57:43,816 --> 03:57:45,251
IT'S STABLE, EXTREMELY ROBUST,

6569
03:57:45,251 --> 03:57:45,618
HIGHLY DURABLE.

6570
03:57:45,618 --> 03:57:48,387
THIS IS NOT TRUE IN HUMANS,

6571
03:57:48,387 --> 03:57:48,955
RIGHT?

6572
03:57:48,955 --> 03:57:50,056
FOR INFLUENZA VACCINE, FOR A LOT

6573
03:57:50,056 --> 03:57:52,458
OF VACCINES, IT'S TRUE FOR THE

6574
03:57:52,458 --> 03:57:54,994
SMALLPOX VACCINE BUT MANY

6575
03:57:54,994 --> 03:57:57,964
VACCINES SUFFER FROM DURABILITY

6576
03:57:57,964 --> 03:57:58,598
ISSUES.

6577
03:57:58,598 --> 03:58:00,766
SO THERE'S NO OBSERVABLE OR

6578
03:58:00,766 --> 03:58:02,335
OBVIOUS DURABILITY ISSUE IN THE

6579
03:58:02,335 --> 03:58:06,105
SPF MICE BUT YOU DO SEE SOME

6580
03:58:06,105 --> 03:58:09,308
DURABILITY ISSUES IN THE mRNA

6581
03:58:09,308 --> 03:58:10,710
VACCINE IN THE DIRTY MICE.

6582
03:58:10,710 --> 03:58:13,179
THIS IS ANOTHER AVENUE WHERE

6583
03:58:13,179 --> 03:58:17,350
THIS IS BETTER RECAPITULATING

6584
03:58:17,350 --> 03:58:20,353
THE RESPONSE IN HUMANS, WE ARGUE

6585
03:58:20,353 --> 03:58:21,020
IT'S UNNATURAL AND NOT

6586
03:58:21,020 --> 03:58:23,322
REPRESENTATIVE OF WHAT'S SEEN IN

6587
03:58:23,322 --> 03:58:24,890
HUMANS.

6588
03:58:24,890 --> 03:58:25,558
DOES THIS MATTER?

6589
03:58:25,558 --> 03:58:29,895
OF COURSE IT DOES.

6590
03:58:29,895 --> 03:58:32,531
SO MEHUL AND JENS ASKED ARE

6591
03:58:32,531 --> 03:58:33,966
ANTIBODIES ABLE TO NEUTRALIZE TO

6592
03:58:33,966 --> 03:58:34,700
THE SAME DEGREE.

6593
03:58:34,700 --> 03:58:35,935
THEY ARE NOT.

6594
03:58:35,935 --> 03:58:38,871
THIS WORKS BETTER IN SPF MICE

6595
03:58:38,871 --> 03:58:39,639
THAN DIRTY MICE.

6596
03:58:39,639 --> 03:58:44,744
AND IN AN EXPERIMENT THAT I WAS

6597
03:58:44,744 --> 03:58:46,979
GLAD MEHUL DECIDED TO DO, WHAT

6598
03:58:46,979 --> 03:58:48,981
DOES THE BREATH LOOK LIKE, WHEN

6599
03:58:48,981 --> 03:58:51,450
LOTS OF VARIANTS ARE ARISING,

6600
03:58:51,450 --> 03:58:53,286
WHAT'S THE BREADTH OF THESE

6601
03:58:53,286 --> 03:58:56,422
RESPONSES, IT'S WORSE IN DIRTY

6602
03:58:56,422 --> 03:58:58,257
MICE, REPERTOIRE IS NARROWER,

6603
03:58:58,257 --> 03:59:05,798
WORSE ON EVERY FRONT. 

6604
03:59:05,798 --> 03:59:06,632
THIS RECAPITULATES IN HUMANS,

6605
03:59:06,632 --> 03:59:08,434
THE BREADTH OF THE RESPONSE IS

6606
03:59:08,434 --> 03:59:08,734
QUITE WEAK.

6607
03:59:08,734 --> 03:59:10,202
THERE ARE A LOT OF WAYS TO

6608
03:59:10,202 --> 03:59:12,305
CREATE THESE DIRTY MOUSE MODELS,

6609
03:59:12,305 --> 03:59:13,873
AND I THINK ALL OF THEM HAVE

6610
03:59:13,873 --> 03:59:14,106
VALUE.

6611
03:59:14,106 --> 03:59:16,509
I THINK ALL OF THEM CAN TEACH US

6612
03:59:16,509 --> 03:59:17,743
SOMETHING, AND WE CAN LEARN

6613
03:59:17,743 --> 03:59:18,611
SOMETHING INTERESTING FROM THEM.

6614
03:59:18,611 --> 03:59:22,815
I WANT TO GIVE ONE QUICK EXAMPLE

6615
03:59:22,815 --> 03:59:24,750
OF A RECENT EXPERIMENT THAT WE

6616
03:59:24,750 --> 03:59:28,487
DID WITH COLLABORATORS FROM

6617
03:59:28,487 --> 03:59:30,890
NORWAY.

6618
03:59:30,890 --> 03:59:34,093
SO, THIS IS OUR PET STORE

6619
03:59:34,093 --> 03:59:34,527
CO-HOUSING.

6620
03:59:34,527 --> 03:59:38,964
HIS MODEL SYSTEM, HE STERILIZES

6621
03:59:38,964 --> 03:59:41,067
MICE, TAKES SPF MICE, HOUSED IN

6622
03:59:41,067 --> 03:59:43,903
A BARN-LIKE ENVIRONMENT EXPOSED

6623
03:59:43,903 --> 03:59:45,438
TO COWS, PIGS, THERE ARE OTHER

6624
03:59:45,438 --> 03:59:47,073
FREE-LIVING MICE THAT CAN COME

6625
03:59:47,073 --> 03:59:48,741
IN, THEY DON'T EXCLUDE THOSE

6626
03:59:48,741 --> 03:59:49,041
NECESSARILY.

6627
03:59:49,041 --> 03:59:51,210
AND SO THEY ARE EXPOSED TO LOTS

6628
03:59:51,210 --> 03:59:53,646
OF THINGS THEY WOULD SEE IN

6629
03:59:53,646 --> 03:59:54,313
NATURE.

6630
03:59:54,313 --> 03:59:56,582
THEY TAKE ONE SMALL STEP FURTHER

6631
03:59:56,582 --> 03:59:58,250
AND WILL DIRECTLY CO-HOUSE THEM

6632
03:59:58,250 --> 04:00:00,653
WITH WILD MICE THEY CAPTURE IN

6633
04:00:00,653 --> 04:00:00,920
NORWAY.

6634
04:00:00,920 --> 04:00:02,722
NOW THERE'S WILD MICE WITH THE

6635
04:00:02,722 --> 04:00:06,325
SPF MICE IN THE BARN-LIKE

6636
04:00:06,325 --> 04:00:06,625
ENVIRONMENT.

6637
04:00:06,625 --> 04:00:06,826
OKAY.

6638
04:00:06,826 --> 04:00:10,963
WE JUST LOOKED AT THE POTENTIAL

6639
04:00:10,963 --> 04:00:12,031
PATHOGEN EXPOSURES.

6640
04:00:12,031 --> 04:00:12,798
I'M SHOWING SEROLOGY.

6641
04:00:12,798 --> 04:00:14,867
WHAT I HOPE YOU CAN APPRECIATE

6642
04:00:14,867 --> 04:00:17,336
IS THAT ACTUALLY PET STORE MICE

6643
04:00:17,336 --> 04:00:18,838
WITH SIGNIFICANTLY DIRTIER.

6644
04:00:18,838 --> 04:00:22,174
NOT NECESSARILY SURPRISING.

6645
04:00:22,174 --> 04:00:24,176
SO PET STORE MICE GET AD LBITUM

6646
04:00:24,176 --> 04:00:25,711
ACCESS TO FOOD AND WATER.

6647
04:00:25,711 --> 04:00:27,346
THEY DON'T HAVE TO FIND FOOD AND

6648
04:00:27,346 --> 04:00:27,546
WATER.

6649
04:00:27,546 --> 04:00:28,981
IF THEY GET SICK THEY DON'T HAVE

6650
04:00:28,981 --> 04:00:31,050
TO BE ABLE TO RUN FAST FROM A

6651
04:00:31,050 --> 04:00:31,250
HAWK.

6652
04:00:31,250 --> 04:00:32,184
THEY ARE QUITE PROTECTED, SO

6653
04:00:32,184 --> 04:00:34,253
IT'S EASIER TO KEEP THEM ALIVE.

6654
04:00:34,253 --> 04:00:40,059
WILD  MICE, IF THEY GET SICK

6655
04:00:40,059 --> 04:00:41,660
THAT'S A SIGNIFICANT DETRIMENT

6656
04:00:41,660 --> 04:00:46,499
TO THEIR  THEIR SURVIVAL.

6657
04:00:46,499 --> 04:00:51,771
WE FOUND NO NATURAL MASS

6658
04:00:51,771 --> 04:00:52,338
PATHOGENS.

6659
04:00:52,338 --> 04:00:54,440
WE DID DEEP SEQUENCING ANALYSES

6660
04:00:54,440 --> 04:00:55,608
TO SEE WHAT VIRUSES WERE

6661
04:00:55,608 --> 04:00:57,977
PRESENT, ARE THERE NOVEL VIRUSES

6662
04:00:57,977 --> 04:00:59,712
PRESENT.

6663
04:00:59,712 --> 04:01:02,248
I WAS A BIT SURPRISED, I'LL JUMP

6664
04:01:02,248 --> 04:01:04,650
HERE, TO FIND VERY FEW VIRUSES

6665
04:01:04,650 --> 04:01:07,086
THAT WERE PRESENT, AS WE LOOKED

6666
04:01:07,086 --> 04:01:11,757
AT SIX ANIMALS, A TON OF TISSUE,

6667
04:01:11,757 --> 04:01:16,896
ONLY FOUND TWO CORONAVIRUSES

6668
04:01:16,896 --> 04:01:18,030
PRESENT.

6669
04:01:18,030 --> 04:01:21,500
TYLER'S MIRIAM AND THIS VIRUS.

6670
04:01:21,500 --> 04:01:23,402
WE COMPARED THE SPF PANEL OF ALL

6671
04:01:23,402 --> 04:01:25,871
OF OUR ANIMAL MODELS, AGAIN

6672
04:01:25,871 --> 04:01:29,708
ABOUT A THOUSAND, TO ABOUT 40

6673
04:01:29,708 --> 04:01:31,043
FROM PREBIN AND LOOKED AT

6674
04:01:31,043 --> 04:01:31,710
PATHOGEN COMBINATIONS.

6675
04:01:31,710 --> 04:01:33,779
YOU CAN SEE THERE ARE SOME

6676
04:01:33,779 --> 04:01:34,380
DIFFERENCES.

6677
04:01:34,380 --> 04:01:36,482
HERE ARE PET STORE CO-HOUSING,

6678
04:01:36,482 --> 04:01:43,756
SOME EXIST IN THIS CLUSTER, IF

6679
04:01:43,756 --> 04:01:44,924
YOU WOULD OVERLAY SPF MICE A LOT

6680
04:01:44,924 --> 04:01:47,760
EXIST OVER HERE, SO DIRTINESS

6681
04:01:47,760 --> 04:01:49,428
KINDS OF CORRELATES WITH WHERE

6682
04:01:49,428 --> 04:01:55,301
THE CO-HOUSING OR HOW THE

6683
04:01:55,301 --> 04:01:55,734
CO-HOUSING OCCURRED.

6684
04:01:55,734 --> 04:01:56,302
DOES THAT MATTER?

6685
04:01:56,302 --> 04:02:00,339
DOES THE DEGREE OF DIRTINESS IN

6686
04:02:00,339 --> 04:02:05,311
THIS SYSTEM MATTER BECAUSE HIS

6687
04:02:05,311 --> 04:02:06,812
ARE SUBSTANTIALLY LESS DIRTY.

6688
04:02:06,812 --> 04:02:08,447
MAYBE, AND MAYBE JUST A LITTLE

6689
04:02:08,447 --> 04:02:08,781
BIT.

6690
04:02:08,781 --> 04:02:10,249
I WON'T OVERINTERPRET DATA.

6691
04:02:10,249 --> 04:02:12,318
THIS IS THE ANTIBODY RESPONSE WE

6692
04:02:12,318 --> 04:02:14,420
SENT HIM, EXACT SAME VACCINE, HE

6693
04:02:14,420 --> 04:02:16,155
VACCINATED HIS ANIMALS, WE

6694
04:02:16,155 --> 04:02:18,224
VACCINATED A SET OF ANIMALS,

6695
04:02:18,224 --> 04:02:19,225
DIRECTLY COMPARED THE RESPONSE

6696
04:02:19,225 --> 04:02:23,662
TO THE SAME VACCINE. 

6697
04:02:23,662 --> 04:02:26,031
THIS IS, AGAIN, THE SPLIT KILLED

6698
04:02:26,031 --> 04:02:26,599
FLU VACCINE.

6699
04:02:26,599 --> 04:02:29,602
MOSTLY THE SAME BUT THERE ARE

6700
04:02:29,602 --> 04:02:31,737
SOME SMALL DIFFERENCENS.

6701
04:02:31,737 --> 04:02:34,473
Ns ARE REASONABLY LARGE, SOLID

6702
04:02:34,473 --> 04:02:38,310
DATA, SMALL CHANGES, VERY SMALL

6703
04:02:38,310 --> 04:02:40,779
IF YOU SQUINT, MOSTLY

6704
04:02:40,779 --> 04:02:41,080
OVERLAPPING.

6705
04:02:41,080 --> 04:02:44,383
BY AREA UNDER THE CURVE YOU SEE

6706
04:02:44,383 --> 04:02:46,819
A FEW PLACE WAS STATISTICAL

6707
04:02:46,819 --> 04:02:47,786
DIFFERENCES, FALLOUT BETWEEN OUR

6708
04:02:47,786 --> 04:02:49,321
MICE AND THEIR MICE.

6709
04:02:49,321 --> 04:02:51,824
BUT, AGAIN, THESE ARE VERY SMALL

6710
04:02:51,824 --> 04:02:53,158
CHANGES, JUST BEING DIRTY MAKES

6711
04:02:53,158 --> 04:02:54,560
A MAJOR DIFFERENCE AND IS THE

6712
04:02:54,560 --> 04:02:59,265
MAJOR SORT OF IMPACT HERE.

6713
04:02:59,265 --> 04:03:01,033
SO QUICKLY IN CONCLUSION, I

6714
04:03:01,033 --> 04:03:07,172
THINK THERE'S LOTS OF DIFFERENT

6715
04:03:07,172 --> 04:03:08,407
MICROBES, A LOT OF DIVERSITY AND

6716
04:03:08,407 --> 04:03:10,209
HETEROGENEITY IN THE INFECTIONS

6717
04:03:10,209 --> 04:03:11,410
WE AS HUMAN EXPERIENCE

6718
04:03:11,410 --> 04:03:12,645
THROUGHOUT OUR LIFETIME.

6719
04:03:12,645 --> 04:03:14,246
WE HAVE CONVINCING DATA THAT

6720
04:03:14,246 --> 04:03:16,048
SUGGESTS THE DIRTY MICE DO

6721
04:03:16,048 --> 04:03:17,983
BETTER RECAPITULATE THE VACCINE

6722
04:03:17,983 --> 04:03:19,852
RESPONSES SEEN TO MULTIPLE

6723
04:03:19,852 --> 04:03:22,821
DIFFERENT VACCINE MODALITIES.

6724
04:03:22,821 --> 04:03:24,323
AND DIRTINESS DOES IMPACT OR

6725
04:03:24,323 --> 04:03:26,058
DOES VARY BASED ON MODEL YOU

6726
04:03:26,058 --> 04:03:27,593
USE, THERE CAN BE SMALL CHANGES

6727
04:03:27,593 --> 04:03:29,562
IN RESULTS YOU WOULD SEE BASED

6728
04:03:29,562 --> 04:03:31,330
ON MODEL SYSTEMS, YOU KNOW,

6729
04:03:31,330 --> 04:03:33,732
WHICH SHOULDN'T BE TERRIBLY

6730
04:03:33,732 --> 04:03:34,266
SURPRISING.

6731
04:03:34,266 --> 04:03:35,935
SO WITH THAT I WILL STOP.

6732
04:03:35,935 --> 04:03:38,203
I'LL THANK ALL THE FOLKS HERE

6733
04:03:38,203 --> 04:03:45,244
WHO DO THIS WORK.

6734
04:03:45,244 --> 04:03:55,788
SO FRANCES SHEPHERD, THE WORK IN

6735
04:03:57,656 --> 04:03:58,891
PREBIN BY AUTUMN SANDERS.

6736
04:03:58,891 --> 04:04:04,830
I'LL STOP AND TAKE QUESTIONS. 

6737
04:04:04,830 --> 04:04:06,231
>> BEAUTIFUL TALK.

6738
04:04:06,231 --> 04:04:08,167
THE DIRTY MOUSE MODEL, A CLEAR

6739
04:04:08,167 --> 04:04:11,804
ARGUMENT TO MAKE FOR USING

6740
04:04:11,804 --> 04:04:13,038
THESE.

6741
04:04:13,038 --> 04:04:14,873
THEY DON'T GET TERRIBLY EXCITED

6742
04:04:14,873 --> 04:04:16,075
WHEN I BRING IT TO OUR BRANCH.

6743
04:04:16,075 --> 04:04:17,876
HOW DO YOU SUGGEST WE DEAL WITH

6744
04:04:17,876 --> 04:04:18,277
THAT?

6745
04:04:18,277 --> 04:04:20,245
ARE THERE THINGS WE CAN DO?

6746
04:04:20,245 --> 04:04:22,214
CAN WE LIKE INFECT MICE WITH

6747
04:04:22,214 --> 04:04:23,616
LIKE, I DON'T KNOW, INFLUENZA

6748
04:04:23,616 --> 04:04:25,818
AND SARS, ANY OF THE VIRUSES YOU

6749
04:04:25,818 --> 04:04:27,820
FIND HERE TO DO THAT INSTEAD?

6750
04:04:27,820 --> 04:04:29,054
>> YEAH, THAT'S A GREAT
POINT.

6751
04:04:29,054 --> 04:04:31,256
I FAIL TO BRING THIS UP AND NEED

6752
04:04:31,256 --> 04:04:32,658
TO REMEMBER TO INTRODUCE THIS AT

6753
04:04:32,658 --> 04:04:33,092
THE BEGINNING.

6754
04:04:33,092 --> 04:04:36,962
WE DO ALL OF OUR EXPERIMENTS IN

6755
04:04:36,962 --> 04:04:39,665
A MODIFIED BSL3 FACILITY.

6756
04:04:39,665 --> 04:04:42,201
MIGHT SEEM LIKE OVERKILL BUT I'M

6757
04:04:42,201 --> 04:04:45,804
HAPPY BECAUSE WE DO A LOT OF

6758
04:04:45,804 --> 04:04:48,741
DEEP SEQUENCING OF OUR SPF MICE

6759
04:04:48,741 --> 04:04:50,209
HOUSED IN OUR FACILITY AND NEVER

6760
04:04:50,209 --> 04:04:57,716
FIND PATHOGENS WITH THE

6761
04:04:57,716 --> 04:05:00,019
EXCEPTION OF ASTRO-1, SOME

6762
04:05:00,019 --> 04:05:00,653
PATHOGENS ARE EXTREMELY

6763
04:05:00,653 --> 04:05:01,920
ENVIRONMENTALLY STABLE.

6764
04:05:01,920 --> 04:05:04,223
I THINK THE OVERKILL IS

6765
04:05:04,223 --> 04:05:04,490
WARRANTED.

6766
04:05:04,490 --> 04:05:06,258
THAT BEING SAID, THERE ARE OTHER

6767
04:05:06,258 --> 04:05:09,595
WAYS TO ACHIEVE THE SAME GOAL.

6768
04:05:09,595 --> 04:05:13,265
SO SKIP AND TIFFANY HAVE THE

6769
04:05:13,265 --> 04:05:14,800
SEQUENTIAL INFECTION EXPERIMENT,

6770
04:05:14,800 --> 04:05:18,337
DONE SEVERAL TIMES AT SEVERAL

6771
04:05:18,337 --> 04:05:19,738
ITERATIONS, MIKE DIAMOND IS

6772
04:05:19,738 --> 04:05:21,573
WORKING ON A SIMILAR SYSTEM

6773
04:05:21,573 --> 04:05:23,809
USING TRACTABLE NATURAL MOUSE

6774
04:05:23,809 --> 04:05:25,844
PATHOGENS FROM DIFFERENT

6775
04:05:25,844 --> 04:05:30,049
KINGDOMS WHERE YOU CAN DELIVER

6776
04:05:30,049 --> 04:05:32,051
THEM WITHOUT BIOSAFETY CONCERNS.

6777
04:05:32,051 --> 04:05:34,920
DAVE AND SKIP COMPARED

6778
04:05:34,920 --> 04:05:36,321
TRANSCRIPTIONAL RESPONSES AND

6779
04:05:36,321 --> 04:05:37,256
THEY WERE QUITE OVERLAPPING,

6780
04:05:37,256 --> 04:05:38,390
AGAIN FITTING WITH THE GENERAL

6781
04:05:38,390 --> 04:05:39,491
THESIS THAT SOME IMMUNE

6782
04:05:39,491 --> 04:05:41,660
EXPERIENCE IS BETTER THAN NONE

6783
04:05:41,660 --> 04:05:47,132
SO I THINK DIRECT INFECTION

6784
04:05:47,132 --> 04:05:50,536
SYSTEM COULD WORK.

6785
04:05:50,536 --> 04:05:50,803
YES?

6786
04:05:50,803 --> 04:05:52,071
>> SO, BEAUTIFUL DATA, AS

6787
04:05:52,071 --> 04:05:52,471
ALWAYS.

6788
04:05:52,471 --> 04:05:54,239
ONE THING I STARTED TO THINK

6789
04:05:54,239 --> 04:05:58,310
ABOUT THIS TIME IS WHETHER THERE

6790
04:05:58,310 --> 04:06:00,579
ARE MICROBIOME CHANGES, AND IS

6791
04:06:00,579 --> 04:06:06,185
THE MICROBIOME WHICH MAYBE IS

6792
04:06:06,185 --> 04:06:09,054
MODIFYING THOSE DE NOVO ANTIBODY

6793
04:06:09,054 --> 04:06:10,689
IMMUNE RESPONSES, YEAH,

6794
04:06:10,689 --> 04:06:10,989
MICROBIOME.

6795
04:06:10,989 --> 04:06:11,757
>> THERE ARE MICROBIOME
CHANGES.

6796
04:06:11,757 --> 04:06:12,758
A BEAUTIFUL QUESTION.

6797
04:06:12,758 --> 04:06:15,360
WE'RE WORKING ON A PROJECT NOW

6798
04:06:15,360 --> 04:06:17,329
NOW TRANSFERRING FECES, WE

6799
04:06:17,329 --> 04:06:18,564
FILTER, WE DON'T FILTER, TO DO

6800
04:06:18,564 --> 04:06:19,298
THIS.

6801
04:06:19,298 --> 04:06:21,066
WE'RE WORKING TO DEWORM THEM.

6802
04:06:21,066 --> 04:06:24,970
I WILL TELL YOU ACTUALLY 100% OF

6803
04:06:24,970 --> 04:06:25,771
THESE ANIMALS HAVE WORMS.

6804
04:06:25,771 --> 04:06:27,072
THEY ARE GROSS.

6805
04:06:27,072 --> 04:06:29,842
SO, YES, WE DON'T KNOW.

6806
04:06:29,842 --> 04:06:31,910
THERE ARE MICROBIOME CHANGES.

6807
04:06:31,910 --> 04:06:34,513
THOSE CHANGES ARE ALSO IMPACTED

6808
04:06:34,513 --> 04:06:37,349
BY VIRUS INFECTION, I DON'T KNOW

6809
04:06:37,349 --> 04:06:40,786
THAT I LOVE THIS WORD DYSBIOSIS

6810
04:06:40,786 --> 04:06:43,589
BUT YOU SEE GUT MICROBIOME

6811
04:06:43,589 --> 04:06:49,595
CHANGES AFTER FLU INFECTION,

6812
04:06:49,595 --> 04:06:59,538
QUANTITATIVELY AND  QUALITATIVEY

6813
04:06:59,538 --> 04:07:00,272
DIFFERENT.

6814
04:07:00,272 --> 04:07:01,907
A PAPER WAS RECENTLY REJECTED,

6815
04:07:01,907 --> 04:07:10,783
ONE OF THE REASONS BECAUSE WE

6816
04:07:10,783 --> 04:07:12,117
USED PRAs, TO BRING THAT BACK,

6817
04:07:12,117 --> 04:07:18,423
IF YOU WERE HERE COME TALK TO

6818
04:07:18,423 --> 04:07:18,991
ME.

6819
04:07:18,991 --> 04:07:20,492
>> I REJECTED THAT BECAUSE
--

6820
04:07:20,492 --> 04:07:22,394
NO, I WANTED TO ACTUALLY ASK

6821
04:07:22,394 --> 04:07:24,596
ABOUT THAT BECAUSE I HAVEN'T

6822
04:07:24,596 --> 04:07:25,430
SEEN THE DATA.

6823
04:07:25,430 --> 04:07:28,300
MY QUESTION WAS IF YOU SEE THE

6824
04:07:28,300 --> 04:07:30,803
SAME CHANGES TRANSCRIPTIONALLY

6825
04:07:30,803 --> 04:07:34,173
AS WELL AS BREATH, LONGEVITY OF

6826
04:07:34,173 --> 04:07:35,707
ANTIBODY RESPONSES AGAINST

6827
04:07:35,707 --> 04:07:39,745
NATURAL INFECTION THAT YOU SEE

6828
04:07:39,745 --> 04:07:40,445
AGAINST VACCINATION.

6829
04:07:40,445 --> 04:07:41,513
>> BEAUTIFUL QUESTION.

6830
04:07:41,513 --> 04:07:42,848
WE HAVEN'T DONE AS MUCH AS WE

6831
04:07:42,848 --> 04:07:43,549
SHOULD.

6832
04:07:43,549 --> 04:07:46,685
WE DID FOCUS ON VACCINES BUT DID

6833
04:07:46,685 --> 04:07:48,220
SOME OF THOSE, AGAIN, PR 8, YOU

6834
04:07:48,220 --> 04:07:50,823
DID SEE THE CHANGES.

6835
04:07:50,823 --> 04:07:51,824
THEY WEREN'T AS PRONOUNCED AS

6836
04:07:51,824 --> 04:07:54,426
WITH THE VACCINE.

6837
04:07:54,426 --> 04:07:55,761
VACCINE RESPONSES WITH QUITE

6838
04:07:55,761 --> 04:08:00,666
DRAMATIC, NOT AS DRAMATIC WITH

6839
04:08:00,666 --> 04:08:01,033
ACUTE INFECTION.

6840
04:08:01,033 --> 04:08:02,100
>> RYAN, FANTASTIC.

6841
04:08:02,100 --> 04:08:05,103
HOW MUCH OF THE CHANGES THAT

6842
04:08:05,103 --> 04:08:09,975
YOU'RE SEEING ARE ACTIVATION

6843
04:08:09,975 --> 04:08:12,044
BASED, BASED ON CO-INFECTION, OR

6844
04:08:12,044 --> 04:08:12,711
TRAINED IMMUNITY?

6845
04:08:12,711 --> 04:08:13,445
>> GREAT QUESTION.

6846
04:08:13,445 --> 04:08:15,113
I WILL SAY WE'VE DONE SOME

6847
04:08:15,113 --> 04:08:16,348
EXPERIMENTS WHERE WE GO OUT WAY

6848
04:08:16,348 --> 04:08:17,850
FURTHER THAN 60 DAYS OF

6849
04:08:17,850 --> 04:08:19,551
CO-HOUSING AND SEE VERY, VERY,

6850
04:08:19,551 --> 04:08:20,752
VERY SIMILAR RESULTS.

6851
04:08:20,752 --> 04:08:23,655
I WOULD SORT OF SUGGEST THAT

6852
04:08:23,655 --> 04:08:24,623
TRAINED IMMUNITY MIGHT LIKELY IS

6853
04:08:24,623 --> 04:08:26,024
NOT INVOLVED.

6854
04:08:26,024 --> 04:08:27,392
THERE AREN'T A LOT OF CHRONIC

6855
04:08:27,392 --> 04:08:28,594
INFECTIONS HERE BUT THERE ARE

6856
04:08:28,594 --> 04:08:28,794
SOME.

6857
04:08:28,794 --> 04:08:31,630
SO IT GETS A LITTLE BIT

6858
04:08:31,630 --> 04:08:34,967
DIFFICULT TO DISENTANGLE.

6859
04:08:34,967 --> 04:08:37,369
WITH SOME EXPERIMENTS THAT SABRA

6860
04:08:37,369 --> 04:08:40,305
WAS SUGGESTING MIGHT GET AT THAT

6861
04:08:40,305 --> 04:08:40,672
EXACT QUESTION.

6862
04:08:40,672 --> 04:08:41,640
IT'S TRICKY, YEAH.

6863
04:08:41,640 --> 04:08:43,041
>> I HAD A QUESTION.

6864
04:08:43,041 --> 04:08:45,043
WHEN YOU LOOK AT THE MICE THAT

6865
04:08:45,043 --> 04:08:48,313
YOU GET FROM THE DIRTY VENDOR AS

6866
04:08:48,313 --> 04:08:50,482
OPPOSED TO CLEAN VENDOR DO YOU

6867
04:08:50,482 --> 04:08:51,416
SEE SIMILAR DIFFERENCES, HAVE

6868
04:08:51,416 --> 04:08:53,352
YOU EVER DONE THIS?

6869
04:08:53,352 --> 04:08:55,621
>> YEAH, WE'VE DONE A
COUPLE

6870
04:08:55,621 --> 04:08:56,755
EXPERIMENTS WHERE WE GOT MICE

6871
04:08:56,755 --> 04:08:59,124
FROM THE PET STORE, WHERE THE

6872
04:08:59,124 --> 04:09:00,259
MICE HAD BEEN SITTING IN THE PET

6873
04:09:00,259 --> 04:09:03,528
STORE FOR A LONG TIME.

6874
04:09:03,528 --> 04:09:05,597
THEY CLEARED A LOT OF THEIR

6875
04:09:05,597 --> 04:09:06,932
ACUTE INFECTION.

6876
04:09:06,932 --> 04:09:08,166
AND THOSE WERE SUBSTANTIALLY

6877
04:09:08,166 --> 04:09:09,234
LESS DIRTY.

6878
04:09:09,234 --> 04:09:11,637
IN THOSE SITUATIONS WE DID NOT

6879
04:09:11,637 --> 04:09:13,171
SEE MAJOR IMPACT WHICH COULD

6880
04:09:13,171 --> 04:09:16,108
SUGGEST THAT IT'S NOT

6881
04:09:16,108 --> 04:09:17,976
MICROBIOME, ACTUALLY SOME ACUTE

6882
04:09:17,976 --> 04:09:22,314
INFECTIONS ARE NECESSARY BUT OUR

6883
04:09:22,314 --> 04:09:25,517
N IS WAY TOO LOW. 

6884
04:09:25,517 --> 04:09:27,386
>> WHEN I SAID DIRTY
VENDOR I

6885
04:09:27,386 --> 04:09:28,754
DIDN'T MEAN PET STORE.

6886
04:09:28,754 --> 04:09:29,955
>> OH, I SEE.

6887
04:09:29,955 --> 04:09:32,257
WE'VE RECENTLY STARTED SCREENING

6888
04:09:32,257 --> 04:09:34,126
OUR MICE FOR ASTRO-1.

6889
04:09:34,126 --> 04:09:35,827
YES, YOU'RE ASKING ABOUT THE

6890
04:09:35,827 --> 04:09:38,563
VENDOR I SHOULDN'T NAME, YEAH, I

6891
04:09:38,563 --> 04:09:40,666
DON'T KNOW.

6892
04:09:40,666 --> 04:09:40,966
>> OKAY.

6893
04:09:40,966 --> 04:09:42,267
>> PEOPLE SHOULD PCR THEIR
MICE,

6894
04:09:42,267 --> 04:09:47,105
I'M GUESSING A LOT OF YOU HAVE

6895
04:09:47,105 --> 04:09:47,306
ASTRO.

6896
04:09:47,306 --> 04:09:48,840
>> ONE QUESTION ABOUT THE
WORMS

6897
04:09:48,840 --> 04:09:51,043
IN PARTICULAR, WHEN YOU CO-HOUSE

6898
04:09:51,043 --> 04:09:52,911
DO YOU SEE THE WORMS CROSSING

6899
04:09:52,911 --> 04:09:55,280
BETWEEN THEM, AND I GUESS

6900
04:09:55,280 --> 04:09:57,316
CURIOSITY WOULD THAT BE MORE

6901
04:09:57,316 --> 04:10:00,018
PERSISTENT INFECTION IF THEY DO

6902
04:10:00,018 --> 04:10:05,357
CROSS OVER A AND DO YOU SEE

6903
04:10:05,357 --> 04:10:06,692
CYTOKINES THAT WOULD MORE

6904
04:10:06,692 --> 04:10:07,893
EOSINOPHILIA IN THE BLOOD.

6905
04:10:07,893 --> 04:10:09,861
>> IT'S NOT LIKE AT THE 60
OR

6906
04:10:09,861 --> 04:10:12,030
PLUS TIME POINT.

6907
04:10:12,030 --> 04:10:12,998
WE HAVE DRAMATIC Th2-LIKE

6908
04:10:12,998 --> 04:10:13,899
RESPONSE, SO I DON'T THINK

6909
04:10:13,899 --> 04:10:15,867
THERE'S A MAJOR IMPACT.

6910
04:10:15,867 --> 04:10:17,536
ARE THE WORMS THERE?

6911
04:10:17,536 --> 04:10:18,136
YES.

6912
04:10:18,136 --> 04:10:20,772
AND YOU CAN SEE THEM, YOU KNOW,

6913
04:10:20,772 --> 04:10:22,341
WITHOUT A MICROSCOPE WHEN YOU

6914
04:10:22,341 --> 04:10:30,115
CUT THE GI TRACT OPEN.

6915
04:10:30,115 --> 04:10:31,717
THEY ARE GROSS.

6916
04:10:31,717 --> 04:10:32,918
>> HAS ANYONE USED THIS
DIRTY

6917
04:10:32,918 --> 04:10:34,920
MOUSE MODEL IN THE CONCEPT OF

6918
04:10:34,920 --> 04:10:37,422
ALLERGY AND ASTHMA TO TEST

6919
04:10:37,422 --> 04:10:39,391
HYGIENE HYPOTHESIS?

6920
04:10:39,391 --> 04:10:41,159
>> YES, IT RECAPITULATES
WHAT

6921
04:10:41,159 --> 04:10:42,394
YOU MIGHT EXPECT.

6922
04:10:42,394 --> 04:10:45,731
A PAPER FROM STEVE JAMISON IN

6923
04:10:45,731 --> 04:10:48,800
NATURE IMMUNOLOGY USING HOUSE

6924
04:10:48,800 --> 04:10:50,502
DUST MITES, AND UNPUBLISHED DATA

6925
04:10:50,502 --> 04:10:52,437
FROM MINNESOTA, THEY GO IN THE

6926
04:10:52,437 --> 04:10:53,705
OPPOSITE DIRECTION LOOKING AT

6927
04:10:53,705 --> 04:10:55,040
AUTOIMMUNE DISEASE, IT ALSO FITS

6928
04:10:55,040 --> 04:10:57,309
WITH WHAT YOU MIGHT EXPECT FROM

6929
04:10:57,309 --> 04:10:59,978
HYGIENE HYPOTHESIS, A FUN DIRECT

6930
04:10:59,978 --> 04:11:01,580
TEST OF THAT HYPOTHESIS.

6931
04:11:01,580 --> 04:11:08,820
YEAH, GREAT QUESTION. 

6932
04:11:08,820 --> 04:11:10,222
ALL RIGHT.

6933
04:11:10,222 --> 04:11:18,663
THANK YOU. 

6934
04:11:18,663 --> 04:11:22,401
>> NEXT SPEAKER IS TALKING
ABOUT

6935
04:11:22,401 --> 04:11:23,802
RESPONSES TO RESPIRATORY

6936
04:11:23,802 --> 04:11:25,837
INFECTION WITH FOCUS ON

6937
04:11:25,837 --> 04:11:26,405
INFLUENZA.

6938
04:11:26,405 --> 04:11:28,206
>> THANK YOU, I CAN
PARTICIPATE

6939
04:11:28,206 --> 04:11:29,841
IN THIS AMAZING WORKSHOP.

6940
04:11:29,841 --> 04:11:35,047
YES, I KEPT THE TITLE LIKE IT

6941
04:11:35,047 --> 04:11:43,221
WAS SUGGESTED, AND I'LL DIVE

6942
04:11:43,221 --> 04:11:46,525
RIGHT IN.

6943
04:11:46,525 --> 04:11:48,160
YEAH, SO THE INFLUENZA VIRUS

6944
04:11:48,160 --> 04:11:49,327
CHALLENGE MODEL WE DISCOVERED

6945
04:11:49,327 --> 04:11:51,663
THIS ALREADY A LITTLE BIT TODAY

6946
04:11:51,663 --> 04:11:53,965
BUT SO IT'S TYPICALLY INTRANASAL

6947
04:11:53,965 --> 04:11:55,500
INFECTION THAT WE USE AT MOUNT

6948
04:11:55,500 --> 04:11:57,869
SINAI, WE DON'T DO AEROSOL FOR

6949
04:11:57,869 --> 04:11:58,203
THE FLU.

6950
04:11:58,203 --> 04:12:01,406
THIS MEANS DEEP LUNG INJECTION,

6951
04:12:01,406 --> 04:12:06,711
USING 50 MICRO LITERS OF VOLUME,

6952
04:12:06,711 --> 04:12:08,013
IT GOES STRAIGHT INTO THE LUNG.

6953
04:12:08,013 --> 04:12:11,183
THE MOUSE MODEL IS NOT A GOOD

6954
04:12:11,183 --> 04:12:12,717
TRANSMISSION MODEL ESPECIALLY

6955
04:12:12,717 --> 04:12:16,188
ADULT MICE SO WE CANNOT USE IT

6956
04:12:16,188 --> 04:12:16,521
FOR THAT.

6957
04:12:16,521 --> 04:12:20,358
SOME LIMITATIONS OF THE MOUSE

6958
04:12:20,358 --> 04:12:22,961
MODEL ALSO FOR FLU WE'RE STUCK

6959
04:12:22,961 --> 04:12:24,830
TO SOME MORE DISRUPTED STRAINS

6960
04:12:24,830 --> 04:12:27,299
LIKE PURATE AND NEED MORE

6961
04:12:27,299 --> 04:12:28,400
VIRUSES MORE RECENT FOR

6962
04:12:28,400 --> 04:12:29,367
VACCINATION STUDIES FOR EXAMPLE

6963
04:12:29,367 --> 04:12:32,204
IF YOU WANT SOME ANTIBODY

6964
04:12:32,204 --> 04:12:32,971
RESPONSES AND PROTECTION

6965
04:12:32,971 --> 04:12:34,306
STUDIES.

6966
04:12:34,306 --> 04:12:36,241
THIS IS ESPECIALLY TRUE FOR H3N2

6967
04:12:36,241 --> 04:12:38,210
AND INFLUENZA B VIRUSES.

6968
04:12:38,210 --> 04:12:41,980
AND ALSO FOR THE MOUSE INFLUENZA

6969
04:12:41,980 --> 04:12:47,853
MODEL, AS OTHER MODELS, WE CAN

6970
04:12:47,853 --> 04:12:51,156
STUDY IMMUNE ANIMALS VERSUS

6971
04:12:51,156 --> 04:12:52,757
PREEXISTING IMMUNITY,

6972
04:12:52,757 --> 04:12:53,492
STERILIZING IMMUNITY THAT

6973
04:12:53,492 --> 04:12:54,659
PREVENTS VIRUS IMPLICATION A

6974
04:12:54,659 --> 04:12:56,495
LOT, THERE'S NOT A LOT OF CHANCE

6975
04:12:56,495 --> 04:12:59,030
FOR VIRUS TO REPLICATE IN THE

6976
04:12:59,030 --> 04:12:59,331
LUNG.

6977
04:12:59,331 --> 04:12:59,998
INFECTION PERMISSIVE IMMUNITY

6978
04:12:59,998 --> 04:13:02,300
WHICH BASICALLY IS A

6979
04:13:02,300 --> 04:13:03,335
BREAKTHROUGH INFECTION.

6980
04:13:03,335 --> 04:13:05,437
INFECTION PERMISSIVE IMMUNITY IS

6981
04:13:05,437 --> 04:13:07,806
SOMETHING THAT'S THE LAB HAS

6982
04:13:07,806 --> 04:13:09,207
BEEN FOCUSING ON A LOT BECAUSE

6983
04:13:09,207 --> 04:13:11,810
IT CAN PROVIDE PARTIAL

6984
04:13:11,810 --> 04:13:13,211
PROTECTION, SOMETIMES BROADLY

6985
04:13:13,211 --> 04:13:13,845
PROTECTIVE, VERY BROADLY

6986
04:13:13,845 --> 04:13:14,546
REACTIVE PROTECTION.

6987
04:13:14,546 --> 04:13:19,784
BUT ALSO CAN BE ASSOCIATED WITH

6988
04:13:19,784 --> 04:13:22,220
ENHANCED DISEASE BECAUSE YOU MAY

6989
04:13:22,220 --> 04:13:24,723
HAVE IMMUNE RESPONSES

6990
04:13:24,723 --> 04:13:25,757
CROSS-REACTIVE THAT NOT PROTECT

6991
04:13:25,757 --> 04:13:28,760
HOST RESPONSE TO INFECTION.

6992
04:13:28,760 --> 04:13:31,596
YOU MAY HAVE MODULATION OF

6993
04:13:31,596 --> 04:13:34,799
DISEASE, WHEN THERE'S INFECTION

6994
04:13:34,799 --> 04:13:35,700
PERMISSIVE IMMUNITY.

6995
04:13:35,700 --> 04:13:38,336
INFECTIONIVE PERMISSIVE IMMUNITY

6996
04:13:38,336 --> 04:13:40,305
CAN BE ADAPTIVE, ALSO WE HAVE TO

6997
04:13:40,305 --> 04:13:41,673
THINK OF INNATE IMMUNITY WHICH

6998
04:13:41,673 --> 04:13:44,643
BY DEFAULT IS ALSO INFECTION

6999
04:13:44,643 --> 04:13:45,410
PERMISSIVE.

7000
04:13:45,410 --> 04:13:47,612
SO, THIS IS INFECTION PERMISSIVE

7001
04:13:47,612 --> 04:13:48,713
IMMUNITY, SOMETHING WE FOCUS ON

7002
04:13:48,713 --> 04:13:50,682
FOR A LONG TIME IN THE LAB.

7003
04:13:50,682 --> 04:13:52,784
I WON'T BRING VACCINATION STUDY

7004
04:13:52,784 --> 04:13:54,986
BUT WE USE VACCINES AS A KIND OF

7005
04:13:54,986 --> 04:13:56,288
WAY TO INDUCE PREEXISTING

7006
04:13:56,288 --> 04:13:57,822
IMMUNITY THAT IS INFECTION

7007
04:13:57,822 --> 04:13:58,290
PERMISSIVE.

7008
04:13:58,290 --> 04:13:59,457
BECAUSE I DON'T WANT TO SAY THAT

7009
04:13:59,457 --> 04:14:04,930
FLU VACCINES MAY NOT WORK, I USE

7010
04:14:04,930 --> 04:14:08,500
VINTAGE VACCINE, 2005 TO 2006,

7011
04:14:08,500 --> 04:14:10,268
BASICALLY VACCINE 20 YEARS IN

7012
04:14:10,268 --> 04:14:16,775
THE FRIDGE, IN OUR FRIDGE.

7013
04:14:16,775 --> 04:14:17,409
DEFINITELY EXPIRES, OBVIOUSLY,

7014
04:14:17,409 --> 04:14:18,009
PRE-PANDEMIC, 2009, ANOTHER

7015
04:14:18,009 --> 04:14:20,712
REASON WE USE THIS VACCINE.

7016
04:14:20,712 --> 04:14:23,515
TYPICALLY FLU VACCINES AIM AT

7017
04:14:23,515 --> 04:14:29,754
INDUCTION OF NEUTRALIZING 

7018
04:14:29,754 --> 04:14:31,389
ANTIBODIES TARGETING H-A.

7019
04:14:31,389 --> 04:14:33,925
A SINGLE VACCINATION OF 3 MICRO

7020
04:14:33,925 --> 04:14:38,530
GAPS OF H-A WILL RESULT IN LOW

7021
04:14:38,530 --> 04:14:41,433
HI TITERS GIVING INFECTION

7022
04:14:41,433 --> 04:14:41,866
PERMISSIVE IMMUNITY.

7023
04:14:41,866 --> 04:14:48,039
STUDY I'M GOING TO BRING, THE

7024
04:14:48,039 --> 04:14:49,441
FIRST PART, WE VACCINATE MICE

7025
04:14:49,441 --> 04:14:52,510
THREE TIMES, OR ONE TIME, OR NOT

7026
04:14:52,510 --> 04:14:59,084
AT ALL WHICH IS PBS I HAVE A

7027
04:14:59,084 --> 04:14:59,951
INTRAMUSCULAR ROUTE, FIRST IS

7028
04:14:59,951 --> 04:15:01,152
FEMALE MICE.

7029
04:15:01,152 --> 04:15:04,189
THREE WEEKS AFTER WE CHALLENGE

7030
04:15:04,189 --> 04:15:09,894
FIRST TIME WITH H1N1, A NEW

7031
04:15:09,894 --> 04:15:13,398
CALEDONIA FROM 99, NC 99, INFECT

7032
04:15:13,398 --> 04:15:18,637
WITH H1N1 OR GIVE MOCK

7033
04:15:18,637 --> 04:15:19,070
INFECTION.

7034
04:15:19,070 --> 04:15:20,105
THIS NC99 IS HUMAN ISOLATE, THIS

7035
04:15:20,105 --> 04:15:21,606
WORKS WELL IN MICE.

7036
04:15:21,606 --> 04:15:24,342
WE WAIT FOR FOUR WEEKS, WE

7037
04:15:24,342 --> 04:15:27,379
RECHALLENGE THESE MICE FOUR

7038
04:15:27,379 --> 04:15:30,915
WEEKS LATER WITH X31, ACTUALLY A

7039
04:15:30,915 --> 04:15:32,317
PURATE-BASED BACKBONE VIRUS WITH

7040
04:15:32,317 --> 04:15:34,819
THE HA AND NA FROM THE STRAIN

7041
04:15:34,819 --> 04:15:35,420
FROM 68.

7042
04:15:35,420 --> 04:15:36,755
THIS IS ANOTHER PROBLEM FOR THE

7043
04:15:36,755 --> 04:15:38,690
MOUSE MODEL.

7044
04:15:38,690 --> 04:15:47,198
WE NEED GOOD H3N2 VIRUSES, STILL

7045
04:15:47,198 --> 04:15:48,633
ON A BACKBONE FROM A LONG TIME

7046
04:15:48,633 --> 04:15:49,601
AGO.

7047
04:15:49,601 --> 04:15:50,835
I'LL BRING THE STORY ABOUT HOST

7048
04:15:50,835 --> 04:15:51,903
RESPONSE, NOT THE VACCINE STUDY

7049
04:15:51,903 --> 04:15:54,072
BUT HOST RESPONSE TO INFECTION.

7050
04:15:54,072 --> 04:15:55,774
I WILL CHOP IN THREE PARTS.

7051
04:15:55,774 --> 04:15:57,942
FIRST WE HAVE VACCINE RESPONSE

7052
04:15:57,942 --> 04:15:59,210
WHICH WE WILL CORRELATE WITH

7053
04:15:59,210 --> 04:16:00,445
PROTECTION AND THE OUTCOME OF

7054
04:16:00,445 --> 04:16:01,680
THE HOST RESPONSE AFTER THE

7055
04:16:01,680 --> 04:16:03,114
FIRST INFECTION AND THEN THE

7056
04:16:03,114 --> 04:16:06,117
HOST RESPONSE AFTER SECOND

7057
04:16:06,117 --> 04:16:06,384
INFECTION.

7058
04:16:06,384 --> 04:16:09,721
VACCINE RESPONSE AS I MENTIONED

7059
04:16:09,721 --> 04:16:12,957
IS SINGLE TIV VACCINATION GIVES

7060
04:16:12,957 --> 04:16:14,092
HARDLY ANY HA ANTIBODIES, YOU

7061
04:16:14,092 --> 04:16:20,799
HAVE TO VACCINATE THREE TIMES TO

7062
04:16:20,799 --> 04:16:22,667
DETECT ELISA VIRUS.

7063
04:16:22,667 --> 04:16:28,406
A SINGLE VACCINATION GIVES YOU

7064
04:16:28,406 --> 04:16:30,575
HI TITER DETECTABLE.

7065
04:16:30,575 --> 04:16:33,278
WE DIDN'T CHECK HA ELISA TITERS

7066
04:16:33,278 --> 04:16:36,815
AGAINST H3, IT'S ALSO  VERY LOW,

7067
04:16:36,815 --> 04:16:39,651
YOU START TO FIND IN

7068
04:16:39,651 --> 04:16:41,920
TRIPLE-VACCINATED ANIMAL.

7069
04:16:41,920 --> 04:16:43,655
SPLIT VACCINE, IT HAS NP, IF YOU

7070
04:16:43,655 --> 04:16:45,323
VACCINATE THREE TIMES YOU GET

7071
04:16:45,323 --> 04:16:47,158
SOME NP ANTIBODIES.

7072
04:16:47,158 --> 04:16:48,693
I'M MENTIONING BECAUSE NP

7073
04:16:48,693 --> 04:16:51,029
ANTIBODIES MAY PROVIDE SOME

7074
04:16:51,029 --> 04:16:52,530
PROTECTION DURING INFECTION.

7075
04:16:52,530 --> 04:16:54,399
SO THEN WE CHECK, WE'RE GOING TO

7076
04:16:54,399 --> 04:16:56,768
FOCUS ON THE HOST RESPONSE AND

7077
04:16:56,768 --> 04:16:58,470
PROTECTION DURING THE FIRST

7078
04:16:58,470 --> 04:16:59,437
INFECTION WITH H1N1.

7079
04:16:59,437 --> 04:17:02,407
WHAT WE CAN SEE IS ANIMALS WITH

7080
04:17:02,407 --> 04:17:05,577
THIS DOSE OF VIRUS THAT ARE NOT

7081
04:17:05,577 --> 04:17:10,515
VACCINATED, SO ANIMALS NOT

7082
04:17:10,515 --> 04:17:13,151
VACCINATED, WILL THEY START TO

7083
04:17:13,151 --> 04:17:14,285
LOSE 20% OF BODY WEIGHT AND

7084
04:17:14,285 --> 04:17:14,652
RECOVER.

7085
04:17:14,652 --> 04:17:16,855
IN THE MOUSE MODEL YOU LOSE

7086
04:17:16,855 --> 04:17:21,226
WEIGHT UNTIL DAY 7, 8, MICE WILL

7087
04:17:21,226 --> 04:17:24,062
SUCCUMB OR START TO RECOVER.

7088
04:17:24,062 --> 04:17:25,930
ANIMALS VACCINATED WITH TIV ONCE

7089
04:17:25,930 --> 04:17:27,966
OR THREE TIMES, THEY STILL SHOW

7090
04:17:27,966 --> 04:17:30,535
THIS KIND OF 5% WEIGHT LOSS

7091
04:17:30,535 --> 04:17:31,936
AFTER INFECTION, THEN THEY

7092
04:17:31,936 --> 04:17:32,470
RECOVER.

7093
04:17:32,470 --> 04:17:34,305
THEY ARE PROTECTED BUT IT'S NOT

7094
04:17:34,305 --> 04:17:37,642
AS MUCH AS A MOUSE FOR EXAMPLE

7095
04:17:37,642 --> 04:17:39,177
THAT GETS THE MOCK CHALLENGE.

7096
04:17:39,177 --> 04:17:41,379
WHEN WE LOOK AT VIRUS TITERS IN

7097
04:17:41,379 --> 04:17:42,714
THE LUNGS THE NON-VACCINATED

7098
04:17:42,714 --> 04:17:45,116
ANIMAL GETS A NICE VIRUS TITER,

7099
04:17:45,116 --> 04:17:47,185
WHICH PEAKS IN THIS CASE AROUND

7100
04:17:47,185 --> 04:17:47,852
DAY 2.

7101
04:17:47,852 --> 04:17:49,687
IT GOES UP, SO REPLICATING

7102
04:17:49,687 --> 04:17:50,088
BASICALLY.

7103
04:17:50,088 --> 04:17:52,490
BUT THEN IT STARTS TO GO DOWN BY

7104
04:17:52,490 --> 04:17:54,426
DAY 3.

7105
04:17:54,426 --> 04:17:55,794
A SINGLE VACCINATED MOUSE, THEY

7106
04:17:55,794 --> 04:18:00,098
STILL HAVE VIRUS TITER IN THE

7107
04:18:00,098 --> 04:18:01,866
LUNGS, DETECTABLE DAY 2 AND DAY

7108
04:18:01,866 --> 04:18:05,069
3, NOT DAY 1, STILL REPLICATING

7109
04:18:05,069 --> 04:18:08,206
BUT NOT THERE NOT DETECTABLE DAY

7110
04:18:08,206 --> 04:18:08,339
1.

7111
04:18:08,339 --> 04:18:09,808
TRIPLE VACCINATED HAS

7112
04:18:09,808 --> 04:18:10,608
STERILIZING IMMUNITY BASICALLY

7113
04:18:10,608 --> 04:18:13,011
YOU CANNOT DETECT VIRUS TITERS

7114
04:18:13,011 --> 04:18:16,080
AT THE EARLY TIME POINTS

7115
04:18:16,080 --> 04:18:16,448
POST-INFECTION.

7116
04:18:16,448 --> 04:18:18,116
SO NOW WE COME TO THE HOST

7117
04:18:18,116 --> 04:18:18,950
RESPONSE.

7118
04:18:18,950 --> 04:18:20,585
I PLOT AGAIN THIS VACCINE,

7119
04:18:20,585 --> 04:18:21,986
SORRY, PLOT AGAIN THE VIRUS

7120
04:18:21,986 --> 04:18:24,756
TITER ON THE RIGHT.

7121
04:18:24,756 --> 04:18:27,158
EVERY ROW IN THIS HEAT MAP IS A

7122
04:18:27,158 --> 04:18:27,992
SINGLE MOUSE.

7123
04:18:27,992 --> 04:18:29,928
IN THE SIDEBAR YOU CAN SEE THE

7124
04:18:29,928 --> 04:18:31,796
ONE DAY, TWO DAY, THREE DAY

7125
04:18:31,796 --> 04:18:33,064
MARKS FOR EVERY GROUP.

7126
04:18:33,064 --> 04:18:34,666
SO WE HAVE THE FIVE VACCINATION

7127
04:18:34,666 --> 04:18:35,266
GROUPS HERE.

7128
04:18:35,266 --> 04:18:37,302
WHAT YOU CAN SEE IS IS ONLY MICE

7129
04:18:37,302 --> 04:18:40,338
THAT DID NOT GET THE VACCINE

7130
04:18:40,338 --> 04:18:43,041
THAT DID GET INFECTED SHOW

7131
04:18:43,041 --> 04:18:44,909
DIFFERENT CYTOKINES, DIFFERENT

7132
04:18:44,909 --> 04:18:45,677
TIME POINTS POST-INFECTION,

7133
04:18:45,677 --> 04:18:47,612
CORRELATES TO SOME EXTENT WITH

7134
04:18:47,612 --> 04:18:49,280
VIRUS TITERS.

7135
04:18:49,280 --> 04:18:50,248
SINGLE VACCINATION MOUSE, MICE,

7136
04:18:50,248 --> 04:18:51,249
THAT GOT A BREAKTHROUGH

7137
04:18:51,249 --> 04:18:53,751
INFECTION YOU CAN STILL SEE

7138
04:18:53,751 --> 04:18:55,887
VIRUS TITERS IN THE LUNGS, LUNG

7139
04:18:55,887 --> 04:18:58,056
ARE SILENT IN TERMS OF

7140
04:18:58,056 --> 04:18:58,790
CYTOKINES.

7141
04:18:58,790 --> 04:19:00,525
THE VACCINE ALLOWS REPLICATION

7142
04:19:00,525 --> 04:19:02,293
BUT THE CYTOKINE PROFILE DOES

7143
04:19:02,293 --> 04:19:04,362
NOT REFLECT THE VIRUS TITERS

7144
04:19:04,362 --> 04:19:06,231
THAT WE DETECT.

7145
04:19:06,231 --> 04:19:09,167
SO THEN WE CHECK MYELOID CELLS

7146
04:19:09,167 --> 04:19:11,402
DAY 7 POST INFECTION, BASICALLY

7147
04:19:11,402 --> 04:19:11,903
HERE.

7148
04:19:11,903 --> 04:19:14,205
THAT'S WHERE IT BECOMES

7149
04:19:14,205 --> 04:19:14,639
INTERESTING.

7150
04:19:14,639 --> 04:19:16,040
UNVACCINATED MICE THAT GET SICK

7151
04:19:16,040 --> 04:19:17,742
AFTER THE FIRST INFECTION, THEY

7152
04:19:17,742 --> 04:19:21,679
WILL LOSE ALL OF THEIR ALVEOLAR

7153
04:19:21,679 --> 04:19:22,347
MACROPHAGES.

7154
04:19:22,347 --> 04:19:24,048
THEY WILL HAVE INFLAMMATORY

7155
04:19:24,048 --> 04:19:25,583
MONOCYTES COMING INTO THE LUNGS.

7156
04:19:25,583 --> 04:19:28,887
A SINGLE OR TRIPLE VACCINATION

7157
04:19:28,887 --> 04:19:30,021
PREVENTS LOSS OF ALVEOLAR

7158
04:19:30,021 --> 04:19:32,156
MACROPHAGES TO SOME EXTENT BUT

7159
04:19:32,156 --> 04:19:34,392
ALSO PREVENTS INFLAMMATORY

7160
04:19:34,392 --> 04:19:35,460
MONOCYTES TO COME IN.

7161
04:19:35,460 --> 04:19:38,630
AND SO WHEN WE THEN DO FLOW

7162
04:19:38,630 --> 04:19:39,998
CYTOMETRY, YOU'RE GOING TO OF

7163
04:19:39,998 --> 04:19:43,668
COURSE FOLLOW THE FATE OF THE

7164
04:19:43,668 --> 04:19:46,838
ALVEOLAR MACROPHAGES BY FLOW

7165
04:19:46,838 --> 04:19:48,907
CYTOMETRY.

7166
04:19:48,907 --> 04:19:54,479
THESE ARE BASELINE, PBS VACCINE

7167
04:19:54,479 --> 04:19:55,480
AND MOCK CHALLENGE.

7168
04:19:55,480 --> 04:19:56,981
SO WHEN YOU VACCINATE ANIMALS

7169
04:19:56,981 --> 04:19:59,384
YOU SEE THE SAME, NOTHING IS

7170
04:19:59,384 --> 04:20:01,719
HAPPENING AT THE ALVEOLAR

7171
04:20:01,719 --> 04:20:03,788
MACROPHAGE STAGE WHICH WE

7172
04:20:03,788 --> 04:20:04,556
EXPECTED.

7173
04:20:04,556 --> 04:20:06,958
IF YOU INFECT ANIMALS WITHOUT

7174
04:20:06,958 --> 04:20:08,927
VACCINATION YOU LOSE ALVEOLAR

7175
04:20:08,927 --> 04:20:09,460
MACROPHAGES.

7176
04:20:09,460 --> 04:20:10,795
WHEN YOU INFECT ANIMALS

7177
04:20:10,795 --> 04:20:12,730
VACCINATED YOU SEE ALL OF A

7178
04:20:12,730 --> 04:20:16,701
SUDDEN THIS BLOCK COMING UP

7179
04:20:16,701 --> 04:20:18,803
WHICH ARE CYCLIC POSITIVE CELLS

7180
04:20:18,803 --> 04:20:20,972
CD 11 NEGATIVE.

7181
04:20:20,972 --> 04:20:23,908
ALL MACROPHAGES ARE POSITIVE,

7182
04:20:23,908 --> 04:20:25,510
THIS IS NOT THEORETICALLY AN

7183
04:20:25,510 --> 04:20:26,477
ALVEOLAR MACROPHAGE BASED ON

7184
04:20:26,477 --> 04:20:27,145
SURFACE MARKERS.

7185
04:20:27,145 --> 04:20:31,349
WE THOUGHT MAYBE THESE ARE

7186
04:20:31,349 --> 04:20:32,650
MONOCYTES INFILTRATING AND

7187
04:20:32,650 --> 04:20:34,419
THEREFORE UPREGULATE CYCLIC F,

7188
04:20:34,419 --> 04:20:45,029
MAYBE STILL IN THE PROCESS  PROF

7189
04:20:48,499 --> 04:20:50,201
UPREGULATING CD11C.

7190
04:20:50,201 --> 04:20:53,705
WE CHECKED SURFACE MARKERS, IN

7191
04:20:53,705 --> 04:20:54,672
THE LUNGS, BASICALLY

7192
04:20:54,672 --> 04:20:55,540
EOSINOPHILS.

7193
04:20:55,540 --> 04:21:00,244
SO WHAT WE SAW IS HERE YOU SEE

7194
04:21:00,244 --> 04:21:01,012
FOLLOWING THE CELL POPULATIONS

7195
04:21:01,012 --> 04:21:04,415
IN THE LUNGS AT ONCE.

7196
04:21:04,415 --> 04:21:07,485
IN SALMON ARE THE MACROPHAGES, I

7197
04:21:07,485 --> 04:21:10,421
PUT A BOX AROUND THE EXPECTED

7198
04:21:10,421 --> 04:21:11,489
EOSINOPHILS.

7199
04:21:11,489 --> 04:21:12,624
IN ANIMALS THAT GET NO VACCINE

7200
04:21:12,624 --> 04:21:17,228
AND NO CHALLENGE YOU GET THE

7201
04:21:17,228 --> 04:21:19,497
ALVEOLAR MACROPHAGE BUT NO

7202
04:21:19,497 --> 04:21:19,797
EOSINOPHILS.

7203
04:21:19,797 --> 04:21:20,632
SAME WITHOUT CHALLENGE.

7204
04:21:20,632 --> 04:21:23,001
IF YOU CHALLENGE WITHOUT VACCINE

7205
04:21:23,001 --> 04:21:24,402
THEY LOSE ALVEOLAR MACROPHAGES,

7206
04:21:24,402 --> 04:21:27,071
YOU DON'T SEE MUCH CHANGE IN THE

7207
04:21:27,071 --> 04:21:29,040
EOSINOPHIL COMPARTMENT, YOU SEE

7208
04:21:29,040 --> 04:21:29,774
DARK BLUE INFLAMMATORY MONOCYTES

7209
04:21:29,774 --> 04:21:30,375
COMING IN.

7210
04:21:30,375 --> 04:21:34,212
IF YOU VACCINATE AND CHALLENGE,

7211
04:21:34,212 --> 04:21:36,314
YOU SEE A LOT OF EOSINOPHILS,

7212
04:21:36,314 --> 04:21:37,615
MACROPHAGES ARE STILL SAVED.

7213
04:21:37,615 --> 04:21:38,950
IF YOU VACCINATE THREE TIMES,

7214
04:21:38,950 --> 04:21:41,352
WHICH MEANS THEY GOT THE

7215
04:21:41,352 --> 04:21:45,556
STERILIZING IMMUNITY, YOU GET

7216
04:21:45,556 --> 04:21:50,962
EVEN MORE EOSINOPHILS. 

7217
04:21:50,962 --> 04:21:54,265
VACCINATION PERIPHERY RESULTS IN

7218
04:21:54,265 --> 04:21:55,933
EOSINOPHIL IN THE LUNGS, IF YOU

7219
04:21:55,933 --> 04:21:59,537
VACCINATE MORE YOU GET MORE

7220
04:21:59,537 --> 04:22:00,071
EOSINOPHILS.

7221
04:22:00,071 --> 04:22:04,742
PREVIOUS INFECTION DOES NOT

7222
04:22:04,742 --> 04:22:05,476
RESULT IN EOSINOPHIL INFLUX,

7223
04:22:05,476 --> 04:22:08,346
VACCINATION IN THE MUSCLE THAT

7224
04:22:08,346 --> 04:22:09,714
TRIGGERS THIS EOSINOPHIL INFLUX

7225
04:22:09,714 --> 04:22:11,582
IN THE LUNGS.

7226
04:22:11,582 --> 04:22:16,354
SO THEN WE CONFIRMED THIS IN

7227
04:22:16,354 --> 04:22:18,823
ANOTHER MOUSE BACKGROUND, THIS

7228
04:22:18,823 --> 04:22:20,858
IS SIX MICE, WE VACCINATE MICE

7229
04:22:20,858 --> 04:22:25,396
IN THE PREVIOUS VACCINE STUDY WE

7230
04:22:25,396 --> 04:22:27,165
USED ADJUVANT, IN THIS CASE DID

7231
04:22:27,165 --> 04:22:31,602
NOT USAGE  -- USE THE ADJUVANT.

7232
04:22:31,602 --> 04:22:32,904
VACCINE PLUS CHALLENGE HAVE MORE

7233
04:22:32,904 --> 04:22:35,039
EOSINOPHILS COMING INTO THE

7234
04:22:35,039 --> 04:22:36,441
LUNGS, ANIMALS WITHOUT VACCINE

7235
04:22:36,441 --> 04:22:38,309
THEY HAVE NO EOSINOPHILS COMING

7236
04:22:38,309 --> 04:22:43,548
IN THE LUNGS.

7237
04:22:43,548 --> 04:22:45,283
THIS INFLUX, EOSINOPHIL INFLUX

7238
04:22:45,283 --> 04:22:46,718
IS ALSO ASSOCIATED WITH TYPE 2

7239
04:22:46,718 --> 04:22:48,686
CYTOKINE RESPONSE IN THE LUNGS

7240
04:22:48,686 --> 04:22:53,658
OF VACCINATED MICE SO IT GETS

7241
04:22:53,658 --> 04:22:55,760
CLASSICAL SUSPECTS LIKE IL-4, 5,

7242
04:22:55,760 --> 04:22:57,662
13, CYTOKINES THAT ARE TYPICAL

7243
04:22:57,662 --> 04:23:02,567
FOR TYPE 2 IMMUNE RESPONSE.

7244
04:23:02,567 --> 04:23:05,837
BASICALLY WE SAW THIS

7245
04:23:05,837 --> 04:23:06,537
INTRAMUSCULAR VACCINATION

7246
04:23:06,537 --> 04:23:12,744
RESULTS IN EOSINOPHIL  INFLUX IN

7247
04:23:12,744 --> 04:23:15,379
BREAKTHROUGH AND STERILIZING

7248
04:23:15,379 --> 04:23:19,417
IMMUNITY, TWO GENETIC

7249
04:23:19,417 --> 04:23:21,185
BACKGROUNDS, BLACK 6 AND BALB/C,

7250
04:23:21,185 --> 04:23:23,921
CORRELATES WITH PROTECTION, NOT

7251
04:23:23,921 --> 04:23:27,091
ENHANCED DISEASE, BUT IMPACT

7252
04:23:27,091 --> 04:23:29,494
DRIVERS OF EOSINOPHIL INFLUX IS

7253
04:23:29,494 --> 04:23:30,161
NOT KNOWN.

7254
04:23:30,161 --> 04:23:32,330
EOSINOPHILS IN THE LUNGS ARE

7255
04:23:32,330 --> 04:23:35,399
INTERESTING AND IN THE FIELD OF

7256
04:23:35,399 --> 04:23:36,801
RESPIRATORY VIRUSES TYPICALLY

7257
04:23:36,801 --> 04:23:39,971
ASSOCIATED DOGMATICALLY CLASS

7258
04:23:39,971 --> 04:23:42,273
FIGHT AS PATHOLOGICAL SYMPTOMS

7259
04:23:42,273 --> 04:23:44,375
LIKE FROM DURING RSV INFECTION,

7260
04:23:44,375 --> 04:23:47,111
CONSIDERED SOMETHING THAT THEY

7261
04:23:47,111 --> 04:23:49,046
DON'T WANT, VACCINE-ASSOCIATED

7262
04:23:49,046 --> 04:23:50,515
ENHANCEMENT OF RESPIRATORY

7263
04:23:50,515 --> 04:23:54,252
DISEASE IS ASSOCIATED WITH

7264
04:23:54,252 --> 04:23:55,686
EOSINOPHIL INFLUKES AND ALLERGIC

7265
04:23:55,686 --> 04:23:56,654
ASTHMA THERE'S A LOT OF

7266
04:23:56,654 --> 04:23:58,756
EOSINOPHILS COMING IN.

7267
04:23:58,756 --> 04:24:00,057
HOWEVER, IF WE THINK OUTSIDE OF

7268
04:24:00,057 --> 04:24:02,593
THIS FIELD OF RESPIRATORY

7269
04:24:02,593 --> 04:24:03,761
VIRUSES AND RESPIRATORY

7270
04:24:03,761 --> 04:24:06,230
DISEASES, EOSINOPHILS ARE ALSO

7271
04:24:06,230 --> 04:24:09,367
INVOLVED IN PROTECTIVE RESPONSES

7272
04:24:09,367 --> 04:24:11,469
AGAINST HELMINTHS AND IMPORTANT

7273
04:24:11,469 --> 04:24:13,504
FOR TISSUE REPAIR, SOMETHING

7274
04:24:13,504 --> 04:24:15,039
THAT WOULD ALSO OCCUR DURING

7275
04:24:15,039 --> 04:24:15,606
RESPIRATORY INFECTION IF YOU

7276
04:24:15,606 --> 04:24:19,744
HAVE A LOT OF DAMAGE IN THE

7277
04:24:19,744 --> 04:24:20,244
LUNGS.

7278
04:24:20,244 --> 04:24:21,546
SO BECAUSE WE THOUGHT THIS WAS

7279
04:24:21,546 --> 04:24:23,181
INTERESTING, ONE OF MY STUDENTS

7280
04:24:23,181 --> 04:24:33,791
WHO USED TO WORK IN RSV GOT 

7281
04:24:33,791 --> 04:24:38,029
FASCINATED AND WROTE A REVIEW ON

7282
04:24:38,029 --> 04:24:41,199
THE FUNCTIONS.

7283
04:24:41,199 --> 04:24:42,967
YOU'LL FIND SOME OVERVIEW OF THE

7284
04:24:42,967 --> 04:24:44,302
FUNCTIONS OF EOSINOPHILS AND

7285
04:24:44,302 --> 04:24:46,938
IT'S NOT ALWAYS ASSOCIATED WITH

7286
04:24:46,938 --> 04:24:47,305
PATHOLOGY.

7287
04:24:47,305 --> 04:24:50,208
WE ALSO SAW THIS ACTUALLY IN

7288
04:24:50,208 --> 04:24:52,343
OTHER RESPIRATORY VIRUS MODELS.

7289
04:24:52,343 --> 04:24:56,180
FOR EXAMPLE WHEN WE DID

7290
04:24:56,180 --> 04:24:57,215
SARS-COV-2 IN HAMSTERS DID

7291
04:24:57,215 --> 04:24:59,784
RNAseq ON LUNGS OF HAMSTERS

7292
04:24:59,784 --> 04:25:06,057
THAT GOT OPTIMAL DOSE OF PFIZER

7293
04:25:06,057 --> 04:25:07,992
mRNA VACCINE AND CHALLENGED

7294
04:25:07,992 --> 04:25:10,761
WITH VIRUSES AND CAUSED

7295
04:25:10,761 --> 04:25:12,964
BREAKTHROUGH INFECTIONS, AND

7296
04:25:12,964 --> 04:25:17,568
COULD SEE USING THE ALGORITHM,

7297
04:25:17,568 --> 04:25:19,170
TRANSCRIPTOME, EOSINOPHILS WERE

7298
04:25:19,170 --> 04:25:21,272
SEEN WITH BREAKTHROUGH INFECTION

7299
04:25:21,272 --> 04:25:24,242
IN VACCINATED ANIMALS WHICH ARE

7300
04:25:24,242 --> 04:25:27,378
DARK BOX PLOTS.

7301
04:25:27,378 --> 04:25:28,813
IN SARS-COV-2 CHALLENGE AND

7302
04:25:28,813 --> 04:25:30,882
MEHUL WILL TELL YOU MORE WE ALSO

7303
04:25:30,882 --> 04:25:32,950
SAW WITH TYPE 2 RESPONSE IN

7304
04:25:32,950 --> 04:25:35,586
VACCINATED ANIMALS WHEN THEY

7305
04:25:35,586 --> 04:25:36,754
RECEIVED RECOMBINANT SPIKE

7306
04:25:36,754 --> 04:25:38,689
PROTEIN WITH ADJUVANT GIVEN IN

7307
04:25:38,689 --> 04:25:45,663
THE MUSCLE BASICALLY IL-4, 5,

7308
04:25:45,663 --> 04:25:47,565
13, AND EOTAX IN.

7309
04:25:47,565 --> 04:25:50,601
WE DIDN'T SEE THIS PROFILE IN

7310
04:25:50,601 --> 04:25:54,505
LUNGS ININFECTED ANIMALS WHEN

7311
04:25:54,505 --> 04:25:56,507
GIVEN INTRANASAL THROUGH MUCOSAL

7312
04:25:56,507 --> 04:25:57,808
SITES WITH MUCOSAL ADJUVANTS.

7313
04:25:57,808 --> 04:26:00,011
I WON'T GO INTO THAT.

7314
04:26:00,011 --> 04:26:03,314
THIS IS SOON TO BE PUBLISHED AS

7315
04:26:03,314 --> 04:26:06,050
WELL AND AVAILABLE AS PRE-PRINT.

7316
04:26:06,050 --> 04:26:08,352
WE FOCUS ON OTHER HOST RESPONSES

7317
04:26:08,352 --> 04:26:11,088
TO INFECTION THAT ARE OCCURRING

7318
04:26:11,088 --> 04:26:13,925
LONGER AFTER INFECTION, AND

7319
04:26:13,925 --> 04:26:15,826
FIRST ONE IS GERMINAL CENTER B

7320
04:26:15,826 --> 04:26:18,729
CELLS IN THE LUNGS, AND

7321
04:26:18,729 --> 04:26:23,434
PERIBELONGAL LIMP NOTES  -- LYMH

7322
04:26:23,434 --> 04:26:27,972
NODES 24 DAYS POST INFECTION. 

7323
04:26:27,972 --> 04:26:32,710
WE TOOK THE LYMPH NODES 24 DAYS

7324
04:26:32,710 --> 04:26:34,211
AND MEASURED GERMINAL CENTER B

7325
04:26:34,211 --> 04:26:38,749
CELLS IN THE LUNGS MEASURED

7326
04:26:38,749 --> 04:26:42,353
OUTSIDE LYMPH NODES, WHAT YOU

7327
04:26:42,353 --> 04:26:44,622
CAN SEE HERE IS GL 7 WE CAN

7328
04:26:44,622 --> 04:26:47,325
STAIN ON B CELLS IN THE LUNGS

7329
04:26:47,325 --> 04:26:50,161
CLOSE TO THE BRONCHUS.

7330
04:26:50,161 --> 04:26:52,563
WHY ARE THEY INTERESTING?

7331
04:26:52,563 --> 04:26:54,765
THEY CORRELATE WITH IMMUNITY AND

7332
04:26:54,765 --> 04:26:58,169
CAN ALSO BE SOURCES OF DE NOVO

7333
04:26:58,169 --> 04:26:59,603
ANTIBODY RESPONSES IN THE LUNGS.

7334
04:26:59,603 --> 04:27:02,206
AND SO WHEN WE CHECK THESE

7335
04:27:02,206 --> 04:27:03,007
LEVELS OF GERMINAL CENTERS IN

7336
04:27:03,007 --> 04:27:05,609
THE LUNGS IN VACCINATED AN

7337
04:27:05,609 --> 04:27:12,950
UNVACCINATED ANIMALS YOU CAN SEE

7338
04:27:12,950 --> 04:27:14,118
TIV VACCINATION INTERFERENCE,

7339
04:27:14,118 --> 04:27:15,886
THEY ARE NICELY INDUCED IN

7340
04:27:15,886 --> 04:27:16,854
INFECTS THE ANIMALS WITHOUT

7341
04:27:16,854 --> 04:27:17,154
VACCINATION.

7342
04:27:17,154 --> 04:27:19,056
WHEN YOU LOOK IN THE GERMINAL

7343
04:27:19,056 --> 04:27:20,558
CENTERS IN THE LYMPH NODES YOU

7344
04:27:20,558 --> 04:27:23,928
CAN SEE VACCINATION IS

7345
04:27:23,928 --> 04:27:24,562
DEFINITELY NOT INHIBITING THIS,

7346
04:27:24,562 --> 04:27:25,763
CONTRARY IF YOU VACCINATE THREE

7347
04:27:25,763 --> 04:27:28,332
TIMES YOU GET MORE GERMINAL

7348
04:27:28,332 --> 04:27:32,503
CENTERS AFTER INFECTION IN THE

7349
04:27:32,503 --> 04:27:35,873
PERIBRONCHIAL LYMPH NODES.

7350
04:27:35,873 --> 04:27:38,476
WE LOOKED AT TISSUE RESIDENT

7351
04:27:38,476 --> 04:27:40,745
MEMORY T CELLS, THEY CAN

7352
04:27:40,745 --> 04:27:45,182
RECOGNIZE COULD BE SERVED

7353
04:27:45,182 --> 04:27:46,384
EPITOPES, PROVIDE IMMUNITY AND

7354
04:27:46,384 --> 04:27:48,586
WE KNOW THEY ARE TISSUE

7355
04:27:48,586 --> 04:27:50,321
RESIDENTS BECAUSE WE FOCUS ON

7356
04:27:50,321 --> 04:27:52,289
CELL SURFACE MARKERS, YOU CAN

7357
04:27:52,289 --> 04:27:54,792
EXCLUDE BY IV LABELING AND ALSO

7358
04:27:54,792 --> 04:27:59,830
HERE YOU CAN SEE TIV VACCINATION

7359
04:27:59,830 --> 04:28:00,598
INTERFERES WITH INDUCTION AFTER

7360
04:28:00,598 --> 04:28:04,568
INFECTION, YOU GET VERY NICELY

7361
04:28:04,568 --> 04:28:06,670
IN MICE NOT VACCINATED.

7362
04:28:06,670 --> 04:28:11,242
SO NOW WE CAN LOOK AT HOST

7363
04:28:11,242 --> 04:28:13,377
RESPONSE DURING INFECTION WITH X

7364
04:28:13,377 --> 04:28:16,013
31 VIRUS, THE PROTECTION YOU CAN

7365
04:28:16,013 --> 04:28:16,614
SEE.

7366
04:28:16,614 --> 04:28:17,982
BASICALLY ANIMALS THAT GOT VERY

7367
04:28:17,982 --> 04:28:24,755
SICK THE FIRST TIME ARE FULLY

7368
04:28:24,755 --> 04:28:26,424
PROTECTED DURING REINFLECTION.

7369
04:28:26,424 --> 04:28:29,927
ANIMALS NOT VACCINATED THE FIRST

7370
04:28:29,927 --> 04:28:31,996
TIME COME TO THE H INFECTION BY

7371
04:28:31,996 --> 04:28:32,897
DAY 7.

7372
04:28:32,897 --> 04:28:34,331
ANIMALS WITH VACCINE WITHOUT

7373
04:28:34,331 --> 04:28:36,967
CHALLENGE SOME ARE PROTECTED AND

7374
04:28:36,967 --> 04:28:38,903
THEY RECOVER BY DAY 6, 7.

7375
04:28:38,903 --> 04:28:40,571
SOME WE LOSE.

7376
04:28:40,571 --> 04:28:43,107
THEN ANIMALS THAT RECEIVE ONE OR

7377
04:28:43,107 --> 04:28:43,841
THREE VACCINATIONS PLUS

7378
04:28:43,841 --> 04:28:45,876
INFECTION, THEY STILL LOSE MORE

7379
04:28:45,876 --> 04:28:47,178
BODY WEIGHT THAN ANIMALS THAT

7380
04:28:47,178 --> 04:28:48,679
GOT VERY SICK THE FIRST TIME BUT

7381
04:28:48,679 --> 04:28:51,215
START TO RECOVER EARLY ON BY DAY

7382
04:28:51,215 --> 04:28:51,949
4.

7383
04:28:51,949 --> 04:28:55,086
THIS IS ALSO REFLECTED IN THE

7384
04:28:55,086 --> 04:28:58,222
LUNG HOMOGENOUS WHEN WE CHECK

7385
04:28:58,222 --> 04:28:59,557
VIRUS TITERS, ANIMALS THAT GOT

7386
04:28:59,557 --> 04:29:02,026
SICK FIRST TIME AFTER INFECTION,

7387
04:29:02,026 --> 04:29:04,628
WELL THEY CONTROL THE H3N2 VIRUS

7388
04:29:04,628 --> 04:29:06,230
DURING INFECTION COMPLETELY, ALL

7389
04:29:06,230 --> 04:29:08,432
THE OTHER GROUPS INCLUDING TIV

7390
04:29:08,432 --> 04:29:10,401
AND TRIPLE TIV MICE THAT

7391
04:29:10,401 --> 04:29:11,802
RECEIVED INFECTION THEY STILL

7392
04:29:11,802 --> 04:29:14,105
HAVE VIRUS IN THEIR LUNGS.

7393
04:29:14,105 --> 04:29:16,740
AND ALSO I HAVE TO SAY THAT

7394
04:29:16,740 --> 04:29:20,811
THESE ARE THE MICE THAT HAVE THE

7395
04:29:20,811 --> 04:29:22,012
TRMs AND GERMINAL CENTER B

7396
04:29:22,012 --> 04:29:23,214
CELLS, THESE ARE MICE THAT DO

7397
04:29:23,214 --> 04:29:24,615
NOT HAVE THESE BECAUSE OF

7398
04:29:24,615 --> 04:29:24,915
VACCINATION.

7399
04:29:24,915 --> 04:29:27,218
SO THEN WE TAKE THE BLOOD FROM

7400
04:29:27,218 --> 04:29:29,420
THESE MICE AND WE'RE GOING TO

7401
04:29:29,420 --> 04:29:32,256
CHECK THAT IT'S DIFFERENCES IN

7402
04:29:32,256 --> 04:29:33,457
CROSS-REACTIVITY IN SERUM OF

7403
04:29:33,457 --> 04:29:33,924
THESE MICE.

7404
04:29:33,924 --> 04:29:43,000
TO DO THIS WE DID A KIND OF IN

7405
04:29:43,000 --> 04:29:49,540
VITRO/IN VIVO MICRO

7406
04:29:49,540 --> 04:29:51,542
NEUTRALIZATION ASSAY.

7407
04:29:51,542 --> 04:29:54,278
WE USED THESE IMMUNE COMPLEXES

7408
04:29:54,278 --> 04:29:56,113
TO KIND OF INFECT NAIVE MICE AND

7409
04:29:56,113 --> 04:30:00,451
SEE HOW MUCH THEY WERE PROTECTED

7410
04:30:00,451 --> 04:30:02,186
AGAINST DISEASE FROM H3N2

7411
04:30:02,186 --> 04:30:02,620
CHALLENGE.

7412
04:30:02,620 --> 04:30:04,188
WE SEE THE OPPOSITE PROTECTION

7413
04:30:04,188 --> 04:30:05,990
THAT WE SAW IN THE PREVIOUS

7414
04:30:05,990 --> 04:30:06,724
SLIDES.

7415
04:30:06,724 --> 04:30:08,959
SO MICE THAT GOT VIRUS THAT WAS

7416
04:30:08,959 --> 04:30:11,529
INCUBATED WITH SERUM FROM NAIVE

7417
04:30:11,529 --> 04:30:14,431
MICE OR SERUM FROM MICE WITHOUT

7418
04:30:14,431 --> 04:30:20,237
CHALLENGE OR RECEIVED SERUM FROM

7419
04:30:20,237 --> 04:30:21,672
MILES THAT RECEIVED H1N1 WITH NO

7420
04:30:21,672 --> 04:30:24,041
VACCINATION DIED, ALL THE MICE

7421
04:30:24,041 --> 04:30:26,210
THAT RECEIVED VIRUS INCUBATED

7422
04:30:26,210 --> 04:30:29,947
WITH TIV PLUS NEW CALEDONIA

7423
04:30:29,947 --> 04:30:30,948
CHALLENGE ALL WERE PROTECTED

7424
04:30:30,948 --> 04:30:33,117
FROM SEVERE DISEASE DURING THIS

7425
04:30:33,117 --> 04:30:34,151
H3N2 CHALLENGE.

7426
04:30:34,151 --> 04:30:36,654
BASICALLY WHAT WE SAW WAS

7427
04:30:36,654 --> 04:30:38,022
COMBINATION OF TIV VACCINATION

7428
04:30:38,022 --> 04:30:40,824
FOLLOWED BY NC 99 CHALLENGE WAS

7429
04:30:40,824 --> 04:30:43,527
REQUIRED TO HAVE PROTECTED

7430
04:30:43,527 --> 04:30:43,727
SERUM.

7431
04:30:43,727 --> 04:30:46,330
THIS MEANS BECAUSE THE MICE THAT

7432
04:30:46,330 --> 04:30:49,366
RECEIVED PBS WITHOUT, SO NO

7433
04:30:49,366 --> 04:30:51,268
VACCINE PLUS NEW CALEDONIA

7434
04:30:51,268 --> 04:30:53,270
CHALLENGE WAS NOT PROTECTED,

7435
04:30:53,270 --> 04:30:55,839
THIS MEANS PROTECTION FROM TIV

7436
04:30:55,839 --> 04:31:00,778
PLUS NEW CALEDONIA CHALLENGE

7437
04:31:00,778 --> 04:31:02,112
RELYING MORE ON ANTIBODIES

7438
04:31:02,112 --> 04:31:05,816
RATHER THAN B CELLS OR MUCOSAL.

7439
04:31:05,816 --> 04:31:09,153
WHAT MAKES THIS HYBRID IMMUNE

7440
04:31:09,153 --> 04:31:10,120
SERA, FROM INFECTION AND

7441
04:31:10,120 --> 04:31:14,491
VACCINATION TOGETHER,  BETTER

7442
04:31:14,491 --> 04:31:20,264
COMPARED TO CONVALESCENT SERUM? 

7443
04:31:20,264 --> 04:31:21,599
MORE CROSS-REACTIVE ANTIBODIES,

7444
04:31:21,599 --> 04:31:23,200
HOW CAN WE INDUCE BY VACCINATION

7445
04:31:23,200 --> 04:31:26,737
OR HOW CAN WE INDUCE AND TARGET

7446
04:31:26,737 --> 04:31:29,873
IBALT AND TRMs WITH MUCOSAL

7447
04:31:29,873 --> 04:31:31,008
VACCINES.

7448
04:31:31,008 --> 04:31:33,210
THEN WE STILL HAVE THE INNATE

7449
04:31:33,210 --> 04:31:36,747
IMMUNITY THAT I DIDN'T ADDRESS

7450
04:31:36,747 --> 04:31:36,981
YET.

7451
04:31:36,981 --> 04:31:38,182
SO, EVERYBODY KNOWS INFECTION

7452
04:31:38,182 --> 04:31:43,387
WILL RESULT IN INNATE IMMUNE

7453
04:31:43,387 --> 04:31:47,491
RESPONSES SHORT-LIVED. 

7454
04:31:47,491 --> 04:31:49,460
HOWEVER, THERE'S MORE EVIDENCE

7455
04:31:49,460 --> 04:31:51,328
FOR INNATE RESPONSES, SO WHAT WE

7456
04:31:51,328 --> 04:31:52,796
WANTED TO CHECK IF THERE WAS

7457
04:31:52,796 --> 04:31:56,800
STILL KIND OF A CHANGE INNATE

7458
04:31:56,800 --> 04:31:58,202
RESPONSIVENESS BY 28 DAYS POST

7459
04:31:58,202 --> 04:31:59,670
FIRST INFECTION.

7460
04:31:59,670 --> 04:32:02,172
THIS IS FOUR WEEKS AFTER THE

7461
04:32:02,172 --> 04:32:03,274
H1N1 INFECTION.

7462
04:32:03,274 --> 04:32:05,409
WE DID THIS EXPERIMENT WHERE WE

7463
04:32:05,409 --> 04:32:06,910
INFECTED MICE OR GIVE THEM A

7464
04:32:06,910 --> 04:32:08,545
MOCK CHALLENGE.

7465
04:32:08,545 --> 04:32:11,615
FOUR WEEKS LATER TOOK THE

7466
04:32:11,615 --> 04:32:13,584
BRONCHIAL ALVEOLAR LAVAGE AND

7467
04:32:13,584 --> 04:32:16,887
CHECKED ESPECIALLY THE ALVEOLAR

7468
04:32:16,887 --> 04:32:19,657
MACROPHAGE COMPARTMENT, I'VE

7469
04:32:19,657 --> 04:32:22,760
SHOWN INFECTION CAN DEPLETE THE

7470
04:32:22,760 --> 04:32:25,763
MACROPHAGES AND THEY COME BACK.

7471
04:32:25,763 --> 04:32:27,131
WE SAW PHENOTYPIC CHANGES ON

7472
04:32:27,131 --> 04:32:31,068
MACROPHAGES OF MICE THAT WENT

7473
04:32:31,068 --> 04:32:31,535
THROUGH INFECTION.

7474
04:32:31,535 --> 04:32:33,237
THEY HAVE HIGH EXPRESSION BUT

7475
04:32:33,237 --> 04:32:36,740
ALSO THEY HAVE LOWER CYCLIC F

7476
04:32:36,740 --> 04:32:37,708
EXPRESSION, AT LEAST POPULATION

7477
04:32:37,708 --> 04:32:38,042
LIKE THIS.

7478
04:32:38,042 --> 04:32:41,078
THIS IS SOMETHING THAT HAS BEEN

7479
04:32:41,078 --> 04:32:42,246
DESCRIBED BEFORE IN OTHER

7480
04:32:42,246 --> 04:32:44,748
STUDIES. 

7481
04:32:44,748 --> 04:32:47,651
FOR EXAMPLE THIS STUDY FROM

7482
04:32:47,651 --> 04:32:50,754
MISHARIN, SORRY IF I SAY IT

7483
04:32:50,754 --> 04:32:53,957
WRONG, TYPICALLY ALVEOLAR 

7484
04:32:53,957 --> 04:32:55,659
MACROPHAGES THAT COME INTO THE

7485
04:32:55,659 --> 04:32:57,428
LUNGS AND THEN BECOME RESIDENTS,

7486
04:32:57,428 --> 04:33:00,931
THIS WAS FIRST DESCRIBED IN

7487
04:33:00,931 --> 04:33:04,501
FIBROSIS MODEL WHERE THEY INDUCE

7488
04:33:04,501 --> 04:33:04,768
FIBROSIS.

7489
04:33:04,768 --> 04:33:08,238
THIS IS ALSO SUGGESTED FOR

7490
04:33:08,238 --> 04:33:09,473
TRAINED IMMUNITY WHERE PEOPLE

7491
04:33:09,473 --> 04:33:11,542
CLAIM ALVEOLAR MACRO FEIGNS CAN

7492
04:33:11,542 --> 04:33:13,377
BE TRAINED BY FIRST FLU

7493
04:33:13,377 --> 04:33:16,914
INFECTION AND HAVE DIFFERENT

7494
04:33:16,914 --> 04:33:19,950
MARKERS OF EXPRESSION, HOWEVER

7495
04:33:19,950 --> 04:33:21,051
THERE'S A GOOD DOCUMENTARY

7496
04:33:21,051 --> 04:33:22,686
RECENTLY WHERE THEY SAY WE HAVE

7497
04:33:22,686 --> 04:33:25,556
TO BE VERY CAREFUL WHEN WE STUDY

7498
04:33:25,556 --> 04:33:28,926
TRAINED IMMUNITY INDUCED BY FLU

7499
04:33:28,926 --> 04:33:32,930
IN THE LUNGS BECAUSE HAVE YOU

7500
04:33:32,930 --> 04:33:34,932
ALVEOLAR MACROPHAGES THAT MIGHT

7501
04:33:34,932 --> 04:33:35,966
GET TRAINED, INFLAMMATORY

7502
04:33:35,966 --> 04:33:38,869
MONOCYTES BECOME RESIDENT AND

7503
04:33:38,869 --> 04:33:39,436
THEREFORE HAVE DIFFERENT

7504
04:33:39,436 --> 04:33:40,771
PHENOTYPE, NOT PERCEIVED OR

7505
04:33:40,771 --> 04:33:44,375
TRAINED BY THE FIRST FLU

7506
04:33:44,375 --> 04:33:46,043
INFECTION.

7507
04:33:46,043 --> 04:33:48,879
SINGLE CELL RNA SYNC ON BALT

7508
04:33:48,879 --> 04:33:51,682
FLUIDS IN THESE MICE TO SEE

7509
04:33:51,682 --> 04:33:53,851
COMPOSITION AND REMODELING IF

7510
04:33:53,851 --> 04:33:55,619
FIRST FLU INFECTION.

7511
04:33:55,619 --> 04:33:58,355
BY SINGLE CELL RNA-SEQ CAN

7512
04:33:58,355 --> 04:34:03,093
DISCRIMINATE IMMUNE CELLS IN THE

7513
04:34:03,093 --> 04:34:05,195
BALF FLUID, WE DEFINE UP TO SIX

7514
04:34:05,195 --> 04:34:06,296
MACROPHAGES CLUSTERS AS WELL AS

7515
04:34:06,296 --> 04:34:08,766
B CELLS AND T CELLS THAT BECAME

7516
04:34:08,766 --> 04:34:10,701
RESIDENT AFTER FIRST INFECTION.

7517
04:34:10,701 --> 04:34:12,836
YOU CAN SEE INFECTION OR MOCK

7518
04:34:12,836 --> 04:34:14,571
CHALLENGE WILL GIVE DIFFERENT

7519
04:34:14,571 --> 04:34:16,774
PROPORTIONS OF DIFFERENT

7520
04:34:16,774 --> 04:34:23,881
MACROPHAGES SUBSETS AS WELL AS T

7521
04:34:23,881 --> 04:34:24,214
CELLS.

7522
04:34:24,214 --> 04:34:28,152
WE WONDERED IF THIS LUNG

7523
04:34:28,152 --> 04:34:29,486
REMODELING BY INFECTION WHICH

7524
04:34:29,486 --> 04:34:33,724
H1N1 CAN BE PROTECTIVE OR NOT,

7525
04:34:33,724 --> 04:34:35,793
CAN IT AFFECT OUTCOME WITH FLU

7526
04:34:35,793 --> 04:34:40,964
B, AND WHY WE TAKE FLU B?

7527
04:34:40,964 --> 04:34:44,034
INFLUENZA A AND B ARE

7528
04:34:44,034 --> 04:34:45,235
ANTIGENICALLY UNRELATED.

7529
04:34:45,235 --> 04:34:46,970
WE INFECTED ANIMALS WITH H1N1 OR

7530
04:34:46,970 --> 04:34:51,175
GIVE THEM MOCK CHALLENGE, WAIT

7531
04:34:51,175 --> 04:34:54,812
FOUR WEEKS, REINFECTED WITH

7532
04:34:54,812 --> 04:34:56,613
B/MAR FROM 2004 CHALLENGED WITH

7533
04:34:56,613 --> 04:35:04,188
THREE DOSES, IF YOU GIVE 520 PFU

7534
04:35:04,188 --> 04:35:05,355
THERE'S SOME PROTECTIVE EFFECT

7535
04:35:05,355 --> 04:35:07,758
FROM PREVIOUS H1N1 SO ANIMALS

7536
04:35:07,758 --> 04:35:10,527
THAT RECEIVED H1N1 FIRST THEY

7537
04:35:10,527 --> 04:35:12,396
LOSE TYPICALLY 10% LESS BODY

7538
04:35:12,396 --> 04:35:14,598
WEIGHT COMPARED TO NAIVE

7539
04:35:14,598 --> 04:35:19,603
ANIMALS. 

7540
04:35:19,603 --> 04:35:22,873
WHEN WE GIVE 2500 PFU IT'S

7541
04:35:22,873 --> 04:35:24,741
BIGGER.

7542
04:35:24,741 --> 04:35:25,943
10,000 PFU YOU STILL CAN KILL

7543
04:35:25,943 --> 04:35:29,313
MOST OF THE ANIMALS ONLY ONE

7544
04:35:29,313 --> 04:35:31,281
MOUSE WILL SURVIVE DESPITE

7545
04:35:31,281 --> 04:35:31,682
HAVING H1N1 FIRST.

7546
04:35:31,682 --> 04:35:32,716
THERE'S SOME PROTECTION FROM

7547
04:35:32,716 --> 04:35:35,919
FIRST INFECTION, YOU CAN STILL

7548
04:35:35,919 --> 04:35:36,553
OVERRULE IF YOU GIVE ENOUGH

7549
04:35:36,553 --> 04:35:46,563
VIRUS OF THE WE WANTED TO KNOW

7550
04:35:46,563 --> 04:35:48,432
IF CD 11+ CELLS ARE PROTECTED.

7551
04:35:48,432 --> 04:35:50,067
WE TRIED TO TRANSFER BY

7552
04:35:50,067 --> 04:35:52,102
TRANSFERRING CELLS FROM ANIMALS

7553
04:35:52,102 --> 04:35:53,871
THAT GOT NC 99 CHALLENGE OR MOCK

7554
04:35:53,871 --> 04:35:55,873
CHALLENGE.

7555
04:35:55,873 --> 04:36:00,744
SO THEREFORE WE COLLECTED

7556
04:36:00,744 --> 04:36:02,946
POSITIVE CELLS FROM BALF FLUIDS,

7557
04:36:02,946 --> 04:36:04,281
TRANSFERRED INTO NAIVE MICE,

7558
04:36:04,281 --> 04:36:08,252
CHALLENGED WITH B VIRUS 24 HOURS

7559
04:36:08,252 --> 04:36:10,354
LATER, FOLLOWED 14 DAYS TO

7560
04:36:10,354 --> 04:36:12,923
MONITOR FOR MORBIDITY AND

7561
04:36:12,923 --> 04:36:13,524
MORTALITY.

7562
04:36:13,524 --> 04:36:18,161
WE CAN SEE THAT CD11+ CELLS CAN

7563
04:36:18,161 --> 04:36:19,796
PROVIDE FULL PROTECTION AGAINST

7564
04:36:19,796 --> 04:36:22,566
THE B VIRUS INFECTION.

7565
04:36:22,566 --> 04:36:24,535
ANIMALS THAT RECEIVED CD11 CELLS

7566
04:36:24,535 --> 04:36:27,237
IN MICE MOCK CHALLENGED, SO THEY

7567
04:36:27,237 --> 04:36:29,773
LOSE 50% OF THE MICE AFTER B

7568
04:36:29,773 --> 04:36:32,543
VIRUS CHALLENGE.

7569
04:36:32,543 --> 04:36:34,478
BUT IF FOUR TIMES MORE CELLS

7570
04:36:34,478 --> 04:36:38,248
FROM ANIMALS THAT RECEIVED H1N1

7571
04:36:38,248 --> 04:36:41,818
FIRST, WE LOSE 100% PROTECTION

7572
04:36:41,818 --> 04:36:44,454
BUT GET 100% MORTALITY.

7573
04:36:44,454 --> 04:36:51,295
YOU CAN TRANSFER PROTECTION BY

7574
04:36:51,295 --> 04:36:52,129
H1N1-EXPOSED CD11+ CELLS BUT TOO

7575
04:36:52,129 --> 04:36:55,699
MUCH AND YOU  LOSE PROTECTION AD

7576
04:36:55,699 --> 04:36:58,368
TURN TO MAR AT THAT TIME, THIN

7577
04:36:58,368 --> 04:36:59,870
LINE BETWEEN PROTECTION AND

7578
04:36:59,870 --> 04:37:00,103
DISEASE.

7579
04:37:00,103 --> 04:37:00,904
WHY IS THIS?

7580
04:37:00,904 --> 04:37:01,738
WE DON'T KNOW.

7581
04:37:01,738 --> 04:37:04,207
CAN BE DUE TO THE FACT CONTEXT

7582
04:37:04,207 --> 04:37:06,009
DEPENDENT BECAUSE YOU TAKE VIRUS

7583
04:37:06,009 --> 04:37:07,611
EXPOSED MACROPHAGES, PUT THEM

7584
04:37:07,611 --> 04:37:11,715
INTO NAIVE ANIMAL, FOR EXAMPLE

7585
04:37:11,715 --> 04:37:13,483
THOSE EPITHELIA HAVE NOT BEEN

7586
04:37:13,483 --> 04:37:14,318
EXPOSED TO H1N1 OR COMPONENTS

7587
04:37:14,318 --> 04:37:15,652
HAVE NOT BEEN EXPOSED TO VIRUS

7588
04:37:15,652 --> 04:37:15,886
BEFORE.

7589
04:37:15,886 --> 04:37:18,355
SO WE DON'T FLOW IF THERE'S A

7590
04:37:18,355 --> 04:37:21,558
FEED -- KNOW IF THERE'S A

7591
04:37:21,558 --> 04:37:29,132
FEEDBACK MECHANIC , STILL FIELDS

7592
04:37:29,132 --> 04:37:32,102
WE CAN EXPLORE.

7593
04:37:32,102 --> 04:37:34,571
WE WERE INTRIGUED BY LINE

7594
04:37:34,571 --> 04:37:35,505
REMODEL, THIN LINE BETWEEN

7595
04:37:35,505 --> 04:37:39,776
PROTECTION AND DISEASE.

7596
04:37:39,776 --> 04:37:41,378
WE DID SECOND EXPERIMENT

7597
04:37:41,378 --> 04:37:42,879
INFECTED WITH H1N1, ALSO

7598
04:37:42,879 --> 04:37:47,284
INCLUDED A SECOND GROUP INFECTED

7599
04:37:47,284 --> 04:37:48,251
WITH SARS-COV-2, THE OMICRON

7600
04:37:48,251 --> 04:37:52,222
STRAIN OR HAD A MOCK CHALLENGE

7601
04:37:52,222 --> 04:37:53,523
GROUP.

7602
04:37:53,523 --> 04:37:55,826
TWO DIFFERENT GENETIC

7603
04:37:55,826 --> 04:37:56,293
BACKGROUNDS.

7604
04:37:56,293 --> 04:38:00,530
THE MICE WITH THE HUMAN H2 WE

7605
04:38:00,530 --> 04:38:04,067
ALREADY DISCUSSED TODAY, 129

7606
04:38:04,067 --> 04:38:12,709
MICE ARE WILDTYPE MICE, MORE

7607
04:38:12,709 --> 04:38:14,411
SUSCEPTIBLE TO SARS-COV-2.

7608
04:38:14,411 --> 04:38:16,913
WE USED A BETA STRAIN TO

7609
04:38:16,913 --> 04:38:18,949
REINFECT, THIS STRAIN CAN ALSO

7610
04:38:18,949 --> 04:38:20,751
INFECT WILDTYPE MICE AND CAUSE

7611
04:38:20,751 --> 04:38:25,222
ABOUT 10 TO 15% BODY WEIGHT LOSS

7612
04:38:25,222 --> 04:38:29,626
IN 129 MICE, LETHAL IN K18 MICE.

7613
04:38:29,626 --> 04:38:31,762
WE SEE THIS IS THE MOCK

7614
04:38:31,762 --> 04:38:33,330
CHALLENGED ANIMAL, THEY DON'T

7615
04:38:33,330 --> 04:38:34,665
LOSE WEIGHT, DEPENDING ON

7616
04:38:34,665 --> 04:38:36,266
GENETIC BACKGROUND WE CAN SEE

7617
04:38:36,266 --> 04:38:41,171
K18 MICE ARE FULLY PROTECTED

7618
04:38:41,171 --> 04:38:43,373
FROM BETA INFECTION, WHEN FIRST

7619
04:38:43,373 --> 04:38:47,544
INFECTED WITH BA.1 VIRUS.

7620
04:38:47,544 --> 04:38:48,478
FIRST INFECTION WITH NEW

7621
04:38:48,478 --> 04:38:50,947
CALEDONIA THE 9 DID NOT PROTECT

7622
04:38:50,947 --> 04:38:52,382
FROM BODY WEIGHT LOSS, BASICALLY

7623
04:38:52,382 --> 04:38:56,286
GAVE THE SAME AS ANIMALS NOT

7624
04:38:56,286 --> 04:38:58,155
PRIOR INFECTED.

7625
04:38:58,155 --> 04:38:59,956
WE CAN SEE IN 129 MICE PRIOR

7626
04:38:59,956 --> 04:39:01,358
INFECTION WITH FLU KIND OF

7627
04:39:01,358 --> 04:39:03,960
PROTECTS THEM TO SOME EXTENT AND

7628
04:39:03,960 --> 04:39:05,195
GIVES FIRST RECOVERY, HOWEVER

7629
04:39:05,195 --> 04:39:07,664
THE BA.1 PRIOR INFECTION RESULTS

7630
04:39:07,664 --> 04:39:14,905
IN NO RECOVERY BY DAY 4.

7631
04:39:14,905 --> 04:39:16,239
WHEREAS BETA INFECTION GIVES

7632
04:39:16,239 --> 04:39:17,407
SOME RECOVERY BY DAY 3 ALREADY.

7633
04:39:17,407 --> 04:39:21,978
THERE'S A  DIFFERENCE IN AGAINST

7634
04:39:21,978 --> 04:39:22,979
BACKGROUNDS REFLECTED IN

7635
04:39:22,979 --> 04:39:25,949
PROTECTION AFTER SECONDARY

7636
04:39:25,949 --> 04:39:30,420
INFECTION WITH UNRELATED VIRUS.

7637
04:39:30,420 --> 04:39:32,289
WE CHECKED CYTOKINE PROFILES,

7638
04:39:32,289 --> 04:39:34,057
VERY DIFFERENT CYTOKINE PROFILES

7639
04:39:34,057 --> 04:39:36,293
DEPENDING ON FIRST TREATMENTS

7640
04:39:36,293 --> 04:39:40,030
BEFORE THE BETA INFECTION, MOCK

7641
04:39:40,030 --> 04:39:43,166
INFECTED BA OR 101 INFECTION,

7642
04:39:43,166 --> 04:39:46,369
DIFFERENT BETWEEN K18 MICE, TOP

7643
04:39:46,369 --> 04:39:47,904
PANEL, VERSUS 129 MICE, BOTTOM

7644
04:39:47,904 --> 04:39:48,972
PANEL.

7645
04:39:48,972 --> 04:39:53,677
WE SEE BA.1 PRIOR INFECTION WILL

7646
04:39:53,677 --> 04:39:56,580
RESULT IN IL-2 AND IL-9 IN K18

7647
04:39:56,580 --> 04:39:59,182
MOUSE, DIFFERENT IF YOU

7648
04:39:59,182 --> 04:40:01,685
PREVIOUSLY INFECT WITH FLU.

7649
04:40:01,685 --> 04:40:04,387
WE TAKE 129 MICE, BA.1 PRIOR

7650
04:40:04,387 --> 04:40:06,356
INFECTION WILL ACTUALLY RESULT

7651
04:40:06,356 --> 04:40:10,293
IN VERY STRONG TYPE 2 RESPONSE,

7652
04:40:10,293 --> 04:40:12,062
IL-15, 4, 5, SO THIS IS

7653
04:40:12,062 --> 04:40:13,797
DIFFERENT AGAIN WHEN YOU

7654
04:40:13,797 --> 04:40:16,833
PREVIOUSLY INFECT ANIMALS WITH

7655
04:40:16,833 --> 04:40:17,367
FLU.

7656
04:40:17,367 --> 04:40:20,003
PRIOR INFECTION DEPENDING ON

7657
04:40:20,003 --> 04:40:22,672
VIRUS GIVERS DIFFERENT CYTOKINE

7658
04:40:22,672 --> 04:40:26,143
RESPONSE, ALSO DIFFERENT BETWEEN

7659
04:40:26,143 --> 04:40:31,114
DIFFERENCE MOUSE STRAINS.

7660
04:40:31,114 --> 04:40:33,784
WE TOOK CD11+ CELLS AND

7661
04:40:33,784 --> 04:40:35,519
STIMULATED BECAUSE IT'S GOING TO

7662
04:40:35,519 --> 04:40:42,726
STIMULATE ALVEOLAR  MACROPHAGES

7663
04:40:42,726 --> 04:40:44,661
AROUND SEE BIG DIFFERENCE

7664
04:40:44,661 --> 04:40:51,802
BETWEEN BA.1 AND DIFFERENT MOUSE

7665
04:40:51,802 --> 04:40:55,172
STRAINS, SO K18s UPREGULATE

7666
04:40:55,172 --> 04:40:59,309
IL-19, 17, 22, AGAIN THIS TYPE 2

7667
04:40:59,309 --> 04:41:00,644
PROFILE IL-4 REDUCTION.

7668
04:41:00,644 --> 04:41:03,914
THIS IS MY LAST DATA SLIDE.

7669
04:41:03,914 --> 04:41:06,016
I SHOWED THAT ACTUALLY TYPE 2

7670
04:41:06,016 --> 04:41:07,317
RESPONSE CAN CORRELATE

7671
04:41:07,317 --> 04:41:08,218
PROTECTION IN VACCINATED MICE

7672
04:41:08,218 --> 04:41:10,587
AFTER FLU BUT ALSO CORRELATES

7673
04:41:10,587 --> 04:41:14,925
WITH LACK OF  PROTECTION IN

7674
04:41:14,925 --> 04:41:16,760
SARS-COV-2 IN REINFLECTION.

7675
04:41:16,760 --> 04:41:17,961
WE'VE EXPANDED TO OTHER MOUSE

7676
04:41:17,961 --> 04:41:20,330
MODELS THAT ARE KNOWN TO HAVE

7677
04:41:20,330 --> 04:41:23,333
TYPE 2 RESPONSE THAT IS NOT

7678
04:41:23,333 --> 04:41:25,368
CORRELATING WITH PROTECTION AND

7679
04:41:25,368 --> 04:41:27,237
SO WE LOOK AT ALLERGY RESPONSES

7680
04:41:27,237 --> 04:41:30,207
TO COMPARE WHAT WE SEE IN FLU

7681
04:41:30,207 --> 04:41:35,579
AND COVID MODELS, WITH SOME

7682
04:41:35,579 --> 04:41:36,546
ALLERGY MODELS.

7683
04:41:36,546 --> 04:41:42,786
WE SENSITIZE MICE AGAINST A

7684
04:41:42,786 --> 04:41:46,489
STANDARDIZED PROTOCOL, FOLLOWED

7685
04:41:46,489 --> 04:41:48,024
BY SOME INTRANASAL CHALLENGES

7686
04:41:48,024 --> 04:41:52,062
AND LET THESE MICE FULLY RECOVER

7687
04:41:52,062 --> 04:41:56,032
AND AGAIN WITH 2,000 PFU OF H1N1

7688
04:41:56,032 --> 04:41:57,567
NEW CALEDONIA VIRUS.

7689
04:41:57,567 --> 04:41:59,936
ALLERGIC MICE LOSE MORE BODY

7690
04:41:59,936 --> 04:42:01,705
WEIGHT AFTER FLU CHALLENGE, IN

7691
04:42:01,705 --> 04:42:03,473
BLACK 6 MICE IT'S NOT BASED ON

7692
04:42:03,473 --> 04:42:06,109
BODY WEIGHT BUT WE CAN SEE IN

7693
04:42:06,109 --> 04:42:08,311
BOTH MOUSE STRAINS THAT THE

7694
04:42:08,311 --> 04:42:14,184
VIRUS TITER IS HIGHER OTHER NOT

7695
04:42:14,184 --> 04:42:16,419
LOWER IN ALLERGIC MICE COMPARED

7696
04:42:16,419 --> 04:42:26,897
TO NONSENSE  NON-SENSITIZED.

7697
04:42:30,901 --> 04:42:32,469
BASICALLY TO SUMMARIZE THIS,

7698
04:42:32,469 --> 04:42:34,004
POINTS FOR FUTURE ATTENTION WE

7699
04:42:34,004 --> 04:42:35,872
SEE HOST IMMUNE RESPONSES IN

7700
04:42:35,872 --> 04:42:38,375
MICE WITH MORE COMPLEX EXPOSURE

7701
04:42:38,375 --> 04:42:39,809
HISTORY ARE DIFFERENT SO THERE'S

7702
04:42:39,809 --> 04:42:41,611
DISEASE MODULATION AND THEN

7703
04:42:41,611 --> 04:42:45,515
ESPECIALLY TYPE 2 RESPONSE WE

7704
04:42:45,515 --> 04:42:46,816
CAN SEE CORRELATES WITH

7705
04:42:46,816 --> 04:42:47,517
PROTECTION.

7706
04:42:47,517 --> 04:42:50,320
AND WE SEE DIFFERENCE BETWEEN

7707
04:42:50,320 --> 04:42:51,321
TRAINED AND POTENTIALLY

7708
04:42:51,321 --> 04:42:53,256
PERSISTENT IMMUNE IMMUNITY,

7709
04:42:53,256 --> 04:42:55,859
ASSOCIATED WITH LUNG REMODELING.

7710
04:42:55,859 --> 04:42:59,362
WE NEED BETTER MODELS FOR

7711
04:42:59,362 --> 04:43:00,363
ENHANCED RESPIRATORY DISEASE,

7712
04:43:00,363 --> 04:43:03,199
BUT WE NEED SOME IN MOUSE MODELS

7713
04:43:03,199 --> 04:43:04,301
BECAUSE THAT'S NOT ESTABLISHED.

7714
04:43:04,301 --> 04:43:06,703
THIS WILL BE LINKED TO

7715
04:43:06,703 --> 04:43:07,637
PREEXISTING IMMUNITY.

7716
04:43:07,637 --> 04:43:08,738
WE HAVE TO CONSIDER HOST

7717
04:43:08,738 --> 04:43:10,707
CONDITION WHEN WE LOOK AT OUR

7718
04:43:10,707 --> 04:43:14,611
MOUSE MODELS.

7719
04:43:14,611 --> 04:43:17,981
AGAINST BACKGROUNDS PLAYS

7720
04:43:17,981 --> 04:43:23,453
IMPORTANT ROLE, CO-MORBIDITIES,

7721
04:43:23,453 --> 04:43:26,790
WE HAVE ADVANCED AGE, OBESITY,

7722
04:43:26,790 --> 04:43:29,526
DIABETES, ENVIRONMENTAL FACTORS.

7723
04:43:29,526 --> 04:43:31,027
CHALLENGED STRAINS ARE NEEDED

7724
04:43:31,027 --> 04:43:33,029
THAT MATCH MOST RECENT VACCINE

7725
04:43:33,029 --> 04:43:40,036
STRAINS TO SEE VACCINE MEDIATED,

7726
04:43:40,036 --> 04:43:40,870
ESPECIALLY FOR H1N 2 AND

7727
04:43:40,870 --> 04:43:41,771
INFLUENZA B VIRUS.

7728
04:43:41,771 --> 04:43:45,675
THESE ARE THE PEOPLE  THAT DO TE

7729
04:43:45,675 --> 04:43:47,310
WORK AND MY COLLABORATORS AT

7730
04:43:47,310 --> 04:43:47,877
MOUNT SINAI.

7731
04:43:47,877 --> 04:43:52,015
THANK YOU.

7732
04:43:52,015 --> 04:43:58,021
>> WE HAVE TIME FOR ONE

7733
04:43:58,021 --> 04:43:58,288
QUESTION.

7734
04:43:58,288 --> 04:43:59,556
>> NICE WORK.

7735
04:43:59,556 --> 04:44:00,924
I HAVE A QUESTION.

7736
04:44:00,924 --> 04:44:03,493
WOULD IT BE GOOD TO LOOK AT

7737
04:44:03,493 --> 04:44:10,200
PATHOLOGY IN YOUR INFLUENZA B

7738
04:44:10,200 --> 04:44:14,337
INFECTION OR CD, POSITIVE, YOU

7739
04:44:14,337 --> 04:44:15,772
GIVE MORE DOSE THE LUNG TISSUE

7740
04:44:15,772 --> 04:44:17,640
IS MORE DAMAGED FROM IMMUNE

7741
04:44:17,640 --> 04:44:19,075
SYSTEM OR THE VIRUS, WHAT CAN

7742
04:44:19,075 --> 04:44:21,911
YOU SAY ABOUT THE PATHOLOGY OF

7743
04:44:21,911 --> 04:44:25,415
THE TISSUE OR CAN YOU SPECULATE?

7744
04:44:25,415 --> 04:44:27,617
>> SO WE SEE LESS
PATHOLOGY, BUT

7745
04:44:27,617 --> 04:44:31,988
WE SEE LUNG REMODEL.

7746
04:44:31,988 --> 04:44:34,424
SO WE SEE IBALT, LESS PATHOLOGY,

7747
04:44:34,424 --> 04:44:37,260
SO THEY ARE PROTECTED.

7748
04:44:37,260 --> 04:44:39,562
 

7749
04:44:39,562 --> 04:44:42,932
>> WE'LL SAVE THE OTHER

7750
04:44:42,932 --> 04:44:48,872
QUESTIONS FOR THE PANEL.

7751
04:44:48,872 --> 04:44:54,010
>> LAST SPEAKER BEFORE THE
BREAK

7752
04:44:54,010 --> 04:44:56,312
IS NEELTJE VAN DOREMALEN.

7753
04:44:56,312 --> 04:44:58,014
>> CLOSE?

7754
04:44:58,014 --> 04:44:58,314
>> ALMOST.

7755
04:44:58,314 --> 04:45:00,383
>> THANK YOU.

7756
04:45:00,383 --> 04:45:02,118
>> MUCOSAL IMMUNE
RESPONSES IN

7757
04:45:02,118 --> 04:45:03,653
ANIMAL MODELS OF SARS-COV-2,

7758
04:45:03,653 --> 04:45:05,722
CURRENT RESEARCH AND FUTURE

7759
04:45:05,722 --> 04:45:06,856
DIRECTIONS.

7760
04:45:06,856 --> 04:45:07,624
>> ALL RIGHT.

7761
04:45:07,624 --> 04:45:09,059
SO, THANKS FOR THE INVITATION,

7762
04:45:09,059 --> 04:45:11,661
I'M VERY EXCITED TO BE HERE,

7763
04:45:11,661 --> 04:45:13,763
REALLY ENJOYED TODAY ALREADY.

7764
04:45:13,763 --> 04:45:15,999
AND I'M GOING TO TALK ABOUT

7765
04:45:15,999 --> 04:45:18,401
MUCOSAL IMMUNE RESPONSES IN

7766
04:45:18,401 --> 04:45:20,503
ANIMAL MODELS OF SARS-COV-2.

7767
04:45:20,503 --> 04:45:24,908
IF I CAN MOVE MY SLIDES, THAT

7768
04:45:24,908 --> 04:45:33,016
IS. 

7769
04:45:33,016 --> 04:45:38,054
 

7770
04:45:38,054 --> 04:45:38,721
OKAY.

7771
04:45:38,721 --> 04:45:39,856
SORRY ABOUT THAT.

7772
04:45:39,856 --> 04:45:42,092
SO I GOT FIRST INTERESTED IN

7773
04:45:42,092 --> 04:45:44,060
THIS WHEN WE DID OUR VACCINE

7774
04:45:44,060 --> 04:45:48,765
STUDY IN NON-HUMAN PRIMATE, IN

7775
04:45:48,765 --> 04:45:49,899
EARLY 2020.

7776
04:45:49,899 --> 04:46:00,376
SO WE LOOKED AT CHADOX1, THE

7777
04:46:00,844 --> 04:46:02,579
ASTRAZENECA VACCINE, ENCODED TO

7778
04:46:02,579 --> 04:46:05,548
THE GENOME OF ADENOVIRUS VECTOR

7779
04:46:05,548 --> 04:46:08,618
VACCINE WHICH IS REPLICATION

7780
04:46:08,618 --> 04:46:10,153
INCONSEQUENT, THE SPIKE PROTEIN

7781
04:46:10,153 --> 04:46:13,323
IS NOT ACTUALLY EXPRESSED ON THE

7782
04:46:13,323 --> 04:46:14,324
OUTSIDE OF THE ADENOVIRUS.

7783
04:46:14,324 --> 04:46:16,059
WE DID A STUDY IN NON-HUMAN

7784
04:46:16,059 --> 04:46:19,662
PRIMATE, NOT THE SMALL ANIMAL

7785
04:46:19,662 --> 04:46:21,297
MODEL OF COURSE.

7786
04:46:21,297 --> 04:46:24,667
WE GAVE SINGLE OR DOUBLE

7787
04:46:24,667 --> 04:46:27,137
VACCINATION, FOUR WEEKS APART

7788
04:46:27,137 --> 04:46:30,473
AND CHALLENGED FOUR WEEKS AFTER

7789
04:46:30,473 --> 04:46:33,243
THAT.

7790
04:46:33,243 --> 04:46:35,678
AS A CONTROL USED CHADOX1.

7791
04:46:35,678 --> 04:46:37,947
AFTER CHALLENGE WE TOOK MULTIPLE

7792
04:46:37,947 --> 04:46:42,252
NASAL SWABS AND DAY 1, 3, 5, 7,

7793
04:46:42,252 --> 04:46:46,022
NECROPSY ON DAY 7 TO SEE IF LUNG

7794
04:46:46,022 --> 04:46:47,357
TISSUE WAS PROTECTED.

7795
04:46:47,357 --> 04:46:51,394
YOU CAN CLEARLY SEE IN SERUM WE

7796
04:46:51,394 --> 04:46:52,162
GET INDUCTION OF VIRUS

7797
04:46:52,162 --> 04:46:53,830
NEUTRALIZE BE ANTIBODIES.

7798
04:46:53,830 --> 04:46:57,667
WHEN WE LOOK AT T-CELL

7799
04:46:57,667 --> 04:46:59,602
RESPONSES, WHEN WE SIMULATED

7800
04:46:59,602 --> 04:47:01,738
PBMCs YOU CAN SEE INCREASE OF

7801
04:47:01,738 --> 04:47:03,840
SPOT FORMING UNITS, THEY WERE

7802
04:47:03,840 --> 04:47:06,276
PRODUCING INTERFERON GAMMA AFTER

7803
04:47:06,276 --> 04:47:06,576
STIMULATION.

7804
04:47:06,576 --> 04:47:07,710
MOST IMPORTANTLY WHAT WE NOTICED

7805
04:47:07,710 --> 04:47:09,579
WHEN WE LOOKED AT LUNG TISSUE

7806
04:47:09,579 --> 04:47:11,181
THESE VACCINATED ANIMALS WERE

7807
04:47:11,181 --> 04:47:11,447
PROTECTED.

7808
04:47:11,447 --> 04:47:12,615
THAT WAS GREAT.

7809
04:47:12,615 --> 04:47:15,051
THIS VACCINE WAS DEVELOPED.

7810
04:47:15,051 --> 04:47:17,754
IT HAS BEEN APPROVED IN

7811
04:47:17,754 --> 04:47:18,555
180-SOMETHING COUNTRIES, FIRST

7812
04:47:18,555 --> 04:47:22,125
YEAR WAS SUPPOSED TO HAVE

7813
04:47:22,125 --> 04:47:23,426
PROTECTED 6 MILLION PEOPLE,

7814
04:47:23,426 --> 04:47:24,294
SAVED THAT MANY LIVES.

7815
04:47:24,294 --> 04:47:26,896
ONE OF THE THINGS I NOTICED IN

7816
04:47:26,896 --> 04:47:29,465
THE STUDY, THIS IS A SURPRISE TO

7817
04:47:29,465 --> 04:47:30,433
ME, PROBABLY SHOULDN'T HAVE BEEN

7818
04:47:30,433 --> 04:47:36,239
BUT WAS, WHEN WE LOOKED AT NASAL

7819
04:47:36,239 --> 04:47:37,807
SWABS THERE WASN'T A DIFFERENCE,

7820
04:47:37,807 --> 04:47:40,710
WE WERE NOT THE ONLY ONES TO

7821
04:47:40,710 --> 04:47:42,478
SHOW THIS.

7822
04:47:42,478 --> 04:47:43,446
OTHER NON-HUMAN PRIMATE STUDIES

7823
04:47:43,446 --> 04:47:45,682
SHOWED THE SAME THING.

7824
04:47:45,682 --> 04:47:48,518
MORE IMPORTANTLY WE NOW KNOW

7825
04:47:48,518 --> 04:47:49,586
VACCINATED INDIVIDUALS WE SEE

7826
04:47:49,586 --> 04:47:50,787
THIS TOO.

7827
04:47:50,787 --> 04:47:52,455
SO WHEN YOU'RE VACCINATED, YOU

7828
04:47:52,455 --> 04:47:54,390
CAN STILL GET INFECTED, YOU CAN

7829
04:47:54,390 --> 04:47:55,725
STILL SHED INFECTIOUS VIRUS.

7830
04:47:55,725 --> 04:47:58,928
WHEN WE LOOK AT VIRAL RNA IN THE

7831
04:47:58,928 --> 04:47:59,996
BEGINNING IT'S VERY LITTLE

7832
04:47:59,996 --> 04:48:03,299
DIFFERENT BETWEEN VACCINATED

7833
04:48:03,299 --> 04:48:05,101
INDIVIDUALS AND UNVACCINATED

7834
04:48:05,101 --> 04:48:05,401
INDIVIDUALS.

7835
04:48:05,401 --> 04:48:07,303
SO, THAT'S OF COURSE AN ISSUE

7836
04:48:07,303 --> 04:48:08,805
BECAUSE IF YOU'RE VACCINATED,

7837
04:48:08,805 --> 04:48:10,506
YOU STILL SHED VIRUS, YOU'RE

7838
04:48:10,506 --> 04:48:16,746
TRANSMITTING THE VIRUS TO OTHER

7839
04:48:16,746 --> 04:48:16,980
PEOPLE.

7840
04:48:16,980 --> 04:48:19,782
AND SO THAT REALLY HAS TWO MAJOR

7841
04:48:19,782 --> 04:48:20,583
CONSEQUENCES.

7842
04:48:20,583 --> 04:48:23,186
FIRST ONE IS THAT

7843
04:48:23,186 --> 04:48:24,954
IMMUNOCOMPROMISED INDIVIDUALS

7844
04:48:24,954 --> 04:48:26,923
ARE STILL SUSCEPTIBLE TO SEVERE

7845
04:48:26,923 --> 04:48:29,158
DISEASE AND WE WOULD RATHER

7846
04:48:29,158 --> 04:48:30,526
PROTECT THEM FROM SEVERE

7847
04:48:30,526 --> 04:48:31,527
DISEASE.

7848
04:48:31,527 --> 04:48:35,265
THE SECOND ONE CONSTANTLY

7849
04:48:35,265 --> 04:48:36,633
DEALING WITH, VARIANTS OF

7850
04:48:36,633 --> 04:48:37,800
CONCERN, SARS-COV-2 HAS BEEN

7851
04:48:37,800 --> 04:48:41,070
ABLE TO ADAPT TO HUMAN HOST AND

7852
04:48:41,070 --> 04:48:46,542
ALSO MOVE AWAY FROM THE IMMUNE

7853
04:48:46,542 --> 04:48:47,310
RESPONSE.

7854
04:48:47,310 --> 04:48:47,944
TO UNDERSTAND THAT BETTER, I

7855
04:48:47,944 --> 04:48:50,380
THINK WE NEED TO UNDERSTAND

7856
04:48:50,380 --> 04:48:52,749
SYSTEMIC VERSUS MUCOSAL

7857
04:48:52,749 --> 04:48:53,416
IMMUNITY.

7858
04:48:53,416 --> 04:48:55,351
SYSTEMIC COMMUNITY IS

7859
04:48:55,351 --> 04:48:57,253
CIRCULATING THROUGHOUT THE BODY.

7860
04:48:57,253 --> 04:48:59,322
MUCOSAL IS MORE LOCALIZED.

7861
04:48:59,322 --> 04:49:01,457
THE KEY PLAYERS ARE TISSUE

7862
04:49:01,457 --> 04:49:07,630
RESIDENT T- AND B-CELLS AS WELL

7863
04:49:07,630 --> 04:49:08,398
AS DIFFERENT ANTIBODIES

7864
04:49:08,398 --> 04:49:09,499
INCLUDING SECRETORY IgA.

7865
04:49:09,499 --> 04:49:12,001
WE KNOW FROM STUDIES IN HUMANS

7866
04:49:12,001 --> 04:49:15,838
MUCOSAL IMMUNITY IS IMPORTANT.

7867
04:49:15,838 --> 04:49:19,909
IN THIS STUDY IN 2022, YOU CAN

7868
04:49:19,909 --> 04:49:23,046
SEE HUMANS HAD HIGH AMOUNT OF

7869
04:49:23,046 --> 04:49:24,280
MUCOSAL IgA, WERE PROTECTED

7870
04:49:24,280 --> 04:49:27,517
AGAINST OR HAD LOWER RISK OF

7871
04:49:27,517 --> 04:49:28,151
OMICRON BREAKTHROUGH INFECTIONS.

7872
04:49:28,151 --> 04:49:31,321
WE DIDN'T FIND THIS IN HUMANS

7873
04:49:31,321 --> 04:49:33,790
THAT HAD HIGH IgG IN THEIR

7874
04:49:33,790 --> 04:49:34,624
MUCOSA.

7875
04:49:34,624 --> 04:49:35,958
WE LOOKED AT VACCINATED

7876
04:49:35,958 --> 04:49:38,795
INDIVIDUALS, THIS IS A STUDY

7877
04:49:38,795 --> 04:49:42,365
DONE IN 2022 AS WELL, LOOKED AT

7878
04:49:42,365 --> 04:49:43,433
MUCOSAL IgA IN HUMANS THAT

7879
04:49:43,433 --> 04:49:46,002
WERE VACCINATED THAT EITHER DID

7880
04:49:46,002 --> 04:49:48,438
OR DID NOT HAVE PREVIOUS

7881
04:49:48,438 --> 04:49:48,905
SARS-COV-2 INFECTION.

7882
04:49:48,905 --> 04:49:51,674
THEY WERE REALLY ONLY ABLE TO

7883
04:49:51,674 --> 04:49:54,043
DETECT MUCOSAL IgA IN PEOPLE

7884
04:49:54,043 --> 04:49:56,379
THAT HAD A SARS 2 INFECTION

7885
04:49:56,379 --> 04:49:57,113
SUGGESTING CURRENT VACCINATIONS

7886
04:49:57,113 --> 04:50:03,920
WE'RE GIVING ARE NOT GIVING US A

7887
04:50:03,920 --> 04:50:06,189
GOOD MUCOSAL IMMUNE RESPONSE.

7888
04:50:06,189 --> 04:50:08,257
I STARTED CARING ABOUT IT, WHY

7889
04:50:08,257 --> 04:50:10,426
SHOULD YOU CARE ABOUT MUCOSAL

7890
04:50:10,426 --> 04:50:11,227
IMMUNITY?

7891
04:50:11,227 --> 04:50:15,064
MOST VIRUSES WE WORK WITH AFFECT

7892
04:50:15,064 --> 04:50:17,700
THE MUCOSAL ROUTE.

7893
04:50:17,700 --> 04:50:19,602
INFLUENZA A, SARS-COV-2, RSV,

7894
04:50:19,602 --> 04:50:20,570
ALL THESE VIRUSES.

7895
04:50:20,570 --> 04:50:23,406
REALLY THE MAJORITY OF VIRUSES

7896
04:50:23,406 --> 04:50:25,174
INFECT BY MUCOSAL ROUTE, WE

7897
04:50:25,174 --> 04:50:27,076
SHOULD CARE ABOUT MUCOSAL

7898
04:50:27,076 --> 04:50:28,311
IMMUNOLOGY, IT'S NOT THAT WELL

7899
04:50:28,311 --> 04:50:30,480
UNDERSTOOD RIGHT NOW.

7900
04:50:30,480 --> 04:50:31,814
KEY PLAYERS WITH MUCOSAL

7901
04:50:31,814 --> 04:50:36,052
IMMUNITY IN THE UPPER

7902
04:50:36,052 --> 04:50:40,423
RESPIRATORY TRACT ARE TONSILS,

7903
04:50:40,423 --> 04:50:47,897
THEY FORM A THE WALDEYER'S RING,

7904
04:50:47,897 --> 04:50:49,399
SECONDARY ORGANS.

7905
04:50:49,399 --> 04:50:51,267
WITHIN THESE TISSUES, YOU GET

7906
04:50:51,267 --> 04:50:52,435
IMMUNE RESPONSE THAT'S SIMILAR

7907
04:50:52,435 --> 04:50:55,738
TO WHAT WE'RE FAMILIAR WITH IN

7908
04:50:55,738 --> 04:50:56,973
LYMPH NODES, YOU HAVE NAIVE T

7909
04:50:56,973 --> 04:50:59,642
CELLS, IF THEY ARE EXPOSED TO

7910
04:50:59,642 --> 04:51:03,946
ANTIGEN THEY GET ACTIVATED, CD6

7911
04:51:03,946 --> 04:51:07,417
IS DOWNREGULATED, UPREGULATION

7912
04:51:07,417 --> 04:51:16,259
OF CD44, T CELLS CAN MIGRATE.

7913
04:51:16,259 --> 04:51:17,560
THEY START UPREGULATING, CD69

7914
04:51:17,560 --> 04:51:19,562
AND CD1 ALLOWING CELLS TO STAY

7915
04:51:19,562 --> 04:51:21,297
IN THE RESPIRATORY TRACT, THEY

7916
04:51:21,297 --> 04:51:28,404
CAN STAY FOR MONTHS OR YEARS

7917
04:51:28,404 --> 04:51:29,005
AFTER INFECTION.

7918
04:51:29,005 --> 04:51:30,807
SO STRUCTURE OF RESPIRATORY

7919
04:51:30,807 --> 04:51:33,242
MUCOSA, YOU'RE LOOKING AT UPPER

7920
04:51:33,242 --> 04:51:35,244
RESPIRATORY TRACT, LOWER

7921
04:51:35,244 --> 04:51:36,979
RESPIRATORY TRACT REGARDING

7922
04:51:36,979 --> 04:51:38,114
EPITHELIUM LOOKS DIFFERENT BUT

7923
04:51:38,114 --> 04:51:40,850
OVERALL WHAT I WANT YOU TO LOOK

7924
04:51:40,850 --> 04:51:45,321
AT IS MUCUS LAYER ON TOP, MUCOSA

7925
04:51:45,321 --> 04:51:47,490
LAMB NAH ON THE BOTTOM.

7926
04:51:47,490 --> 04:51:49,325
THE LAYER IS IN PLACE TO CATCH

7927
04:51:49,325 --> 04:51:51,027
DIFFERENT THINGS YOU BREATHE IN

7928
04:51:51,027 --> 04:51:54,530
ALL THE TIME, BACTERIA, VIRUSES,

7929
04:51:54,530 --> 04:51:56,933
ALSO OTHER ALLERGENS.

7930
04:51:56,933 --> 04:52:02,171
WITHIN THAT MUSOUS LAYER YOU CAN

7931
04:52:02,171 --> 04:52:04,807
FIND PEPTIDES AND ANTIBODIES

7932
04:52:04,807 --> 04:52:10,046
SUCH AS SECRETORY IgA.

7933
04:52:10,046 --> 04:52:12,748
LAMINA COPA, DIFFERENT IMMUNE

7934
04:52:12,748 --> 04:52:17,720
CELLS, REALLY NICE RED D C

7935
04:52:17,720 --> 04:52:20,690
PROBING THROUGH, TRYING TO FIND

7936
04:52:20,690 --> 04:52:20,957
ANTIGENS.

7937
04:52:20,957 --> 04:52:23,292
WE'LL TAKE THROUGH LYMPH NODES,

7938
04:52:23,292 --> 04:52:24,927
TONSILS AND STARTS IMMUNE

7939
04:52:24,927 --> 04:52:25,428
RESPONSE.

7940
04:52:25,428 --> 04:52:34,370
YOU CAN SEE OTHER IMMUNE CELLS

7941
04:52:34,370 --> 04:52:34,937
THERE.

7942
04:52:34,937 --> 04:52:37,773
AND THIS RESPONSE FUNCTIONS AS

7943
04:52:37,773 --> 04:52:40,710
FIRST LINE OF DEFENSE AGAINST

7944
04:52:40,710 --> 04:52:42,879
PATHOGENS, PLASMA CELLS

7945
04:52:42,879 --> 04:52:45,081
PRODUCING, FOR EXAMPLE, IgA,

7946
04:52:45,081 --> 04:52:46,649
THAT GET ACTIVELY TRANSPORTED

7947
04:52:46,649 --> 04:52:49,385
ACROSS EPITHELIUM AND CAN

7948
04:52:49,385 --> 04:52:52,088
DIRECTLY NEUTRALIZE VIRUSES WITH

7949
04:52:52,088 --> 04:52:53,856
OTHER FUNCTIONS, TISSUE RESIDENT

7950
04:52:53,856 --> 04:52:56,592
T CELLS CAN START PRODUCING

7951
04:52:56,592 --> 04:52:58,227
CYTOKINES AND CHEMOKINES, THERE

7952
04:52:58,227 --> 04:53:02,164
BY PRODUCING ANTI-VIRAL STATES

7953
04:53:02,164 --> 04:53:03,799
BY INDUCTION OF ISG, CAN ALSO

7954
04:53:03,799 --> 04:53:05,768
RESULT IN ACTIVATION OF OTHER

7955
04:53:05,768 --> 04:53:16,479
IMMUNE CELLS, RECRUIT  RECRUITME

7956
04:53:20,816 --> 04:53:22,318
LAMINA PROPRIA WITHIN THREE

7957
04:53:22,318 --> 04:53:22,752
HOURS AFTER.

7958
04:53:22,752 --> 04:53:24,754
ONCE THEY ARE SITTING IN A LUNG

7959
04:53:24,754 --> 04:53:28,424
THEY CAN ACT VERY QUICKLY.

7960
04:53:28,424 --> 04:53:33,296
THIS IS AN INFLUENZA STUDY DONE

7961
04:53:33,296 --> 04:53:35,231
THAT SHOWED IN IMMUNE CELLS THEY

7962
04:53:35,231 --> 04:53:36,566
ONLY HAVE TISSUE RESIDENT T

7963
04:53:36,566 --> 04:53:38,534
CELLS, DON'T HAVE ANTIBODIES AT

7964
04:53:38,534 --> 04:53:41,904
ALL, WHEN THESE MICE WERE

7965
04:53:41,904 --> 04:53:43,472
INFECTED WITH INFLUENZA LUNGS

7966
04:53:43,472 --> 04:53:45,641
WERE FULLY PROTECTED SHOWING T

7967
04:53:45,641 --> 04:53:47,677
CELLS ARE INCREDIBLY IMPORTANT

7968
04:53:47,677 --> 04:53:50,913
IN PROTECTING LUNG TISSUE.

7969
04:53:50,913 --> 04:53:52,448
SO WE'VE BEEN TALKING ABOUT

7970
04:53:52,448 --> 04:53:53,983
ANIMAL MODELS THROUGHOUT HERE.

7971
04:53:53,983 --> 04:53:56,552
THE MAIN MODELS THAT I LIKE TO

7972
04:53:56,552 --> 04:54:02,725
LOOK AT ARE THE MOUSE, HAMSTER,

7973
04:54:02,725 --> 04:54:04,760
FERRET, A SMALL ANIMAL MODELS,

7974
04:54:04,760 --> 04:54:05,928
EVEN A FERRET IS QUESTIONABLE

7975
04:54:05,928 --> 04:54:07,830
WHETHER IT'S A SMALL ANIMAL

7976
04:54:07,830 --> 04:54:10,099
MODEL, IT NEEDS VERY LARGE CAGES

7977
04:54:10,099 --> 04:54:11,300
TO WORK WITH.

7978
04:54:11,300 --> 04:54:13,469
MY FAVORITE MODEL RIGHT NOW IS

7979
04:54:13,469 --> 04:54:14,270
THE MOUSE.

7980
04:54:14,270 --> 04:54:15,905
THAT ISN'T BECAUSE I THINK THE

7981
04:54:15,905 --> 04:54:17,039
MOUSE HAS A RESPIRATORY TRACT

7982
04:54:17,039 --> 04:54:19,609
THAT LOOKS LIKE THE HUMAN

7983
04:54:19,609 --> 04:54:20,710
RESPIRATORY TRACT, IT'S PURELY

7984
04:54:20,710 --> 04:54:22,345
BECAUSE OF THE REAGENTS WE HAVE

7985
04:54:22,345 --> 04:54:22,612
AVAILABLE.

7986
04:54:22,612 --> 04:54:25,348
IF YOU WANT TO DO DEEP DIVE INTO

7987
04:54:25,348 --> 04:54:28,751
IMMUNOLOGY, IT'S GOING TO BE

7988
04:54:28,751 --> 04:54:32,655
PRETTY DIFFICULT TO THAT WITH

7989
04:54:32,655 --> 04:54:39,462
HAMSTERS AND  FERRETS, IMPORTANT

7990
04:54:39,462 --> 04:54:42,365
TO BE RESOLVED BECAUSE MUCOSAL

7991
04:54:42,365 --> 04:54:43,666
IMMUNOLOGY CAN BE STUDIED ON ANY

7992
04:54:43,666 --> 04:54:44,967
ANIMAL MODEL, INCLUDING HUMANS.

7993
04:54:44,967 --> 04:54:48,004
SO WE HAVE DIFFERENT TOOLS TO

7994
04:54:48,004 --> 04:54:48,571
INVESTIGATE MUCOSAL IMMUNE

7995
04:54:48,571 --> 04:54:50,840
RESPONSE IN MICE.

7996
04:54:50,840 --> 04:54:52,408
I REALLY LIKE LOOKING AT

7997
04:54:52,408 --> 04:54:55,244
LYMPHOID TISSUE.

7998
04:54:55,244 --> 04:54:57,747
YOU CAN SEE TWO TRIANGLES,

7999
04:54:57,747 --> 04:55:01,050
LOCATED RIGHT ABOVE OF THE SOFT

8000
04:55:01,050 --> 04:55:03,219
PALLIATE, YOU CANNOT SEE THESE

8001
04:55:03,219 --> 04:55:07,289
WITH THE NAKED EYE, YOU NEED

8002
04:55:07,289 --> 04:55:09,492
GOOD PATHOLOGISTS TO HELP

8003
04:55:09,492 --> 04:55:11,861
COLLECT TISSUES, LUCKILY WE HAVE

8004
04:55:11,861 --> 04:55:12,061
THOSE.

8005
04:55:12,061 --> 04:55:14,730
NOW THEY ARE FUNCTIONING LIKE

8006
04:55:14,730 --> 04:55:17,366
THE TONSILS IN HUMANS, DIFFERENT

8007
04:55:17,366 --> 04:55:18,701
LOCATION IN UPPER RESPIRATORY

8008
04:55:18,701 --> 04:55:25,107
TRACT, IT'S REALLY GOOD AT

8009
04:55:25,107 --> 04:55:25,374
MODELING.

8010
04:55:25,374 --> 04:55:28,144
HERE WE BASICALLY STAIN FOR

8011
04:55:28,144 --> 04:55:28,711
DIFFERENT IMMUNE POPULATIONS

8012
04:55:28,711 --> 04:55:30,379
WITHIN THE MOUSE.

8013
04:55:30,379 --> 04:55:32,148
WE'RE LOOKING AT T- AND B-CELLS

8014
04:55:32,148 --> 04:55:34,984
ON TOP.

8015
04:55:34,984 --> 04:55:42,024
REALLY NICE

8016
04:55:42,024 --> 04:55:46,295
COMPARTMENTALIZATION, NAIVE

8017
04:55:46,295 --> 04:55:48,564
MOUSE, DOING STUDY WE CAN ALSO

8018
04:55:48,564 --> 04:55:53,169
TAKE THAT MOUSE, PUT IT IN

8019
04:55:53,169 --> 04:55:56,338
MEDIA, INTUBATE, COLLECT AND ASK

8020
04:55:56,338 --> 04:55:57,106
WHAT ANTIBODIES DID THOSE B

8021
04:55:57,106 --> 04:55:59,208
CELLS PRODUCE IN THAT TIME.

8022
04:55:59,208 --> 04:56:00,943
YOU CAN TRUE TO UNDERSTAND THAT

8023
04:56:00,943 --> 04:56:04,647
ANTIBODIES WE GET IN UPPER

8024
04:56:04,647 --> 04:56:06,716
RESPIRATORY WE GET.

8025
04:56:06,716 --> 04:56:07,783
WE CAN UNDERSTAND THE LOWER

8026
04:56:07,783 --> 04:56:11,554
RESPIRATORY TRACT AND LOOK AT

8027
04:56:11,554 --> 04:56:16,492
SERUM TO LOOK AT RESPONSE.

8028
04:56:16,492 --> 04:56:20,196
WE NOW HAVE T- AND B-CELL

8029
04:56:20,196 --> 04:56:21,363
ELISPOTS.

8030
04:56:21,363 --> 04:56:22,998
WE CAN LOOK AT SPIKE SPECIFIC

8031
04:56:22,998 --> 04:56:24,867
RESPONSES IN MICE AND ONE OF MY

8032
04:56:24,867 --> 04:56:27,837
FAVORITE TOOLS, SOMEBODY ELSE

8033
04:56:27,837 --> 04:56:29,839
MENTIONED EARLIER, DOING AN IV

8034
04:56:29,839 --> 04:56:32,742
INFECTION WITH TD 45 BEFORE WE

8035
04:56:32,742 --> 04:56:39,148
DO FLOW CYTOMETRY.

8036
04:56:39,148 --> 04:56:41,450
WE USE ANTI-CD45, INJECT RETRO

8037
04:56:41,450 --> 04:56:42,084
ORBITICALLY, CIRCULATES THROUGH

8038
04:56:42,084 --> 04:56:45,454
THE BODY OF THE MOUSE BUT NOT

8039
04:56:45,454 --> 04:56:47,056
PENETRATING THE TISSUES.

8040
04:56:47,056 --> 04:56:49,692
WE THEN HARVEST THE TISSUES AND

8041
04:56:49,692 --> 04:56:55,664
DO FLOW CYTOMETRY B CELLS ARE

8042
04:56:55,664 --> 04:57:06,208
CD4 POSITIVE, C  CELLS ARE NOT. 

8043
04:57:09,578 --> 04:57:11,714
DOES INTRANASAL VACCINATION

8044
04:57:11,714 --> 04:57:12,114
PROTECT?

8045
04:57:12,114 --> 04:57:15,217
WE WENT TO THE MOUSE MODEL,

8046
04:57:15,217 --> 04:57:16,318
VACCINATED ANIMALS VIA

8047
04:57:16,318 --> 04:57:17,486
INTRAMUSCULAR ROUTE WITH mRNA,

8048
04:57:17,486 --> 04:57:18,687
THREE WEEKS APART.

8049
04:57:18,687 --> 04:57:19,688
WE WAITED SIX WEEKS.

8050
04:57:19,688 --> 04:57:23,626
THIS IS WHERE WE DIVIDED MICE IN

8051
04:57:23,626 --> 04:57:26,662
TWO GROUPS AND EITHER GAVE

8052
04:57:26,662 --> 04:57:28,430
mRNA VACCINATION

8053
04:57:28,430 --> 04:57:33,135
INTRAMUSCULARLY AGAIN OR GAVE

8054
04:57:33,135 --> 04:57:33,836
INTRANASAL VACCINATION CHADOX,

8055
04:57:33,836 --> 04:57:36,605
THAT I WAS TALKING ABOUT BEFORE.

8056
04:57:36,605 --> 04:57:38,941
HARVESTED TISSUES 3 AND 14 DAYS

8057
04:57:38,941 --> 04:57:39,341
AFTER VACCINATION.

8058
04:57:39,341 --> 04:57:41,343
WE'RE LOOKING AT THREE DAYS POST

8059
04:57:41,343 --> 04:57:44,113
VACCINATION, ONLY LOOKING AT THE

8060
04:57:44,113 --> 04:57:46,215
CELLS THAT WERE CD45 NEGATIVE,

8061
04:57:46,215 --> 04:57:51,120
RESIDENTIAL CELLS IN THE LUNGS.

8062
04:57:51,120 --> 04:57:52,988
WE THEN USED UNSUPERVISED

8063
04:57:52,988 --> 04:57:55,057
ANALYSIS TO LOOK AT WHAT CELL

8064
04:57:55,057 --> 04:57:56,158
POPULATIONS WE CAN FIND IN THE

8065
04:57:56,158 --> 04:57:57,359
LUNG TISSUE.

8066
04:57:57,359 --> 04:58:00,329
WE PULLED THAT APART LOOKING AT

8067
04:58:00,329 --> 04:58:02,031
TWO VACCINE GROUPS, SO YOU CAN

8068
04:58:02,031 --> 04:58:03,732
IMMEDIATELY SEE IN THE mRNA

8069
04:58:03,732 --> 04:58:05,801
GROUP YOU HAVE CERTAIN

8070
04:58:05,801 --> 04:58:13,709
POPULATIONS THAT ARE

8071
04:58:13,709 --> 04:58:16,879
OVERREPRESENTED, COMPARED TO THE

8072
04:58:16,879 --> 04:58:17,546
CHADOX GROUP.

8073
04:58:17,546 --> 04:58:26,288
YOU CAN LOOK AT WHAT MARKERS ARE

8074
04:58:26,288 --> 04:58:26,589
UPREGULATED.

8075
04:58:26,589 --> 04:58:29,859
PAY ATTENTION TO 1 AND 5, BROWN

8076
04:58:29,859 --> 04:58:34,263
AND ORANGE, IN THE TIFFANY PLOT,

8077
04:58:34,263 --> 04:58:43,439
UPREGULATED CD11C, MAY BE

8078
04:58:43,439 --> 04:58:44,240
DENDRITIC CELLS.

8079
04:58:44,240 --> 04:58:46,942
IF WE GO BACK TO TRADITIONAL

8080
04:58:46,942 --> 04:58:50,679
GATING, ONLY LOOK AT CD11C, WE

8081
04:58:50,679 --> 04:58:53,148
SEE NO DIFFERENCE IN VACCINE

8082
04:58:53,148 --> 04:58:54,183
GROUPS.

8083
04:58:54,183 --> 04:58:57,052
IF WE ADD CD11B TO TRADITIONAL

8084
04:58:57,052 --> 04:58:59,555
GATING NOW WE'RE STARTING TO SEE

8085
04:58:59,555 --> 04:59:00,222
DIFFERENCES BETWEEN VACCINE

8086
04:59:00,222 --> 04:59:00,456
GROUPS.

8087
04:59:00,456 --> 04:59:04,693
THIS IS A REALLY NICE WAY OF

8088
04:59:04,693 --> 04:59:07,630
GOING IN LIKE WITHOUT AN IDEA

8089
04:59:07,630 --> 04:59:09,164
WHAT SHOULD CHANGE BUT SEEING

8090
04:59:09,164 --> 04:59:12,167
WHAT ARE THE DIFFERENCES WE'RE

8091
04:59:12,167 --> 04:59:12,401
FINDING.

8092
04:59:12,401 --> 04:59:14,336
WE THEN LOOKED AT TISSUE

8093
04:59:14,336 --> 04:59:16,972
RESIDENT CD8 T CELLS WHICH MAY

8094
04:59:16,972 --> 04:59:17,706
BE MY FAVORITE CELL POPULATION

8095
04:59:17,706 --> 04:59:20,743
AT THE MOMENT.

8096
04:59:20,743 --> 04:59:21,911
WE'RE LOOKING AT LUNG TISSUE,

8097
04:59:21,911 --> 04:59:25,014
AND THE QUESTION WE ASK IS WHAT

8098
04:59:25,014 --> 04:59:28,884
PERCENTAGE OF CD8 T CELLS IN THE

8099
04:59:28,884 --> 04:59:29,652
LUNG IS RESIDENTIAL.

8100
04:59:29,652 --> 04:59:35,024
WE TACK ALL  -- TOOK ALL THE

8101
04:59:35,024 --> 04:59:36,425
CELLS IN THE LUNG.

8102
04:59:36,425 --> 04:59:39,128
YOU CAN SEE IN DAY 3 WE GET

8103
04:59:39,128 --> 04:59:40,930
INFLUX OF CD8 T CELLS IN THE

8104
04:59:40,930 --> 04:59:46,735
LUNG TISSUE AND STILL THERE AT

8105
04:59:46,735 --> 04:59:48,804
DAY 14.

8106
04:59:48,804 --> 04:59:54,143
WE CAN ASK HAVE THESE CELLS SEEN

8107
04:59:54,143 --> 04:59:55,110
ANTIGEN, AND INDEED CELLS THAT

8108
04:59:55,110 --> 05:00:02,885
ARE MOVING INTO THE LUNG WITH

8109
05:00:02,885 --> 05:00:03,786
ANTIGEN EXPERIENCE.

8110
05:00:03,786 --> 05:00:05,854
SO ARE THESE CELLS SPECIFIC FOR

8111
05:00:05,854 --> 05:00:06,055
SPIKE?

8112
05:00:06,055 --> 05:00:08,490
THE NEXT QUESTION WE LOOK BY

8113
05:00:08,490 --> 05:00:09,892
USING TETRAMER, YOU CAN SEE DAY

8114
05:00:09,892 --> 05:00:13,295
3 EVEN THOUGH IT WAS MOSTLY

8115
05:00:13,295 --> 05:00:14,496
ANTIGEN EXPERIENCED CELLS THEY

8116
05:00:14,496 --> 05:00:15,264
ARE NOT SPIKE SPECIFIC.

8117
05:00:15,264 --> 05:00:17,266
SOME ARE BUT THERE'S NOT

8118
05:00:17,266 --> 05:00:18,100
SIGNIFICANT INCREASE COMPARED

8119
05:00:18,100 --> 05:00:19,868
TO mRNA GROUP.

8120
05:00:19,868 --> 05:00:22,705
ON DAY 14 WE ARE ASKING

8121
05:00:22,705 --> 05:00:30,279
SIGNIFICANT DIFFERENCE BETWEEN

8122
05:00:30,279 --> 05:00:32,181
mRNA AND CHADO X-1 GROUPS THESE

8123
05:00:32,181 --> 05:00:33,916
CELLS ARE LIKELY TO STAY IN THE

8124
05:00:33,916 --> 05:00:34,116
LUNG.

8125
05:00:34,116 --> 05:00:39,588
IF YOU LOOK AT THE PURPLE

8126
05:00:39,588 --> 05:00:40,589
POPULATION YOU SEE

8127
05:00:40,589 --> 05:00:44,626
CO-EXPRESSION, WE SEE INCREASE

8128
05:00:44,626 --> 05:00:48,664
IN ANIMALS WITH CHADOX1 AT DAY

8129
05:00:48,664 --> 05:00:51,400
14 BUT NOT DAY 3.

8130
05:00:51,400 --> 05:00:53,102
WHAT ABOUT THE NOSE?

8131
05:00:53,102 --> 05:00:54,636
THE TISSUE I'M CURRENTLY

8132
05:00:54,636 --> 05:00:56,739
INTERESTED, A LOT OF PEOPLE HAVE

8133
05:00:56,739 --> 05:00:58,741
LOOKED AT THE LUNG BEFORE,-DAY

8134
05:00:58,741 --> 05:01:01,944
DATA IN UPPER RESPIRATORY TRACT,

8135
05:01:01,944 --> 05:01:03,112
STILL LACKING.

8136
05:01:03,112 --> 05:01:05,080
SO HERE WE'RE LOOKING AT ANTIGEN

8137
05:01:05,080 --> 05:01:06,415
EXPERIENCE CELLS, A NUMBER OF

8138
05:01:06,415 --> 05:01:08,584
THEM.

8139
05:01:08,584 --> 05:01:13,555
ON DAY 3 INFLUX OF CELLS IN THE

8140
05:01:13,555 --> 05:01:16,425
NOSE WITH THE CHADOX1 ON DAY 14

8141
05:01:16,425 --> 05:01:17,593
HAS EQUALIZED.

8142
05:01:17,593 --> 05:01:19,128
WHEN WE LOOK AT B CELLS SPIKE

8143
05:01:19,128 --> 05:01:22,231
SPECIFIC WE SEE DIFFERENCE

8144
05:01:22,231 --> 05:01:24,166
BETWEEN ANIMALS WITH CHADOX1

8145
05:01:24,166 --> 05:01:26,568
AND mRNA VACCINATION.

8146
05:01:26,568 --> 05:01:28,637
IN PARTICULAR ON DAY 14.

8147
05:01:28,637 --> 05:01:33,375
AND B CELLS ALSO MUCH MORE

8148
05:01:33,375 --> 05:01:43,852
LIKELY TO EXPRESS CD 69 AND

8149
05:01:44,453 --> 05:01:44,586
CD103.

8150
05:01:44,586 --> 05:01:46,588
WE ISOLATED CELLS FROM LYMPH

8151
05:01:46,588 --> 05:01:49,224
NODES, CERVICAL LYMPH NODE IS

8152
05:01:49,224 --> 05:01:54,363
DRAINING UPPER RESPIRATORY

8153
05:01:54,363 --> 05:01:56,665
TRACT, INGUINAL IS CLOSE TO

8154
05:01:56,665 --> 05:01:57,966
MUSCULAR VACCINATION.

8155
05:01:57,966 --> 05:02:03,372
WE SEE CELLS POSITIVE FOR CD8

8156
05:02:03,372 --> 05:02:06,508
TETRAMER SPIKE SPECIFIC, ANIMALS

8157
05:02:06,508 --> 05:02:11,647
WITH A CHADOX1 VACCINATION MUCH

8158
05:02:11,647 --> 05:02:12,614
HIGHER POPULATION IN CERVICAL

8159
05:02:12,614 --> 05:02:16,452
LYMPH NODES, SUGGESTING A LOCAL

8160
05:02:16,452 --> 05:02:18,420
RESPONSE WE'RE MEASURING.

8161
05:02:18,420 --> 05:02:22,391
WE CAN LOOK AT B CELLS, CD19

8162
05:02:22,391 --> 05:02:26,095
EXPRESSING ON THE SURFACE AS

8163
05:02:26,095 --> 05:02:28,197
WELL AS IgA, ON THE NOSE TOP

8164
05:02:28,197 --> 05:02:31,433
PANEL DAY 3 INFLUX OF CELLS IN

8165
05:02:31,433 --> 05:02:32,868
THE UPPER RESPIRATORY TRACT, IN

8166
05:02:32,868 --> 05:02:34,570
THE LUNGS THAT'S NOT HAPPENING

8167
05:02:34,570 --> 05:02:34,903
YET.

8168
05:02:34,903 --> 05:02:39,108
DAY 14 WE SEE THIS POPULATION

8169
05:02:39,108 --> 05:02:41,510
INCREASING UPPER AND LOWER

8170
05:02:41,510 --> 05:02:42,211
RESPIRATORY TRACT.

8171
05:02:42,211 --> 05:02:44,146
THIS IS EXPRESSION ON THE

8172
05:02:44,146 --> 05:02:46,014
SURFACE OF B CELLS, CAN ALSO

8173
05:02:46,014 --> 05:02:53,755
LOOK AT ACTUAL PRODUCTION OF

8174
05:02:53,755 --> 05:02:57,092
IgA USING B CELL.

8175
05:02:57,092 --> 05:02:59,228
WE'RE COMPARING CELLS ISOLATED

8176
05:02:59,228 --> 05:03:02,297
FROM THE LUNGS, LOOKING AT THE

8177
05:03:02,297 --> 05:03:05,601
SPLEEN THERE ISN'T A DIFFERENCE,

8178
05:03:05,601 --> 05:03:09,304
RESPONSE SIMILAR TO mRNA AND

8179
05:03:09,304 --> 05:03:10,272
CHADOX1 VACCINATED, CONTROL

8180
05:03:10,272 --> 05:03:17,312
ANIMALS DIDN'T HAVE IgA B

8181
05:03:17,312 --> 05:03:18,847
CELLS SITE SPECIFIC.

8182
05:03:18,847 --> 05:03:19,815
WE'RE ONLY SEEING IgA

8183
05:03:19,815 --> 05:03:28,223
PRODUCTION IN ANIMALS THAT GOT A

8184
05:03:28,223 --> 05:03:28,657
CHADOX1 VACCINATION.

8185
05:03:28,657 --> 05:03:31,727
WE USED NASOPLEX TO LOOK AT

8186
05:03:31,727 --> 05:03:33,929
ANTIBODY RESPONSES, YOU'RE

8187
05:03:33,929 --> 05:03:36,765
SEEING NINE ANTIGENS IN ONE

8188
05:03:36,765 --> 05:03:37,199
WELL.

8189
05:03:37,199 --> 05:03:39,501
AND FURTHER OUT FROM THE MIDDLE,

8190
05:03:39,501 --> 05:03:41,503
THE HIGHER THE BINDING RESPONSE

8191
05:03:41,503 --> 05:03:43,005
TO DIFFERENT ANTIGENS.

8192
05:03:43,005 --> 05:03:50,212
YOU CAN SEE mRNA GROUP IN

8193
05:03:50,212 --> 05:03:51,813
BLUE, CHADOX1 IN PURPLE, IN

8194
05:03:51,813 --> 05:03:54,383
SERUM 14 DAYS AFTER VACCINATION

8195
05:03:54,383 --> 05:03:54,983
NOT SEEING DIFFERENCE BETWEEN

8196
05:03:54,983 --> 05:03:55,817
THE TWO GROUPS.

8197
05:03:55,817 --> 05:03:58,320
WHEN WE LOOK IN RESPIRATORY

8198
05:03:58,320 --> 05:04:00,722
TRACT WE SEE STRIKING

8199
05:04:00,722 --> 05:04:01,156
DIFFERENCE.

8200
05:04:01,156 --> 05:04:02,157
NASAL ASSOCIATED LYMPHOID TISSUE

8201
05:04:02,157 --> 05:04:06,762
IS REPRESENTATIVE OF THE UPPER

8202
05:04:06,762 --> 05:04:08,297
RESPIRATORY TRACT, BRONCHIAL

8203
05:04:08,297 --> 05:04:11,166
ALVEOLAR LAVAGE IN LOWER,

8204
05:04:11,166 --> 05:04:15,103
BEAUTIFUL EXPRESSION OF IgA

8205
05:04:15,103 --> 05:04:22,477
AND IN THE CHADOX1 BUT NOT THE

8206
05:04:22,477 --> 05:04:24,746
INTRAMUSCULAR VACCINATION.

8207
05:04:24,746 --> 05:04:30,919
SO, IS THIS VACCINATION ABLE TO

8208
05:04:30,919 --> 05:04:33,121
REDUCE  SHEDDING?

8209
05:04:33,121 --> 05:04:38,227
WE DID A STUDY IN HAMSTERS.

8210
05:04:38,227 --> 05:04:40,862
WE CHALLENGED ANIMALS AND TAKE

8211
05:04:40,862 --> 05:04:43,065
ORAL SWABS, YOU CAN SEE UPON

8212
05:04:43,065 --> 05:04:44,666
INTRANASAL VACCINATION WE SEE

8213
05:04:44,666 --> 05:04:47,502
REDUCTION IN THE AMOUNT OF

8214
05:04:47,502 --> 05:04:48,170
INFECTIOUS VIRUS SHED.

8215
05:04:48,170 --> 05:04:51,573
AND ON TOP OF THAT WE ALSO SEE A

8216
05:04:51,573 --> 05:04:52,874
REDUCTION IN AMOUNT OF

8217
05:04:52,874 --> 05:04:55,611
INFECTIOUS VIRUS IN LUNG TISSUE,

8218
05:04:55,611 --> 05:04:56,645
IMPORTANT BECAUSE WE DON'T

8219
05:04:56,645 --> 05:04:59,548
NECESSARILY WANT TO SACRIFICE

8220
05:04:59,548 --> 05:05:00,449
IMMUNITY IN LOWER RESPIRATORY

8221
05:05:00,449 --> 05:05:02,851
TRACT FOR IMMUNITY IN UPPER

8222
05:05:02,851 --> 05:05:05,887
BECAUSE THAT'S ASSOCIATED WITH

8223
05:05:05,887 --> 05:05:07,556
SEVERE DISEASE.

8224
05:05:07,556 --> 05:05:12,027
IN NON-HUMAN PRIMATE WE COMPARED

8225
05:05:12,027 --> 05:05:16,431
CHADOX 1 AND 19, GAVE TWO

8226
05:05:16,431 --> 05:05:18,166
VACCINATIONS FOUR WEEKS APART,

8227
05:05:18,166 --> 05:05:20,035
CHALLENGED FOUR WEEKS LATER,

8228
05:05:20,035 --> 05:05:21,803
SHEDDING IS REDUCED COMPARED TO

8229
05:05:21,803 --> 05:05:24,606
OUR CONTROL ANIMALS WHICH IS IN

8230
05:05:24,606 --> 05:05:27,175
CONTRAST TO WHAT WE SAW WITH

8231
05:05:27,175 --> 05:05:28,443
INTRAMUSCULAR VACCINATION.

8232
05:05:28,443 --> 05:05:37,519
LIKEWISE WHEN WE LOOK AT

8233
05:05:37,519 --> 05:05:41,123
BRONCHIAL A ALVEOLAR LAVAGE WE

8234
05:05:41,123 --> 05:05:42,658
SUE VERY LITTLE VIRUS.

8235
05:05:42,658 --> 05:05:43,659
LOWER RESPIRATORY TRACT WAS

8236
05:05:43,659 --> 05:05:47,829
NICELY PROTECTED IN VACCINATED

8237
05:05:47,829 --> 05:05:48,397
ANIMALS.

8238
05:05:48,397 --> 05:05:49,698
WE WANTED TO UNDERSTAND WHAT

8239
05:05:49,698 --> 05:05:51,400
FUNCTIONALITY IS OF THESE

8240
05:05:51,400 --> 05:05:52,234
ANTIBODIES.

8241
05:05:52,234 --> 05:05:56,471
THIS IS IN NON-HUMAN PRIMATE.

8242
05:05:56,471 --> 05:06:00,976
THIS WAS WORK DONE IN OUR LAB,

8243
05:06:00,976 --> 05:06:03,378
SHE SHOWED ANTIBODIES IN SERUM

8244
05:06:03,378 --> 05:06:06,014
WERE ABLE TO NEUTRALIZE VIRUS

8245
05:06:06,014 --> 05:06:10,719
RESULTING IN COMPLEMENT

8246
05:06:10,719 --> 05:06:12,721
ACTIVATION, OXYGENATION AND

8247
05:06:12,721 --> 05:06:22,431
PHAGOCYTOSIS AND N CASE CELLULAR

8248
05:06:22,431 --> 05:06:22,764
CYTOTOXICITY.

8249
05:06:22,764 --> 05:06:25,901
IgA WAS INDUCED, WE LOOKED AT

8250
05:06:25,901 --> 05:06:29,104
RESIDENTIAL T CELLS, TOOK A

8251
05:06:29,104 --> 05:06:30,605
LAVAGE SEVEN DAYS AFTER

8252
05:06:30,605 --> 05:06:34,209
VACCINATION, YOU CAN SEE CDAND

8253
05:06:34,209 --> 05:06:37,779
CD8 T CELLS START PRODUCING

8254
05:06:37,779 --> 05:06:43,719
INTERFERON GAMMA TNS ALPHA AND

8255
05:06:43,719 --> 05:06:45,987
SPIKE AT THAT TIME.

8256
05:06:45,987 --> 05:06:47,055
I THINK MUCOSAL IMMUNOLOGY WE

8257
05:06:47,055 --> 05:06:49,358
HAVE A LOT OF GAPS IN OUR

8258
05:06:49,358 --> 05:06:50,359
KNOWLEDGE STILL.

8259
05:06:50,359 --> 05:06:51,760
I ONLY MENTIONED A FEW HERE.

8260
05:06:51,760 --> 05:06:52,961
I KNOW THERE ARE MORE.

8261
05:06:52,961 --> 05:06:54,196
THESE ARE THE MOST IMPORTANT

8262
05:06:54,196 --> 05:06:57,032
ONES THAT WE SHOULD TRY TO

8263
05:06:57,032 --> 05:06:59,234
ANSWER RIGHT NOW.

8264
05:06:59,234 --> 05:07:00,435
I'VE SHOWN INDUCTION OF IMMUNE

8265
05:07:00,435 --> 05:07:02,504
PARAMETERS IN RESPIRATORY TRACT.

8266
05:07:02,504 --> 05:07:04,272
I'VE SHOWN SOME PROTECTION.

8267
05:07:04,272 --> 05:07:07,275
THOSE ARE NOT CORRELATEIVE

8268
05:07:07,275 --> 05:07:07,576
PROTECTION.

8269
05:07:07,576 --> 05:07:08,510
WE REALLY NEED TO UNDERSTAND

8270
05:07:08,510 --> 05:07:09,578
CORRELATE OF PROTECTION.

8271
05:07:09,578 --> 05:07:12,481
WHAT DO WE NEED TO PROTECT UPPER

8272
05:07:12,481 --> 05:07:13,682
RESPIRATORY TRACT?

8273
05:07:13,682 --> 05:07:16,051
SECONDLY, WHAT MUCOSAL IMMUNITY

8274
05:07:16,051 --> 05:07:18,787
IS INDUCED BY INFECTION WITH

8275
05:07:18,787 --> 05:07:21,223
VIRUSES, HOW DOES IT DIFFER WITH

8276
05:07:21,223 --> 05:07:21,490
VACCINES?

8277
05:07:21,490 --> 05:07:22,991
I'M ONLY SHOWING VACCINATION

8278
05:07:22,991 --> 05:07:24,826
DATA, VERY LITTLE WORK IN

8279
05:07:24,826 --> 05:07:27,896
SARS-COV-2 FIELD LOOKING AT

8280
05:07:27,896 --> 05:07:28,663
MUCOSAL IMMUNOLOGY, DIFFERENT

8281
05:07:28,663 --> 05:07:30,098
STORY WITH INFLUENZA.

8282
05:07:30,098 --> 05:07:32,134
BUT I THINK IT'S IMPORTANT TO

8283
05:07:32,134 --> 05:07:32,768
UNDERSTAND DIFFERENCE.

8284
05:07:32,768 --> 05:07:36,738
WE KNOW WE CAN GET REINFECTED

8285
05:07:36,738 --> 05:07:38,707
WITH SARS-COV-2 SO HOW IS THAT

8286
05:07:38,707 --> 05:07:41,710
IMMUNITY INDUCED BY INFECTION.

8287
05:07:41,710 --> 05:07:42,444
ARE DIFFERENCES BETWEEN MUCOSAL

8288
05:07:42,444 --> 05:07:44,279
IMMUNOLOGY AND UPPER AND LOWER

8289
05:07:44,279 --> 05:07:45,947
TRACTS, THE ANSWER IS YES BUT WE

8290
05:07:45,947 --> 05:07:48,550
NEED TO UNDERSTAND THIS BETTER.

8291
05:07:48,550 --> 05:07:51,286
AND FINALLY ARE CERTAIN VACCINE

8292
05:07:51,286 --> 05:07:52,854
PLATFORMS BETTER AT INDUCING

8293
05:07:52,854 --> 05:07:54,256
MUCOSAL IMMUNE RESPONSE, I THINK

8294
05:07:54,256 --> 05:07:57,959
THE ANSWER IS YES, SUBUNIT

8295
05:07:57,959 --> 05:08:00,128
VACCINE IS NOT AS GOOD, FOR

8296
05:08:00,128 --> 05:08:02,664
EXAMPLE, AS A LIVE ATTENUATED

8297
05:08:02,664 --> 05:08:07,702
VIRUS BUT WE NEED TO SHOW THIS.

8298
05:08:07,702 --> 05:08:07,903
OKAY.

8299
05:08:07,903 --> 05:08:09,438
WHAT IS NEEDED?

8300
05:08:09,438 --> 05:08:11,306
AS I MENTIONED BEFORE

8301
05:08:11,306 --> 05:08:15,110
HOST-SPECIFIC REAGENTS ARE

8302
05:08:15,110 --> 05:08:18,780
IMPORTANT HERE. 

8303
05:08:18,780 --> 05:08:20,615
HAMSTERS AND FERRETS, CURRENTLY

8304
05:08:20,615 --> 05:08:20,949
DIFFICULT.

8305
05:08:20,949 --> 05:08:22,050
WE WANT TO UNDERSTAND WHAT'S

8306
05:08:22,050 --> 05:08:25,287
HAPPENING IN HUMANS AS WELL.

8307
05:08:25,287 --> 05:08:27,889
SO CAN RESULTS BE OBTAINED IN

8308
05:08:27,889 --> 05:08:30,725
ANIMAL STUDIES BE TRANSLATED TO

8309
05:08:30,725 --> 05:08:31,493
HUMANS?

8310
05:08:31,493 --> 05:08:32,694
I THINK EXPERIMENTAL INFECTION

8311
05:08:32,694 --> 05:08:33,862
STUDIES ARE FASCINATING.

8312
05:08:33,862 --> 05:08:35,096
WE NEED TO DO MORE OF THOSE.

8313
05:08:35,096 --> 05:08:37,499
WE CAN ALSO GO TO PEOPLE THAT

8314
05:08:37,499 --> 05:08:42,504
HAVE INFECTION AND START ASKING

8315
05:08:42,504 --> 05:08:43,738
WHAT IS HAPPENING IN UPPER

8316
05:08:43,738 --> 05:08:46,708
RESPIRATORY TRACT.

8317
05:08:46,708 --> 05:08:48,343
WE NEED TO OPTIMIZE A TOOL.

8318
05:08:48,343 --> 05:08:53,248
THINK ABOUT HOW YOU COLLECT

8319
05:08:53,248 --> 05:08:59,154
THOSE, RETRO ORBITAL INFECTION

8320
05:08:59,154 --> 05:09:03,792
OF CD45, NASAL TURBINATE DURING

8321
05:09:03,792 --> 05:09:04,626
INJECTION OF CD45 IN 9 NOSE

8322
05:09:04,626 --> 05:09:05,927
BECAUSE YOU GET MORE

8323
05:09:05,927 --> 05:09:06,595
CONTAMINATION OF CELLS COMING

8324
05:09:06,595 --> 05:09:12,300
FROM THE BONE MARROW.

8325
05:09:12,300 --> 05:09:15,403
I ALREADY TOLD RYAN I LOVE THE

8326
05:09:15,403 --> 05:09:18,006
DIRTY MICE, WE SHOULD BE USING

8327
05:09:18,006 --> 05:09:18,640
THEM.

8328
05:09:18,640 --> 05:09:21,409
OVERALL WE NEED TO INCREASE

8329
05:09:21,409 --> 05:09:22,577
UNDERSTANDING OF MUCOSAL

8330
05:09:22,577 --> 05:09:23,812
IMMUNOLOGY ESPECIALLY IN

8331
05:09:23,812 --> 05:09:24,479
RESPIRATORY TRACT.

8332
05:09:24,479 --> 05:09:26,081
WITH THAT I WOULD LIKE TO THANK

8333
05:09:26,081 --> 05:09:29,251
EVERYBODY THAT'S INVOLVED IN

8334
05:09:29,251 --> 05:09:31,353
THESE STUDIES, IN PARTICULAR

8335
05:09:31,353 --> 05:09:32,854
VINCENT FOR ALLOWING ME TO DO

8336
05:09:32,854 --> 05:09:39,661
STUDIES IN HIS LAB AND THE

8337
05:09:39,661 --> 05:09:46,167
PEOPLE THAT HELPED, AND FINALLY

8338
05:09:46,167 --> 05:09:49,738
MY LONGSTANDING COLLABORATORS

8339
05:09:49,738 --> 05:09:52,140
TERESA LAMBE AT SARAH GILBERT AT

8340
05:09:52,140 --> 05:09:53,475
OXFORD UNIVERSITY.

8341
05:09:53,475 --> 05:09:55,777
>> WE HAVE TIME FOR A FEW

8342
05:09:55,777 --> 05:09:58,246
QUESTIONS.

8343
05:09:58,246 --> 05:10:01,750
>> THAT WAS NICE.

8344
05:10:01,750 --> 05:10:04,786
I'M CURIOUS, USING THE mRNA

8345
05:10:04,786 --> 05:10:10,525
VACCINE, YOU USED ADENOVIRUS

8346
05:10:10,525 --> 05:10:11,159
VACCINE.

8347
05:10:11,159 --> 05:10:12,694
ADENOVIRUS VACCINE WILL

8348
05:10:12,694 --> 05:10:13,929
INTERNALIZE AND REPLICATE, AT

8349
05:10:13,929 --> 05:10:15,764
LEAST YOU'LL GET INFECTION IN

8350
05:10:15,764 --> 05:10:17,499
NEIGHBORING CELLS, OR INTO

8351
05:10:17,499 --> 05:10:17,699
CELLS.

8352
05:10:17,699 --> 05:10:22,103
HAVE YOU TRIED JUST LIKE

8353
05:10:22,103 --> 05:10:23,338
INACTIVATED VIRUS?

8354
05:10:23,338 --> 05:10:26,474
LOOKING EITHER GIVEN

8355
05:10:26,474 --> 05:10:28,577
INTRAMUSCULARLY VERSUS

8356
05:10:28,577 --> 05:10:31,012
INTRANASALLY TO THE RESPONSE IN

8357
05:10:31,012 --> 05:10:35,050
THE NALT?

8358
05:10:35,050 --> 05:10:36,585
>> WE HAVEN'T HAD TIME
YET.

8359
05:10:36,585 --> 05:10:37,986
WHAT VACCINE PLATFORM WE USE IS

8360
05:10:37,986 --> 05:10:40,055
GOING TO BE REALLY, REALLY

8361
05:10:40,055 --> 05:10:42,223
IMPORTANT IN WHAT IMMUNE

8362
05:10:42,223 --> 05:10:46,528
RESPONSE YOU GET. 

8363
05:10:46,528 --> 05:10:56,972
SUBUNIT  WE NEED TO USAGE

8364
05:10:58,607 --> 05:11:04,012
ACKNOWLEDGE ADVANCE. 

8365
05:11:04,012 --> 05:11:07,082
>> IN FERRETS ACTIVE
REPLICATION

8366
05:11:07,082 --> 05:11:08,083
RATHER THAN ACTIVATED WHOLE

8367
05:11:08,083 --> 05:11:10,919
VIRUS PROVIDES SOME LEVEL OF

8368
05:11:10,919 --> 05:11:12,454
PROTECTION FROM TRANSMISSION IN

8369
05:11:12,454 --> 05:11:14,990
OUR CASE, THAT'S WHERE THE

8370
05:11:14,990 --> 05:11:16,191
MUCOSAL IMMUNITY MIGHT BE

8371
05:11:16,191 --> 05:11:19,327
IMPORTANT FOR A VIRUS, AT LEAST

8372
05:11:19,327 --> 05:11:22,163
LOW LEVEL, LIVE ATTENUATED

8373
05:11:22,163 --> 05:11:23,064
VACCINES, POTENTIAL PLATFORMS

8374
05:11:23,064 --> 05:11:24,766
MIGHT BE INTERESTING.

8375
05:11:24,766 --> 05:11:28,603
>> I HAVE A STUDENT IN
SEPTEMBER

8376
05:11:28,603 --> 05:11:30,505
LOOKING AT TRANSCRIPTOMICS OF

8377
05:11:30,505 --> 05:11:31,473
THE VACCINATION, TRYING TO

8378
05:11:31,473 --> 05:11:33,141
UNDERSTAND WHAT THE IMMUNE

8379
05:11:33,141 --> 05:11:35,443
RESPONSE ACTUALLY LOOKS LIKE,

8380
05:11:35,443 --> 05:11:36,745
WHAT INFLAMMATION WE'RE SEEING

8381
05:11:36,745 --> 05:11:37,912
AFTER VACCINATION.

8382
05:11:37,912 --> 05:11:39,681
I THINK THAT'S GOING TO GET AT

8383
05:11:39,681 --> 05:11:43,852
THOSE QUESTIONS AS WELL.

8384
05:11:43,852 --> 05:11:45,920
>> A SIMILAR FOLLOW-UP
QUESTION,

8385
05:11:45,920 --> 05:11:46,688
BECAUSE YOU'RE FOLLOWING WITH

8386
05:11:46,688 --> 05:11:49,724
THE LIVE VIRUS DO YOU HAVE ANY

8387
05:11:49,724 --> 05:11:52,127
ANTI-VECTOR IMMUNITY OR DO YOU

8388
05:11:52,127 --> 05:11:55,897
NOT HAVE ANTI-VECTOR COMMUNITY

8389
05:11:55,897 --> 05:11:57,766
BECAUSE mRNA PROVIDES PURE

8390
05:11:57,766 --> 05:11:58,500
MUCOSAL IMMUNITY, IS THIS

8391
05:11:58,500 --> 05:12:04,506
SOMETHING TOO NEEDS TO BE

8392
05:12:04,506 --> 05:12:04,806
CONSIDERED.

8393
05:12:04,806 --> 05:12:07,375
>> WITH THE CHADOX 1 IT
DOESN'T

8394
05:12:07,375 --> 05:12:10,845
HAVE SPIKES ON THE SURFACE.

8395
05:12:10,845 --> 05:12:13,448
SOME STUDIES NOW, A LOT OF

8396
05:12:13,448 --> 05:12:14,649
PEOPLE ASK ABOUT VECTOR

8397
05:12:14,649 --> 05:12:17,786
IMMUNITY, A VERY IMPORTANT

8398
05:12:17,786 --> 05:12:21,423
QUESTION TO ASK.

8399
05:12:21,423 --> 05:12:22,857
SHE'S VACCINATED WITH ONE

8400
05:12:22,857 --> 05:12:24,726
CHADOX1, COMPARED TO A SINGLE

8401
05:12:24,726 --> 05:12:25,593
VACCINATION, SEEING FAIRLY

8402
05:12:25,593 --> 05:12:26,461
SIMILAR RESPONSES.

8403
05:12:26,461 --> 05:12:28,396
WE HAVE ALWAYS SHOWED WHEN WE DO

8404
05:12:28,396 --> 05:12:30,065
A BOOST WITH THE SAME VACCINE WE

8405
05:12:30,065 --> 05:12:32,934
DO GET A BOOST IN RESPONSE AS

8406
05:12:32,934 --> 05:12:33,168
WELL.

8407
05:12:33,168 --> 05:12:35,437
I THINK VECTOR IMMUNE RESPONSES

8408
05:12:35,437 --> 05:12:36,638
WILL LIKELY PLAY A ROLE.

8409
05:12:36,638 --> 05:12:38,506
I DON'T KNOW HOW MUCH OF A ROLE

8410
05:12:38,506 --> 05:12:42,444
THEY WILL PLAY.

8411
05:12:42,444 --> 05:12:45,080
>> TYPE 3 INTERFERENCE
VERY

8412
05:12:45,080 --> 05:12:55,256
IMPORTANT FOR MUCOSAL IMMUNITY.

8413
05:12:55,256 --> 05:12:58,493
DID YOU TEST WHETHER -- THE

8414
05:12:58,493 --> 05:12:58,860
RESPONSE?

8415
05:12:58,860 --> 05:13:00,962
>> NO, I FULLY AGREE,
THOSE ARE

8416
05:13:00,962 --> 05:13:02,497
STUDIES THAT WE HAVEN'T HAD THE

8417
05:13:02,497 --> 05:13:03,598
TIME YET TO DO.

8418
05:13:03,598 --> 05:13:05,967
YEAH, THOSE ARE ALL THINGS.

8419
05:13:05,967 --> 05:13:09,904
WE DO TRANSCRIPTOMICS IN THESE

8420
05:13:09,904 --> 05:13:11,473
ANIMALS, WE JUST FINISHED A

8421
05:13:11,473 --> 05:13:13,441
STUDY WHERE WE CHALLENGED THESE

8422
05:13:13,441 --> 05:13:15,844
MICE THAT HAD THESE

8423
05:13:15,844 --> 05:13:17,612
VACCINATIONS, AND WE HAVE

8424
05:13:17,612 --> 05:13:19,013
TISSUES, WHICH WE'RE GOING TO

8425
05:13:19,013 --> 05:13:25,253
LOOK EXACTLY AT THAT. 

8426
05:13:25,253 --> 05:13:28,356
>> THE REASON I ASK,
RECEPTOR

8427
05:13:28,356 --> 05:13:32,127
AND KNOCKOUT, HAVE YOU TRIED TO

8428
05:13:32,127 --> 05:13:38,299
CONVINCE THE WORLD TO USE THEM,

8429
05:13:38,299 --> 05:13:42,137
UNTIL RECENTLY -- YEAH, I NEED

8430
05:13:42,137 --> 05:13:42,337
MORE.

8431
05:13:42,337 --> 05:13:49,444
THANK YOU. 

8432
05:13:49,444 --> 05:13:50,979
>> ONE QUICK QUESTION, IN
A

8433
05:13:50,979 --> 05:13:54,516
WORLD IN WHICH WE AGENT

8434
05:13:54,516 --> 05:13:55,817
LIMITATIONS ARE NOT AN ISSUE,

8435
05:13:55,817 --> 05:13:57,886
MAYBE COST LIMITATIONS WHAT IS

8436
05:13:57,886 --> 05:14:01,389
YOUR PREFERRED MODEL FOR THESE

8437
05:14:01,389 --> 05:14:01,823
THINGS?

8438
05:14:01,823 --> 05:14:03,158
>> THE HUMAN.

8439
05:14:03,158 --> 05:14:07,595
>> WHAT IS YOUR PREFERRED
SMALL

8440
05:14:07,595 --> 05:14:08,296
ANIMAL MODEL?

8441
05:14:08,296 --> 05:14:10,932
>> I THINK FOR SARS 2,
JUST A

8442
05:14:10,932 --> 05:14:12,000
PRACTICALITY THING, THE HAMSTER

8443
05:14:12,000 --> 05:14:13,501
IS REALLY GOOD AT LOOKING AT

8444
05:14:13,501 --> 05:14:14,335
TRANSMISSION STUDIES.

8445
05:14:14,335 --> 05:14:15,870
IF YOU WANT TO TAKE IT FURTHER

8446
05:14:15,870 --> 05:14:20,542
AND LOOK AT TRANSMISSION OF THE

8447
05:14:20,542 --> 05:14:25,480
VIRUS, WHEN YOU START LOOKING AT

8448
05:14:25,480 --> 05:14:26,781
THE FERRET, THE PHYSIOLOGY OF

8449
05:14:26,781 --> 05:14:28,316
THE LUNG IS MUCH MORE LIKE A

8450
05:14:28,316 --> 05:14:30,485
HUMAN.

8451
05:14:30,485 --> 05:14:31,853
 

8452
05:14:31,853 --> 05:14:32,887
>> THANK YOU.

8453
05:14:32,887 --> 05:14:34,322
WE'LL TAKE A 15-MINUTE BREAK NOW

8454
05:14:34,322 --> 05:14:41,866
AND COME BACK AT 3:30. 

8455
05:14:41,866 --> 05:14:43,635
WE'LL HAVE THE LAST TALK OF

8456
05:14:43,635 --> 05:14:46,571
THE SESSION, AND WE'LL HAVE A

8457
05:14:46,571 --> 05:14:48,206
PANEL DISCUSSION.

8458
05:14:48,206 --> 05:14:50,842
SO THE SPEAKER NOW IS MEHUL

8459
05:14:50,842 --> 05:14:52,410
SUTHAR, WHO WILL TALK ABOUT

8460
05:14:52,410 --> 05:14:54,879
EXAMINING THE INNATE AND

8461
05:14:54,879 --> 05:14:56,247
ADAPTIVE IMMUNES RESPONSES TO

8462
05:14:56,247 --> 05:14:57,983
SARS-COV-2 INFECTION.

8463
05:14:57,983 --> 05:14:58,817
>> THANK YOU SO MUCH.

8464
05:14:58,817 --> 05:15:02,854
I WANT TO THANK THE ORGANIZERS

8465
05:15:02,854 --> 05:15:03,855
ESPECIALLY MICHELLE FOR GIVING

8466
05:15:03,855 --> 05:15:05,490
ME OPPORTUNITY TO PRESENT WORK

8467
05:15:05,490 --> 05:15:11,396
IN MY LAB ABOUT MOUSE MODELS OF

8468
05:15:11,396 --> 05:15:11,963
SARS-COV-2.

8469
05:15:11,963 --> 05:15:15,467
WE ANCHOR ON WHAT OBSERVATIONS

8470
05:15:15,467 --> 05:15:17,369
WE'RE MAKING IN HUMANS TO

8471
05:15:17,369 --> 05:15:18,436
DEVELOP SOME LEVEL OF

8472
05:15:18,436 --> 05:15:23,241
UNDERSTANDING IN MICE AND FEED

8473
05:15:23,241 --> 05:15:25,543
THAT BACK INTO WHAT MIGHT BE

8474
05:15:25,543 --> 05:15:26,745
HAPPENING IN HUMANS BASED ON

8475
05:15:26,745 --> 05:15:29,514
OBSERVATIONS OF MICE.

8476
05:15:29,514 --> 05:15:31,683
IF THE SWISS CHEESE MODEL THAT

8477
05:15:31,683 --> 05:15:33,651
DEMONSTRATES THE MANY LAYERS OF

8478
05:15:33,651 --> 05:15:37,922
IMMUNITY THAT ARE PRESENT, THE

8479
05:15:37,922 --> 05:15:38,857
SARS-COV-2 VARIANTS OVERCOMING

8480
05:15:38,857 --> 05:15:46,731
THROUGH HOLES IN OUR IMMUNE

8481
05:15:46,731 --> 05:15:47,766
SYSTEM.

8482
05:15:47,766 --> 05:15:50,001
ELEMENTS OF INNATE RESPONSE, B

8483
05:15:50,001 --> 05:15:51,236
CELL RESPONSE, C TELL, RESIDENTS

8484
05:15:51,236 --> 05:15:52,637
CIRCULATING PLAYING A ROLE.

8485
05:15:52,637 --> 05:15:54,606
WE THINK ABOUT THIS WE WOULD

8486
05:15:54,606 --> 05:15:56,041
LIKE TO MODEL DIFFERENT ASPECTS

8487
05:15:56,041 --> 05:15:57,008
IN MICE.

8488
05:15:57,008 --> 05:16:00,545
ONE OF THE FIRST THINGS IN EARLY

8489
05:16:00,545 --> 05:16:06,418
2020 WAS WORK CLOSELY TO HELP

8490
05:16:06,418 --> 05:16:07,852
DEVELOP SARS-COV-2 MOUSE MODELS

8491
05:16:07,852 --> 05:16:11,022
IN NATURE AND DEVELOP MODELS AND

8492
05:16:11,022 --> 05:16:12,557
UNDERSTAND INNATE AND ADAPTIVE

8493
05:16:12,557 --> 05:16:15,660
IMMUNE RESPONSE, SOME WORK WE

8494
05:16:15,660 --> 05:16:16,895
RECENTLY -- WORK RECENTLY

8495
05:16:16,895 --> 05:16:18,096
ACCEPTED TO UNDERSTAND

8496
05:16:18,096 --> 05:16:20,465
CONTRIBUTION OF T CELLS IN THE

8497
05:16:20,465 --> 05:16:21,866
RESPIRATORY TRACT, PRIMARY

8498
05:16:21,866 --> 05:16:22,200
INFECTION.

8499
05:16:22,200 --> 05:16:29,007
LASTLY I'LL TOUCH ON WORK THAT

8500
05:16:29,007 --> 05:16:30,775
IS IN PREPARATION TO UNDERSTAND

8501
05:16:30,775 --> 05:16:33,078
AND MODEL VACCINE BREAKTHROUGH,

8502
05:16:33,078 --> 05:16:35,814
AS MICHAEL ALLUDED TO, POTENTIAL

8503
05:16:35,814 --> 05:16:37,115
PROTECTIVE ROLE OF EOSINOPHILS

8504
05:16:37,115 --> 05:16:41,086
IN THIS CONTEXT.

8505
05:16:41,086 --> 05:16:44,989
WE'VE DISCUSSED THIS BUT N 501Y

8506
05:16:44,989 --> 05:16:49,060
OCCURRED PRIOR TO THAT,

8507
05:16:49,060 --> 05:16:50,361
INVESTIGATORS IN BEIJING HAD

8508
05:16:50,361 --> 05:16:52,197
PASSAGED THEIR STRAIN OF I

8509
05:16:52,197 --> 05:16:55,400
BELIEVE B1 IN MICE RESULTING IN

8510
05:16:55,400 --> 05:16:59,904
A MUTATION AT N 51Y ALLOWS FOR

8511
05:16:59,904 --> 05:17:01,606
MOUSE INFECTION, HELPED

8512
05:17:01,606 --> 05:17:05,910
INTERACTION WITH MOUSE ACE-2

8513
05:17:05,910 --> 05:17:14,786
WITH HISTIDINE AT 353.

8514
05:17:14,786 --> 05:17:25,263
THAT WAS FURTHER PASSAGED IN

8515
05:17:27,632 --> 05:17:30,301
BALB-C MICE, MUTATIONS IN THE

8516
05:17:30,301 --> 05:17:33,004
SPIKE PROTEIN, N 501Y WAS

8517
05:17:33,004 --> 05:17:38,610
RETAINED, THIS VIRUS PICKED UP

8518
05:17:38,610 --> 05:17:40,912
NK 417N NOW NATURALLY OCCURRING

8519
05:17:40,912 --> 05:17:43,181
IN VARIANTS, AGAIN PRIOR TO

8520
05:17:43,181 --> 05:17:44,716
EMERGENCE OF VARIANTS.

8521
05:17:44,716 --> 05:17:47,886
WE SAW MUTATION AT POSITION 655Y

8522
05:17:47,886 --> 05:17:50,321
THAT OCCURRED WITHIN THE SPIKE

8523
05:17:50,321 --> 05:17:52,390
PROTEIN AND COLLECTIVELY THIS

8524
05:17:52,390 --> 05:17:56,027
ALLOWED FOR THIS VIRUS TO CAUSE

8525
05:17:56,027 --> 05:18:01,766
WEIGHT LOSS IN MICE, NICE LUNG

8526
05:18:01,766 --> 05:18:03,001
VIRUS REPLICATION, LIMITED

8527
05:18:03,001 --> 05:18:03,468
EXTRA-PULMONARY VIRUS

8528
05:18:03,468 --> 05:18:06,104
REPLICATION, SOME IN THE HEART

8529
05:18:06,104 --> 05:18:08,339
HE OBSERVED, THIS REPLICATED IN

8530
05:18:08,339 --> 05:18:09,908
THE LARGE AIRWAY WITH LESS

8531
05:18:09,908 --> 05:18:11,075
REPLICATION IN THE SMALLER

8532
05:18:11,075 --> 05:18:12,610
AIRWAYS BUT THERE WAS

8533
05:18:12,610 --> 05:18:14,045
INFLAMMATION THAT OCCURRED, I'LL

8534
05:18:14,045 --> 05:18:22,353
SLOW SOME DATA WE PRODUCED USING

8535
05:18:22,353 --> 05:18:28,626
THIS VIRUS WE STARTED TO WORK

8536
05:18:28,626 --> 05:18:33,765
WITH CMA 3 P20 BUT THE BETA

8537
05:18:33,765 --> 05:18:39,204
VARIANT IS A WORK HORSE, AFFECTS

8538
05:18:39,204 --> 05:18:41,039
MICE, DOSE DEPENDENT, AGE

8539
05:18:41,039 --> 05:18:46,077
DEPENDENT, WEIGHT LOSS 8 TO 20

8540
05:18:46,077 --> 05:18:48,046
WEEKS, SIMILAR TO SARS-COV-1,

8541
05:18:48,046 --> 05:18:50,882
YOU SEE INCREASE IN WEIGHT LOSS

8542
05:18:50,882 --> 05:18:54,619
WITH INCREASE IN AGE, 5 TO 10%

8543
05:18:54,619 --> 05:18:55,820
INTRANASALLY RESULTING IN 30%

8544
05:18:55,820 --> 05:18:58,756
MORTALITY IN THESE MICE.

8545
05:18:58,756 --> 05:19:01,626
MOST STUDIES WE TYPICALLY USED 1

8546
05:19:01,626 --> 05:19:03,394
TIMES 10 TO THE 6 AND COMPARED

8547
05:19:03,394 --> 05:19:05,363
SIDE BY SIDE WITH MOUSE ADAPTED

8548
05:19:05,363 --> 05:19:07,966
STRAINS IN DATA NOT SHOWING BUT

8549
05:19:07,966 --> 05:19:10,501
VIRUS REPLICATES WELL IN THE

8550
05:19:10,501 --> 05:19:16,407
LUNGS, CLEARED INFECTIOUS

8551
05:19:16,407 --> 05:19:19,377
VIRUS-WISE BY DAY 10 POST

8552
05:19:19,377 --> 05:19:21,980
INFECTION, INDUCED NICE

8553
05:19:21,980 --> 05:19:22,847
SPIKE-SPECIFIC ANTIBODIES,

8554
05:19:22,847 --> 05:19:23,881
NUCLEOCAPSID ANTIBODIES,

8555
05:19:23,881 --> 05:19:26,451
NEUTRALIZING, AND YOU SEE VERY

8556
05:19:26,451 --> 05:19:28,286
NICE INNATE IMMUNE RESPONSES,

8557
05:19:28,286 --> 05:19:31,723
SEVERAL SPEAKERS HAVE SHOWN

8558
05:19:31,723 --> 05:19:34,058
PRIOR TO THIS PRESENTATION.

8559
05:19:34,058 --> 05:19:35,560
IN MY LAB WE HAVE A BASIC

8560
05:19:35,560 --> 05:19:36,361
QUESTION, WHAT IS HAPPENING IN

8561
05:19:36,361 --> 05:19:37,996
THE LUNGS AND HOW DOES THIS LOOK

8562
05:19:37,996 --> 05:19:45,303
SIMILAR TO WHAT WE SEE IN

8563
05:19:45,303 --> 05:19:46,738
HUMANS.

8564
05:19:46,738 --> 05:19:49,474
ACROSS MULTIPLE MODELS WE USE A

8565
05:19:49,474 --> 05:19:53,478
LABELING TECHNIQUE TO TAG TISSUE

8566
05:19:53,478 --> 05:19:54,145
RESIDENT CELLS VERSUS

8567
05:19:54,145 --> 05:19:56,514
CIRCULATING CELLS, ISOLATED BY

8568
05:19:56,514 --> 05:19:58,082
FLOW CYTOMETRY, AND FOLLOWING

8569
05:19:58,082 --> 05:20:00,184
SARS-COV-2 INFECTION THIS IS

8570
05:20:00,184 --> 05:20:05,556
WORK PUBLISHED IN 2020, 2021, WE

8571
05:20:05,556 --> 05:20:07,992
SEE INFLUX OF NEUTROPHILS,

8572
05:20:07,992 --> 05:20:12,163
EOSINOPHILS, MONOCYTES COMING

8573
05:20:12,163 --> 05:20:15,433
IN, INFLAMMATORY MONOCYTES,

8574
05:20:15,433 --> 05:20:22,240
DIFFERENTIATED BASED ON LY 6

8575
05:20:22,240 --> 05:20:26,577
HIGH AND LOW, AND USE LABELING,

8576
05:20:26,577 --> 05:20:33,584
ISOLATE CELLS, WE USE MAGNETIC

8577
05:20:33,584 --> 05:20:37,322
SORT COLUMN OR MAGNETIC

8578
05:20:37,322 --> 05:20:40,591
DEISOLATION TO ISOLATE, TAKE

8579
05:20:40,591 --> 05:20:43,995
NEGATIVE CELLS WHICH ARE TISSUE

8580
05:20:43,995 --> 05:20:46,864
RESIDENT AND PERFORM SINGLE CELL

8581
05:20:46,864 --> 05:20:49,000
RNAseq, LOOKING AT TISSUE

8582
05:20:49,000 --> 05:20:52,103
RESIDENCE, INNATE IMMUNE CELLS,

8583
05:20:52,103 --> 05:20:53,104
PERFORM CLUSTERING ANALYSIS,

8584
05:20:53,104 --> 05:20:55,039
SHOWING SIMILAR TO FLOW

8585
05:20:55,039 --> 05:20:57,542
CYTOMETRY, ALL THESE POPULATIONS

8586
05:20:57,542 --> 05:21:02,613
OF CELLS, SIMILAR TO WHAT

8587
05:21:02,613 --> 05:21:03,681
MICHAEL MENTIONED, ALVEOLAR

8588
05:21:03,681 --> 05:21:05,350
MACROPHAGE POPULATION DECREASE

8589
05:21:05,350 --> 05:21:06,284
FOLLOWING INFECTION, REBOUNDING

8590
05:21:06,284 --> 05:21:07,118
30 DAYS AFTER INFECTION.

8591
05:21:07,118 --> 05:21:13,858
ONE OF THE THINGS WE OBSERVED IN

8592
05:21:13,858 --> 05:21:23,368
THIS SINGLE CELL  RNAseq IS

8593
05:21:23,368 --> 05:21:24,669
UPREGULATION, WHAT ROLE DOES IT

8594
05:21:24,669 --> 05:21:25,002
PLAY?

8595
05:21:25,002 --> 05:21:27,939
WE GOT OUR HANDS ON KNOCKOUT

8596
05:21:27,939 --> 05:21:30,241
MICE, WE SEE GREATER WEIGHT LOSS

8597
05:21:30,241 --> 05:21:35,046
BY DAY 3, DAY 4, POST-INFECTION,

8598
05:21:35,046 --> 05:21:38,015
SOME MICE DO RECOVER.

8599
05:21:38,015 --> 05:21:39,984
60% MORTALITY DEMONSTRATING

8600
05:21:39,984 --> 05:21:44,889
IMPORTANCE THAT CCR 2 PLAYS AND

8601
05:21:44,889 --> 05:21:45,790
INNATE IMMUNE RESPONSE

8602
05:21:45,790 --> 05:21:48,292
PROTECTING AGAINST INFECTION.

8603
05:21:48,292 --> 05:21:49,827
WE SEE SLIGHT INCREASE IN VIRAL

8604
05:21:49,827 --> 05:21:50,027
LOAD.

8605
05:21:50,027 --> 05:21:53,431
IN WILDTYPE MICE WE SEE MUCH

8606
05:21:53,431 --> 05:21:55,500
MORE RESTRICTED VIRUS

8607
05:21:55,500 --> 05:21:56,701
REPLICATION IN LARGE AIRWAYS.

8608
05:21:56,701 --> 05:21:59,904
CCR 2 KNOCKOUTS MORE EXPANDED

8609
05:21:59,904 --> 05:22:01,572
REPLICATION BEYOND JUST LARGE

8610
05:22:01,572 --> 05:22:05,910
AIRWAYS, WE SEE IT IN THE SMALL

8611
05:22:05,910 --> 05:22:07,311
AIRWAYS, INNATE RESPONSE IS VERY

8612
05:22:07,311 --> 05:22:09,814
IMPORTANT FOR RESTRICTING WHERE

8613
05:22:09,814 --> 05:22:16,087
THIS VIRUS REPLICATES WITHIN THE

8614
05:22:16,087 --> 05:22:16,454
LUNGS.

8615
05:22:16,454 --> 05:22:19,090
WE'VE DONE SOME WORK LOOKING AT

8616
05:22:19,090 --> 05:22:22,827
TYPE I INTERFERON GROUP, RALPH'S

8617
05:22:22,827 --> 05:22:25,863
GROUP LOOKED, KNOCKOUT MICE LIVE

8618
05:22:25,863 --> 05:22:27,031
IN SARS-COV-2 INFECTION, ONE OF

8619
05:22:27,031 --> 05:22:30,101
THE FEW VIRUSES I KNOW OF THAT

8620
05:22:30,101 --> 05:22:34,071
DOESN'T KILL IT IN FRONT OF A

8621
05:22:34,071 --> 05:22:34,505
KNOCKOUT MOUSE.

8622
05:22:34,505 --> 05:22:36,441
TYPE 3 INTERFERONS ARE VERY

8623
05:22:36,441 --> 05:22:39,110
IMPORTANT, MAY BE OVERLAPPING

8624
05:22:39,110 --> 05:22:39,877
FUNCTION BETWEEN TYPE I AND TYPE

8625
05:22:39,877 --> 05:22:40,511
II INTERFERON.

8626
05:22:40,511 --> 05:22:42,146
ONE OF THE MORE IMPORTANT

8627
05:22:42,146 --> 05:22:44,015
QUESTIONS WE'RE NOW STARTING TO

8628
05:22:44,015 --> 05:22:46,317
ASK WHAT IS THE IMPORTANCE OF

8629
05:22:46,317 --> 05:22:47,518
THE UPPER VERSUS LOWER

8630
05:22:47,518 --> 05:22:49,921
RESPIRATORY TRACT, I'LL SO DATA

8631
05:22:49,921 --> 05:22:52,557
FROM T CELLS, GOING BACK TO

8632
05:22:52,557 --> 05:22:54,525
SYSTEMATIC ACROSS TIME POINTS

8633
05:22:54,525 --> 05:22:56,160
FROM ACUTE INFECTION TO RECOVERY

8634
05:22:56,160 --> 05:22:59,664
IN THE UPPER AND LOWER

8635
05:22:59,664 --> 05:23:00,865
RESPIRATORY TRACT OF INFECTION.

8636
05:23:00,865 --> 05:23:02,200
I'LL SO DATA ABOUT VACCINE

8637
05:23:02,200 --> 05:23:04,068
BREAKTHROUGH, WHAT IS THE ROLE

8638
05:23:04,068 --> 05:23:11,375
OF THE INNATE IMMUNE RESPONSE?

8639
05:23:11,375 --> 05:23:13,244
AND SO WE'RE FAMILIAR THAT T

8640
05:23:13,244 --> 05:23:14,879
CELLS ARE VERY IMPORTANT IN

8641
05:23:14,879 --> 05:23:20,485
SARS-COV-2 INFECTION IN HUMANS.

8642
05:23:20,485 --> 05:23:25,823
T CELLS ARE INDUCED, YOU SEE IN

8643
05:23:25,823 --> 05:23:27,391
PERIPHERAL BLOOD.

8644
05:23:27,391 --> 05:23:29,227
MANY HAVE SHOWN T CELLS ARE

8645
05:23:29,227 --> 05:23:33,498
INDUCED IN PERIPHERAL BLOOD,

8646
05:23:33,498 --> 05:23:35,900
MAINTAINED, QUITE STABLE IN

8647
05:23:35,900 --> 05:23:36,767
DURABILITY, AFTER INFECTION OR

8648
05:23:36,767 --> 05:23:37,068
VACCINATION.

8649
05:23:37,068 --> 05:23:39,070
ONE OF THE MORE RECENT FINDINGS

8650
05:23:39,070 --> 05:23:41,138
PEOPLE HAD LOOKING IN HUMANS

8651
05:23:41,138 --> 05:23:42,373
BREAKTHROUGH INFECTIONS DO

8652
05:23:42,373 --> 05:23:45,910
INDUCE NASAL CD4 AND CD8 T-CELL

8653
05:23:45,910 --> 05:23:46,444
RESPONSES.

8654
05:23:46,444 --> 05:23:48,212
WE WANTED TO ASK IN MOUSE

8655
05:23:48,212 --> 05:23:49,480
MODELS, BLACK 6 MOUSE MODELS,

8656
05:23:49,480 --> 05:23:58,756
WHAT IS THE ROLE OF T CELLS?

8657
05:23:58,756 --> 05:23:59,891
USING LABELING, HARVESTING

8658
05:23:59,891 --> 05:24:01,859
TISSUE FROM LUNG AND NASAL

8659
05:24:01,859 --> 05:24:03,594
COMPARTMENT, ALSO THE SPLEEN,

8660
05:24:03,594 --> 05:24:07,265
I'M NOT SHOWING THAT DATA TODAY.

8661
05:24:07,265 --> 05:24:09,967
FOLLOWING INFECTION TO REDUCE

8662
05:24:09,967 --> 05:24:11,369
RECRUITMENT OF CD4 AND CD8 T

8663
05:24:11,369 --> 05:24:14,338
CELLS IN THE LUNGS AS WELL AS

8664
05:24:14,338 --> 05:24:15,139
WITHIN THE NASAL COMPARTMENT,

8665
05:24:15,139 --> 05:24:17,742
THIS IS LOOKING AT DAY 8

8666
05:24:17,742 --> 05:24:18,109
POST-INFECTION.

8667
05:24:18,109 --> 05:24:20,545
WE SEE 3 1/2-FOLD INCREASE IN

8668
05:24:20,545 --> 05:24:25,850
CD8 T CELLS IN THE LUNG, 1st

8669
05:24:25,850 --> 05:24:33,357
INCREASE OF CD4 T CELLS,

8670
05:24:33,357 --> 05:24:38,062
STRONGER INCREASE IN THE NASAL

8671
05:24:38,062 --> 05:24:39,263
COMPARTMENT, SUGGESTING CD8 T

8672
05:24:39,263 --> 05:24:41,232
CELLS MAY PLAY IMPORTANT ROLE IN

8673
05:24:41,232 --> 05:24:44,835
UPPER RESPIRATORY TRACT.

8674
05:24:44,835 --> 05:24:46,704
WE PERFORMED PEPTIDE

8675
05:24:46,704 --> 05:24:51,943
RESTIMULATION, ANTIGEN SPECIFIC

8676
05:24:51,943 --> 05:24:53,911
RESPONSES.

8677
05:24:53,911 --> 05:24:56,881
LOOKING AT GRANZYME B,

8678
05:24:56,881 --> 05:24:58,749
UPREGULATION IN NASAL AND LUNG

8679
05:24:58,749 --> 05:24:59,951
COMPARTMENT FOLLOWING INFECTION.

8680
05:24:59,951 --> 05:25:05,289
CD 4 CELLS WE SEE BOTH SINGLE

8681
05:25:05,289 --> 05:25:06,090
POSITIVE, INTERFERON GAMMA, TNF,

8682
05:25:06,090 --> 05:25:06,991
DOUBLE POSITIVE CELLS.

8683
05:25:06,991 --> 05:25:08,059
THERE ARE SLIGHT DIFFERENCES IN

8684
05:25:08,059 --> 05:25:10,761
WHAT WE'RE SEEING BETWEEN THE

8685
05:25:10,761 --> 05:25:11,562
UPPER AND LOWER RESPIRATORY

8686
05:25:11,562 --> 05:25:12,396
TRACT.

8687
05:25:12,396 --> 05:25:15,066
FOR INSTANCE IN NASAL

8688
05:25:15,066 --> 05:25:16,701
COMPARTMENT, IT'S PREDOMINANTLY

8689
05:25:16,701 --> 05:25:18,102
SINGLE POSITIVE TNF ALPHA AND

8690
05:25:18,102 --> 05:25:19,203
INTERFERON GAMMA POSITIVE CELLS.

8691
05:25:19,203 --> 05:25:22,573
IN THE LUNGS WE DO SEE

8692
05:25:22,573 --> 05:25:23,941
POPULATION OF DOUBLE POSITIVE

8693
05:25:23,941 --> 05:25:26,043
CELLS FOR CD4.

8694
05:25:26,043 --> 05:25:28,579
GO TO CD8 T CELLS WE SEE BETWEEN

8695
05:25:28,579 --> 05:25:31,816
THE LUNGS AND NASAL COMPARTMENT

8696
05:25:31,816 --> 05:25:33,317
HIGHER LEVELS OF TNF ALPHA

8697
05:25:33,317 --> 05:25:34,118
PRODUCING CD8 T CELLS IN THE UP

8698
05:25:34,118 --> 05:25:35,152
HE WERE.

8699
05:25:35,152 --> 05:25:38,222
IN THE LUNGS WE SEE LOWER LEVELS

8700
05:25:38,222 --> 05:25:39,757
OF TNF ALPHA RELATIVE TO

8701
05:25:39,757 --> 05:25:42,493
INTERFERON GAMMA SO THERE ARE

8702
05:25:42,493 --> 05:25:44,662
ANATOMIC DIFFERENCES BEHIND HOW

8703
05:25:44,662 --> 05:25:45,830
THESE CD8 T CELLS FUNCTION

8704
05:25:45,830 --> 05:25:49,066
WITHIN THE UPPER AND LOWER

8705
05:25:49,066 --> 05:25:50,267
COMPARTMENT.

8706
05:25:50,267 --> 05:25:52,970
WE LOOKED AT DURABILITY THROUGH

8707
05:25:52,970 --> 05:25:56,941
28 DAYS WITHIN THESE

8708
05:25:56,941 --> 05:25:58,576
COMPARTMENTS AS SIMPLY DO THESE

8709
05:25:58,576 --> 05:26:01,445
T CELLS -- ARE THEY MAINTAINED

8710
05:26:01,445 --> 05:26:02,713
IN COMPARTMENTS DIFFERENTLY.

8711
05:26:02,713 --> 05:26:05,016
WE LOOKED IN THE LUNGS.

8712
05:26:05,016 --> 05:26:06,384
SORRY, NASAL COMPARTMENT.

8713
05:26:06,384 --> 05:26:09,186
WE LOOKED AT ANTIGEN SPECIFIC,

8714
05:26:09,186 --> 05:26:12,857
WHETHER TNF ALPHA OR INTERFERON

8715
05:26:12,857 --> 05:26:14,558
GAMMA.

8716
05:26:14,558 --> 05:26:21,232
WE SEE A SINGLE POSITIVE, SEEMED

8717
05:26:21,232 --> 05:26:24,235
TO BE STABLE FOR CD4 CELLS,

8718
05:26:24,235 --> 05:26:25,069
DOUBLE POSITIVE CELLS MORE

8719
05:26:25,069 --> 05:26:28,339
STABLE WITHIN THE LUNGS COMPARED

8720
05:26:28,339 --> 05:26:29,373
TO NASAL COMPARTMENT.

8721
05:26:29,373 --> 05:26:36,714
CD8 T CELLS WE SEE DIFFERENT

8722
05:26:36,714 --> 05:26:40,718
PROFILE, MORE STABLE IN THE

8723
05:26:40,718 --> 05:26:43,788
NASAL COMPARTMENT COMPARED TO

8724
05:26:43,788 --> 05:26:44,922
LUNGS.

8725
05:26:44,922 --> 05:26:47,792
INTERFERE GAMMA HIGHER IN THE

8726
05:26:47,792 --> 05:26:50,261
LUNGS, DIMINISHES, IF YOU LOOK

8727
05:26:50,261 --> 05:26:52,329
AT DOUBLE POSITIVE CELLS THESE

8728
05:26:52,329 --> 05:26:57,234
CELLS SHOW HIGHER LEVEL AT DAY

8729
05:26:57,234 --> 05:27:03,040
7, DIMINISH THROUGH DAY 28.

8730
05:27:03,040 --> 05:27:05,910
WE LOOKED AT THE CONTRIBUTION OF

8731
05:27:05,910 --> 05:27:10,815
CD4 AND CD8 T CELLS OR BOTH IN

8732
05:27:10,815 --> 05:27:13,517
TANDEM, FOLLOWING SARS-COV-2 SO

8733
05:27:13,517 --> 05:27:16,187
WE TOOK A VERY SLEDGEHAMMER

8734
05:27:16,187 --> 05:27:18,823
APPROACH TO MAKE SURE T CELLS

8735
05:27:18,823 --> 05:27:20,491
HAVE BEEN DEPLETED, INJECT MICE

8736
05:27:20,491 --> 05:27:25,496
THREE TIMES BEFORE WE INSPECT

8737
05:27:25,496 --> 05:27:28,032
AND EVERY WEEK PROVIDE

8738
05:27:28,032 --> 05:27:29,533
ADDITIONAL ANTIBODIES THROUGH

8739
05:27:29,533 --> 05:27:31,202
DAY 28 POST-INFECTION.

8740
05:27:31,202 --> 05:27:33,904
CD8 T CELLS AND CD4 T CELLS

8741
05:27:33,904 --> 05:27:36,073
DEPLETED QUITE WELL WITHIN THE

8742
05:27:36,073 --> 05:27:37,241
LUNGS AND NASAL COMPARTMENT.

8743
05:27:37,241 --> 05:27:39,977
FOR THE MOST PART WE SEE THESE

8744
05:27:39,977 --> 05:27:42,813
DEPLETED IN THE BLOOD AS WELL

8745
05:27:42,813 --> 05:27:44,515
THROUGH DAY 28, NOT JUST BEFORE

8746
05:27:44,515 --> 05:27:46,784
INFECTION, WE FOLLOW THESE

8747
05:27:46,784 --> 05:27:49,720
THROUGH INFECTION AS WELL.

8748
05:27:49,720 --> 05:27:50,588
SURPRISINGLY, THE LACK OF T

8749
05:27:50,588 --> 05:27:53,457
CELLS DOES NOT KILL A MOUSE,

8750
05:27:53,457 --> 05:27:54,625
WHICH FURTHER SUPPORTS INNATE

8751
05:27:54,625 --> 05:27:55,693
IMMUNE RESPONSE IS QUITE

8752
05:27:55,693 --> 05:27:56,761
IMPORTANT FOR PROTECTION.

8753
05:27:56,761 --> 05:27:58,395
WE DON'T SEE MUCH OF A

8754
05:27:58,395 --> 05:28:01,265
DIFFERENCE IN WEIGHT LOSS WITH

8755
05:28:01,265 --> 05:28:04,368
SINGLE DEPLETION OR TANDEM

8756
05:28:04,368 --> 05:28:05,836
DEPLETED MICE, MIRRORS WHAT

8757
05:28:05,836 --> 05:28:11,275
RALPH'S LAB HAD SEEN MANY YEARS

8758
05:28:11,275 --> 05:28:12,376
AGO WITH SARS-COV-1, IF YOU

8759
05:28:12,376 --> 05:28:15,880
DON'T HAVE THE CELLS THE MICE

8760
05:28:15,880 --> 05:28:17,014
LIVE, QUITE IMPORTANT FOR

8761
05:28:17,014 --> 05:28:17,748
DRIVING PROTECTION.

8762
05:28:17,748 --> 05:28:26,390
THAT'S ONE OF THE SIMILAR

8763
05:28:26,390 --> 05:28:29,727
ASPECTS BETWEEN BOTH VIRUSES.

8764
05:28:29,727 --> 05:28:36,467
IN THE LUNGS DAY 3, DAY 10 AND

8765
05:28:36,467 --> 05:28:38,202
DAY 28, TYPICALLY WHERE YOU HAVE

8766
05:28:38,202 --> 05:28:41,172
VERY LOW LEVELS OF VIRAL RNA.

8767
05:28:41,172 --> 05:28:43,774
IN EITHER THE SINGLE OR DOUBLE

8768
05:28:43,774 --> 05:28:47,178
DEPLETED MICE BY DAY 28

8769
05:28:47,178 --> 05:28:48,612
POST-INFECTION THIS VIRUS IS

8770
05:28:48,612 --> 05:28:49,713
PRETTY WELL CONTROLLED.

8771
05:28:49,713 --> 05:28:51,682
DAY 10 THERE MAY BE SLIGHT

8772
05:28:51,682 --> 05:28:54,051
DIFFERENCE IN VIRAL CONTROL AS

8773
05:28:54,051 --> 05:28:56,053
TANDEM DEPLETED MICE CD4 AND CD8

8774
05:28:56,053 --> 05:29:03,594
DEPLETED SHOW HIGHER LEVELS OF

8775
05:29:03,594 --> 05:29:06,230
VIRUS REPLICATION, IMPACT OF

8776
05:29:06,230 --> 05:29:06,997
VIRAL KINETICS.

8777
05:29:06,997 --> 05:29:09,800
WITHOUT T CELLS THESE MICE

8778
05:29:09,800 --> 05:29:12,503
COMPLETELY CONTROL INFECTION.

8779
05:29:12,503 --> 05:29:16,907
LOOKING IN NASAL COMPARTMENT

8780
05:29:16,907 --> 05:29:19,143
DEPLETION OF CD4 T CELLS,

8781
05:29:19,143 --> 05:29:21,645
SLIGHTLY HIGHER ELEVATED BUT

8782
05:29:21,645 --> 05:29:23,547
TANDEM DEPLETED ARE NOT

8783
05:29:23,547 --> 05:29:25,149
SIGNIFICANTLY HIGHER.

8784
05:29:25,149 --> 05:29:27,351
DAY 28 POST-INFECTION TANDEM

8785
05:29:27,351 --> 05:29:29,220
DEPLETED MICE SHOW HIGHER LEVEL

8786
05:29:29,220 --> 05:29:31,789
OF VIRUS REPLICATION COMPARED TO

8787
05:29:31,789 --> 05:29:38,796
EITHER SINGLE DEPLETED CD4 CD8

8788
05:29:38,796 --> 05:29:40,130
OR CONTROL, SUGGESTING

8789
05:29:40,130 --> 05:29:42,199
IMPORTANCE FOR CLEARING VIRUS

8790
05:29:42,199 --> 05:29:43,267
INFECTION.

8791
05:29:43,267 --> 05:29:46,070
WE WANTED TO ASK WHAT ROLE DO

8792
05:29:46,070 --> 05:29:46,837
ANTIBODIES PLAY?

8793
05:29:46,837 --> 05:29:51,542
IF YOU LOOK AT SPIKE BINDING,

8794
05:29:51,542 --> 05:29:53,277
RBD OR NUCLEOCAPSID BINDING, YOU

8795
05:29:53,277 --> 05:29:55,546
LOSE ANTIBODY RESPONSES SO IT'S

8796
05:29:55,546 --> 05:29:56,881
A T CELL-DEPENDENT RESPONSE,

8797
05:29:56,881 --> 05:29:59,717
VERY SIMILAR TO WHAT YOU SEE IN

8798
05:29:59,717 --> 05:30:03,420
HUMANS, AS WELL AS OTHER ANIMAL

8799
05:30:03,420 --> 05:30:03,654
MODELS.

8800
05:30:03,654 --> 05:30:08,292
IF WE GET RID OF CDs 8, NO

8801
05:30:08,292 --> 05:30:08,859
IMPACT.

8802
05:30:08,859 --> 05:30:15,966
WHEN YOU GET RID OF CD4, LOSE

8803
05:30:15,966 --> 05:30:20,170
NEUTRALIZATION, CD8 DON'T REALLY

8804
05:30:20,170 --> 05:30:21,772
HAVE EFFECT, IT'S NOT DUE TO

8805
05:30:21,772 --> 05:30:22,773
ANTIBODIES OR LACK OF

8806
05:30:22,773 --> 05:30:24,842
ANTIBODIES, IT HAS TO DO WITH T

8807
05:30:24,842 --> 05:30:28,445
CELLS THAT ARE PRESENT IN THE

8808
05:30:28,445 --> 05:30:29,179
UPPER RESPIRATORY TRACT.

8809
05:30:29,179 --> 05:30:31,482
WE WANTED TO ASK CAN WE ISOLATE

8810
05:30:31,482 --> 05:30:33,250
INFECTIOUS VIRUS IN THE UPPER

8811
05:30:33,250 --> 05:30:35,019
RESPIRATORY TRACT, VIRAL RNA

8812
05:30:35,019 --> 05:30:38,055
THAT'S PERSISTING OR IS IT

8813
05:30:38,055 --> 05:30:38,455
INFECTIOUS VIRUS.

8814
05:30:38,455 --> 05:30:41,926
FROM ALL THE MICE WE HAD TANDEM

8815
05:30:41,926 --> 05:30:44,695
DEPLETED, ONLY IN THOSE MICE CAN

8816
05:30:44,695 --> 05:30:52,436
WE RECOVER INFECTIOUS VIRUS FROM

8817
05:30:52,436 --> 05:30:53,771
THESE UPPER RESPIRATORY TRACT,

8818
05:30:53,771 --> 05:30:55,072
CAN'T RECOVER THE VIRUS FROM

8819
05:30:55,072 --> 05:30:56,307
LOWER RESPIRATORY TRACT.

8820
05:30:56,307 --> 05:30:59,076
WE WANTED TO ASK WHERE IS THE

8821
05:30:59,076 --> 05:31:00,110
VIRUS REPLICATING.

8822
05:31:00,110 --> 05:31:02,513
THIS IS DONE IN COLLABORATION

8823
05:31:02,513 --> 05:31:07,318
WITH ROBIN KLEIN'S LAB, MY

8824
05:31:07,318 --> 05:31:10,020
FORMER POSTDOC ABIGAIL, THERE'S

8825
05:31:10,020 --> 05:31:13,190
ABSOLUTELY NO VIRAL RNA OR VIRAL

8826
05:31:13,190 --> 05:31:15,192
PROTEIN STAINING WITHIN THE

8827
05:31:15,192 --> 05:31:15,592
BRAIN.

8828
05:31:15,592 --> 05:31:17,361
DESPITE HAVING PERSISTENT VIRUS

8829
05:31:17,361 --> 05:31:18,996
REPLICATION IN UPPER RESPIRATORY

8830
05:31:18,996 --> 05:31:20,230
TRACT WE'RE NOT SEEING THE VIRUS

8831
05:31:20,230 --> 05:31:21,765
GO INTO THE BRAIN.

8832
05:31:21,765 --> 05:31:24,168
SO THAT I THINK WAS VERY

8833
05:31:24,168 --> 05:31:25,269
IMPORTANT OBSERVATION GIVEN SOME

8834
05:31:25,269 --> 05:31:27,471
CONFLICTING DATA WE'VE SEEN WITH

8835
05:31:27,471 --> 05:31:29,306
THE K18 MOUSE MODEL WHERE YOU

8836
05:31:29,306 --> 05:31:30,941
GET INFECTION OF THE BRAIN, IN

8837
05:31:30,941 --> 05:31:39,717
THIS MODEL WE DON'T SEE THAT.

8838
05:31:39,717 --> 05:31:41,485
THERE'S VARIATION BETWEEN MICE

8839
05:31:41,485 --> 05:31:42,786
WHERE IT REPLICATION AND HOW

8840
05:31:42,786 --> 05:31:45,723
MUCH BUT REGARDLY WE CONTINUALLY

8841
05:31:45,723 --> 05:31:48,258
SEE PERSISTENT VIRAL INFECTION.

8842
05:31:48,258 --> 05:31:51,028
WE NEXT WORKED WITH THE NIH TO

8843
05:31:51,028 --> 05:31:52,396
ASK DOES THAT PERSISTENT VIRUS

8844
05:31:52,396 --> 05:31:53,731
CHANGE OVER TIME.

8845
05:31:53,731 --> 05:31:57,201
SO WE DID A COMPLICATED

8846
05:31:57,201 --> 05:32:00,537
ANALYSIS, WE HAVE OUR INNOCULUM

8847
05:32:00,537 --> 05:32:04,875
STOCK, DEEP SEQUENCE THAT, DEEP

8848
05:32:04,875 --> 05:32:07,444
SEQUENCE VIRUS PASSAGE TO SEE IF

8849
05:32:07,444 --> 05:32:08,645
THERE'S CHANGES.

8850
05:32:08,645 --> 05:32:10,080
WE ALSO DEEP SEQUENCE VIRUS

8851
05:32:10,080 --> 05:32:11,782
FOUND AT DAY 3 POST-INFECTION TO

8852
05:32:11,782 --> 05:32:13,684
SEE IF THE FIRST THREE DAYS IS

8853
05:32:13,684 --> 05:32:16,186
THERE ANY CHANGE THAT OCCURS.

8854
05:32:16,186 --> 05:32:19,456
WE DEEP SEQUENCE THE VIRUS WE

8855
05:32:19,456 --> 05:32:20,891
GET AT DAY 28 POST-INFECTION.

8856
05:32:20,891 --> 05:32:25,629
AND WHAT WE SEE IS THAT THROUGH

8857
05:32:25,629 --> 05:32:30,067
EITHER INNOCULUM STOCK,

8858
05:32:30,067 --> 05:32:31,668
INNOCULUM WE PASSAGE ONCE, WHAT

8859
05:32:31,668 --> 05:32:33,804
WE DO WHEN WE ISOLATE FROM THE

8860
05:32:33,804 --> 05:32:39,510
UPPER  RESPIRATORY TRACT OR THRE

8861
05:32:39,510 --> 05:32:40,944
DAYS POST-INFECTION VIRTUALLY NO

8862
05:32:40,944 --> 05:32:41,345
CHANGES.

8863
05:32:41,345 --> 05:32:44,381
REALLY NO CHANGES IN VIRUS

8864
05:32:44,381 --> 05:32:46,150
SEQUENCES THROUGH DAY 3

8865
05:32:46,150 --> 05:32:46,850
POST-INFECTION.

8866
05:32:46,850 --> 05:32:50,954
MOST CHANGES OCCUR BY DAY 28

8867
05:32:50,954 --> 05:32:51,522
POST-INFECTION.

8868
05:32:51,522 --> 05:32:53,891
THESE ARE SOMEWHAT SPORADIC,

8869
05:32:53,891 --> 05:32:55,459
THEY OCCUR AT VARIOUS PLACES.

8870
05:32:55,459 --> 05:32:57,428
I'LL SHOW THAT IN THE NEXT

8871
05:32:57,428 --> 05:32:57,661
SLIDE.

8872
05:32:57,661 --> 05:33:00,864
BY DAY 28 YOU DO START TO SEE

8873
05:33:00,864 --> 05:33:02,399
QUASI-SPECIES OCCURRING IN THIS

8874
05:33:02,399 --> 05:33:03,333
INNOCULUM STOCK.

8875
05:33:03,333 --> 05:33:04,134
WHERE ARE THESE OCCURRING?

8876
05:33:04,134 --> 05:33:07,071
THEY SEEM TO BE OCCURRING

8877
05:33:07,071 --> 05:33:08,372
PRIMARILY WITHIN THE

8878
05:33:08,372 --> 05:33:10,074
NON-STRUCTURAL REGION.

8879
05:33:10,074 --> 05:33:11,308
AGAIN, DIFFERENT BETWEEN

8880
05:33:11,308 --> 05:33:12,509
DIFFERENT MICE.

8881
05:33:12,509 --> 05:33:14,378
VERTICALLY ARE DIFFERENT MICE

8882
05:33:14,378 --> 05:33:15,913
THAT WERE SEQUENCED.

8883
05:33:15,913 --> 05:33:18,115
AND WHERE THESE MUTATIONS FALL.

8884
05:33:18,115 --> 05:33:20,417
WHAT'S INTERESTING IS WE

8885
05:33:20,417 --> 05:33:23,887
OBSERVED SOME AT LEAST FOR THE

8886
05:33:23,887 --> 05:33:30,894
MICE HAD DELETIONS IN ORF6, ORF

8887
05:33:30,894 --> 05:33:32,329
6 POTENTIALLY LINKED TO

8888
05:33:32,329 --> 05:33:33,664
REGULATION OF THE INNATE IMMUNE

8889
05:33:33,664 --> 05:33:35,732
RESPONSE IN THE CONTEXT OF

8890
05:33:35,732 --> 05:33:36,600
SARS-COV-2.

8891
05:33:36,600 --> 05:33:41,338
SO THERE MAY BE SOME PRESSURE

8892
05:33:41,338 --> 05:33:44,675
THAT'S PLACED ON THIS VIRUS AS

8893
05:33:44,675 --> 05:33:45,576
IT PERSISTS TO PERSISTENTLY LIVE

8894
05:33:45,576 --> 05:33:48,212
IN THE NOSE.  THERE MAY BE SOME

8895
05:33:48,212 --> 05:33:49,413
CHANGES OCCURRING.

8896
05:33:49,413 --> 05:33:50,514
WHAT WAS SURPRISING WE DIDN'T

8897
05:33:50,514 --> 05:33:52,149
SEE MANY CHANGES IF ANY WITHIN

8898
05:33:52,149 --> 05:33:54,218
THE SPIKE PROTEIN DURING THESE

8899
05:33:54,218 --> 05:33:55,085
FIRST 28 DAYS.

8900
05:33:55,085 --> 05:33:56,487
THIS IS SOMETHING WE'RE NOW

8901
05:33:56,487 --> 05:33:58,689
FOLLOWING UP ON, WHAT THE IMPACT

8902
05:33:58,689 --> 05:34:01,425
OF THESE MUTATIONS ACTUALLY ARE

8903
05:34:01,425 --> 05:34:02,092
ON PERSISTENCE.

8904
05:34:02,092 --> 05:34:05,129
ANOTHER ANGLE WE ALSO WANTED TO

8905
05:34:05,129 --> 05:34:08,232
LOOK AT WAS TO ASK NOW THAT

8906
05:34:08,232 --> 05:34:10,501
WE'VE DEVELOPED A PERSISTENT

8907
05:34:10,501 --> 05:34:16,039
INFECTION MODEL, WE WANTED TO

8908
05:34:16,039 --> 05:34:17,107
ASK HOW DO ANTI-VIRALS WE USE

8909
05:34:17,107 --> 05:34:18,976
WORK IN THIS MODEL.

8910
05:34:18,976 --> 05:34:20,944
WE HANDED THIS OVER TO GEORGIA

8911
05:34:20,944 --> 05:34:23,447
STATE UNIVERSITY, THE PAPER IS

8912
05:34:23,447 --> 05:34:26,750
IN bioRxiv FOR REVIEW, HIS

8913
05:34:26,750 --> 05:34:27,417
LABORATORY RECAPITULATED

8914
05:34:27,417 --> 05:34:30,787
OBSERVATIONS WE MADE IN TERMS OF

8915
05:34:30,787 --> 05:34:35,659
VIRAL PERSISTENCE AND TESTED TWO

8916
05:34:35,659 --> 05:34:46,170
ANTI-VIRAL DRUGS PAXLOVID AND

8917
05:34:47,504 --> 05:34:49,840
MALNOPIRAVIR, ARE THEY CAPABLE

8918
05:34:49,840 --> 05:34:52,342
OF REDUCING.

8919
05:34:52,342 --> 05:35:01,051
IF YOU LOOK AT PANEL E,

8920
05:35:01,051 --> 05:35:02,386
MALNOPIRAVIR THROUGH DAY 7 OF

8921
05:35:02,386 --> 05:35:06,557
TREATMENT, AND 14 DAYS AFTER THE

8922
05:35:06,557 --> 05:35:08,358
INITIAL TREATMENT, MALNOPIRAVIR

8923
05:35:08,358 --> 05:35:13,463
WAS ABLE TO ELIMINATE VIRUS IN

8924
05:35:13,463 --> 05:35:14,965
UPPER RESPIRATORY TRACT.

8925
05:35:14,965 --> 05:35:17,968
PAXLOVID WAS NOT ABLE TO FULLY

8926
05:35:17,968 --> 05:35:19,002
REDUCE REPLICATION BUT THIS DOES

8927
05:35:19,002 --> 05:35:22,306
ALLOW ONE TO TAKE A MODEL OF

8928
05:35:22,306 --> 05:35:24,074
PERSISTENT VIRAL INFECTION AND

8929
05:35:24,074 --> 05:35:28,645
ASK QUESTIONS ABOUT HOW

8930
05:35:28,645 --> 05:35:33,283
ANTI-VIRALS CAN WORK IN THE

8931
05:35:33,283 --> 05:35:34,117
RESPIRATORY TRACT, ESPECIALLY

8932
05:35:34,117 --> 05:35:37,221
UPPER, NOW LOOKING AT INNATE

8933
05:35:37,221 --> 05:35:39,156
IMMUNE RESPONSE, OTHER ASPECTS

8934
05:35:39,156 --> 05:35:41,825
OF I ADAPTIVE IMMUNE RESPONSE TO

8935
05:35:41,825 --> 05:35:44,127
UNDERSTAND WHAT IS CONTRIBUTING

8936
05:35:44,127 --> 05:35:45,862
TO VIRAL PERSISTENCE.

8937
05:35:45,862 --> 05:35:49,466
THE LAST BIT I'LL TALK ABOUT ONE

8938
05:35:49,466 --> 05:35:51,468
STORY WE'RE WORKING ON, TO

8939
05:35:51,468 --> 05:35:53,303
CONNECT SOME WORK WE'RE DOING

8940
05:35:53,303 --> 05:35:55,806
WITH SEROLOGY ASSAYS IN THE

8941
05:35:55,806 --> 05:35:58,075
LABORATORY LOOKING AT WANING

8942
05:35:58,075 --> 05:35:59,676
IMMUNITY IN THE CONTEXT OF

8943
05:35:59,676 --> 05:36:01,745
HUMANS THAT GET VACCINES OR

8944
05:36:01,745 --> 05:36:02,212
INFECTION.

8945
05:36:02,212 --> 05:36:03,680
WHAT DOES IT MEAN IN VIVO WHEN

8946
05:36:03,680 --> 05:36:07,117
ONE GETS A BREAKTHROUGH

8947
05:36:07,117 --> 05:36:07,618
INFECTION?

8948
05:36:07,618 --> 05:36:11,922
AND SO THERE'S SEVERAL WAYS FOR

8949
05:36:11,922 --> 05:36:13,090
US TO MODEL THIS.

8950
05:36:13,090 --> 05:36:14,858
AND SO ONE OF THE THINGS WE

8951
05:36:14,858 --> 05:36:17,728
WANTED TO BETTER UNDERSTAND IS

8952
05:36:17,728 --> 05:36:20,464
THAT WHEN YOU HAVE LOWER LEVELS

8953
05:36:20,464 --> 05:36:22,399
OF PROTECTION, YOU HAVE HIGHER

8954
05:36:22,399 --> 05:36:26,570
LEVELS OF VIRUS REPLICATION, AS

8955
05:36:26,570 --> 05:36:30,407
YOU INCREASE PROTECTION, AND

8956
05:36:30,407 --> 05:36:31,842
VACCINE RESPONSES YOU CAN

8957
05:36:31,842 --> 05:36:32,609
CERTAINLY DRIVE PROTECTION, AS

8958
05:36:32,609 --> 05:36:34,778
WE'VE SEEN IN THE LAST

8959
05:36:34,778 --> 05:36:35,112
PRESENTATION.

8960
05:36:35,112 --> 05:36:36,446
WE WANTED TO KNOW WHAT DOES THIS

8961
05:36:36,446 --> 05:36:39,316
MEAN IN VIVO AND HOW DOES THE

8962
05:36:39,316 --> 05:36:40,584
NATURE IMMUNE RESPONSE HELP

8963
05:36:40,584 --> 05:36:43,420
CONTROL INFECTION?

8964
05:36:43,420 --> 05:36:45,188
THIS IS ANOTHER SCHEMATIC OF THE

8965
05:36:45,188 --> 05:36:46,290
APPROACH WE'RE TAKING.

8966
05:36:46,290 --> 05:36:47,924
IN THE NAIVE INFECTION I'VE

8967
05:36:47,924 --> 05:36:50,227
SHOWN MONOCYTES PLAY A VERY

8968
05:36:50,227 --> 05:36:51,662
IMPORTANT ROLE, T CELLS PLAY AN

8969
05:36:51,662 --> 05:36:57,367
IMPORTANT ROLE IN THE UPPER AND

8970
05:36:57,367 --> 05:36:59,436
POSSIBLY KINETIC OF VIRAL

8971
05:36:59,436 --> 05:37:02,639
CONTROL IN THE LOWER RESPIRATORY

8972
05:37:02,639 --> 05:37:03,340
TRACT.

8973
05:37:03,340 --> 05:37:04,775
INNATE MOLECULES AND CELLS PLAY

8974
05:37:04,775 --> 05:37:06,543
AN IMPORTANT ROLE, WHAT DOES IT

8975
05:37:06,543 --> 05:37:08,278
MEAN IN THE CONTEXT OF

8976
05:37:08,278 --> 05:37:08,578
VACCINATION?

8977
05:37:08,578 --> 05:37:12,316
WE'VE SEEN FROM WORK FROM MIKE

8978
05:37:12,316 --> 05:37:15,619
DIAMONDS GROUP AND OTHERS

8979
05:37:15,619 --> 05:37:16,186
ANTIBODY EFFECTOR MECHANISMS

8980
05:37:16,186 --> 05:37:18,255
PLAY A CRITICAL ROLE IN DRIVING

8981
05:37:18,255 --> 05:37:18,555
PROTECTION.

8982
05:37:18,555 --> 05:37:21,425
T CELLS ALSO PLAY QUITE AN

8983
05:37:21,425 --> 05:37:23,694
IMPORTANT ROLE IN WORK DAN

8984
05:37:23,694 --> 05:37:26,697
BAROUCH AND OTHERS HAVE DONE AS

8985
05:37:26,697 --> 05:37:27,397
WELL.

8986
05:37:27,397 --> 05:37:32,469
ONE WAY TO MODEL IN THE

8987
05:37:32,469 --> 05:37:36,707
LABORATORY IS BY USING PRIMER

8988
05:37:36,707 --> 05:37:37,774
SPIKE PROTEIN WITH ADDAVAX,

8989
05:37:37,774 --> 05:37:40,143
VACCINATE MICE AND BOOST THEM 30

8990
05:37:40,143 --> 05:37:42,446
DAYS LATER, CHALLENGE THEM.

8991
05:37:42,446 --> 05:37:45,816
AND WE USE TWO DOSES TO BE ABLE

8992
05:37:45,816 --> 05:37:46,817
TO MODEL WANING IMMUNITY, IN THE

8993
05:37:46,817 --> 05:37:48,452
ABSENCE OF BEING ABLE TO

8994
05:37:48,452 --> 05:37:51,188
ACTUALLY HOLD THESE MICE FOR SIX

8995
05:37:51,188 --> 05:37:53,924
MONTHS OR A YEAR, WE TRY TO GIVE

8996
05:37:53,924 --> 05:37:56,059
TWO DOSES SPREAD OUT BY ABOUT

8997
05:37:56,059 --> 05:37:58,762
TEN-FOLD, TO BE ABLE TO AT LEAST

8998
05:37:58,762 --> 05:38:00,764
GET INFECTION OF THE LUNGS.

8999
05:38:00,764 --> 05:38:01,932
THAT'S OUR GOAL.

9000
05:38:01,932 --> 05:38:05,969
AND SO WHEN WE NOW VACCINATE

9001
05:38:05,969 --> 05:38:10,040
THESE MICE, AT FIVE MICROGRAMS,

9002
05:38:10,040 --> 05:38:12,476
.5 MICRO GAPS, SAME LEVEL, WE

9003
05:38:12,476 --> 05:38:15,679
CHALLENGE THEM WITH BETA

9004
05:38:15,679 --> 05:38:18,448
VARIANT, IN THIS CASE WA 1 SPIKE

9005
05:38:18,448 --> 05:38:21,385
PROTEIN, A BIT OF DIVERGENCE IN

9006
05:38:21,385 --> 05:38:25,889
SPIKE VERSUS VIRUS.

9007
05:38:25,889 --> 05:38:30,961
NAIVE 15 TO 20% WEIGHT LOSS.

9008
05:38:30,961 --> 05:38:32,229
FIVE MICROGRAM DOSES DON'T SEE

9009
05:38:32,229 --> 05:38:35,265
WEIGHT LOSS, MICE ARE WELL

9010
05:38:35,265 --> 05:38:35,932
PROTECTED.

9011
05:38:35,932 --> 05:38:38,468
.5 MICROGRAMS INTERMEDIATE

9012
05:38:38,468 --> 05:38:40,337
WEIGHT LOSS, FOR THE MOST PART

9013
05:38:40,337 --> 05:38:40,704
PROTECTED.

9014
05:38:40,704 --> 05:38:44,074
WE SEE IN THE LUNGS WE DON'T SEE

9015
05:38:44,074 --> 05:38:46,910
VIRUS REPLICATION, INFECTIOUS

9016
05:38:46,910 --> 05:38:50,313
VIRUS AT FIVE.

9017
05:38:50,313 --> 05:38:52,716
AT .5 LOG, LOG AND A HALF

9018
05:38:52,716 --> 05:38:53,116
REDUCTION.

9019
05:38:53,116 --> 05:38:57,320
WE WANTED TO UNDERSTAND INNATE

9020
05:38:57,320 --> 05:38:59,389
IMMUNE RESPONSE CORRECTING TO

9021
05:38:59,389 --> 05:38:59,790
PROTECTION.

9022
05:38:59,790 --> 05:39:07,364
WE LOOKED AT STAINED SECTIONS,

9023
05:39:07,364 --> 05:39:09,933
IN SITU HYBRIDIZATION.

9024
05:39:09,933 --> 05:39:11,435
THIS VIRUS REPLICATES IN THE

9025
05:39:11,435 --> 05:39:14,304
LARGE AIRWAYS, YOU DO START TO

9026
05:39:14,304 --> 05:39:16,373
SEE INFLAMMATION AROUND THESE

9027
05:39:16,373 --> 05:39:19,543
AREAS OF VIRUS REPLICATION.

9028
05:39:19,543 --> 05:39:23,713
.5  5 MICROGRAMS LOTS OF INFECTN

9029
05:39:23,713 --> 05:39:25,348
IN THE LUNGS, LOTS OF DEBRIS IN

9030
05:39:25,348 --> 05:39:31,121
THE LARGE AIR WAYS WHERE VIRAL

9031
05:39:31,121 --> 05:39:33,190
NUCLEOCAPSID STAINING IS

9032
05:39:33,190 --> 05:39:33,757
OCCURRING.

9033
05:39:33,757 --> 05:39:36,626
AT FIVE MICROGRAMS DON'T SEE

9034
05:39:36,626 --> 05:39:39,763
VIRUS REPLICATION IN MICE,

9035
05:39:39,763 --> 05:39:46,570
SIMILAR TO WHAT WE'VE SEEN WITH

9036
05:39:46,570 --> 05:39:48,672
INFECTIOUS VIRUS REPLICATION, WE

9037
05:39:48,672 --> 05:39:50,207
I.D. LABEL, HARVEST IMMUNE

9038
05:39:50,207 --> 05:39:51,942
CELLS, PERFORM FLOW CYTOMETRY OR

9039
05:39:51,942 --> 05:39:55,345
DO SINGLE CELL RNA SEQUENCING.

9040
05:39:55,345 --> 05:39:57,914
WE SEE AT LOW DOSE VACCINATION

9041
05:39:57,914 --> 05:40:00,150
WE SEE HIGHER LEVELS OF

9042
05:40:00,150 --> 05:40:02,319
INFLAMMATION, SIMILAR TORE
H&E,

9043
05:40:02,319 --> 05:40:03,720
MUCH HIGHER THAN NAIVE

9044
05:40:03,720 --> 05:40:03,987
INFECTION.

9045
05:40:03,987 --> 05:40:05,689
ONE OF THE MORE STRIKING

9046
05:40:05,689 --> 05:40:08,024
OBSERVATIONS THAT WE MADE IS

9047
05:40:08,024 --> 05:40:10,760
THAT IN THE LOW DOSE VACCINATED

9048
05:40:10,760 --> 05:40:13,230
MICE YOU SEE HIGHER PROPORTION

9049
05:40:13,230 --> 05:40:15,966
OF EOSINOPHILS IN THE LUNGS

9050
05:40:15,966 --> 05:40:18,702
COMPARED TO NAIVE INFECTION.

9051
05:40:18,702 --> 05:40:22,038
IT IN NAIVE MORE DOMINATED BY

9052
05:40:22,038 --> 05:40:26,409
NEUTROPHILS RATHER THAN

9053
05:40:26,409 --> 05:40:27,377
EOSINOPHILS.

9054
05:40:27,377 --> 05:40:28,478
GRANULOCYTE POPULATION, IT'S

9055
05:40:28,478 --> 05:40:31,014
STRIKING, YOU SEE A HIGH

9056
05:40:31,014 --> 05:40:33,149
PERCENTAGE OF EOSINOPHILS COMING

9057
05:40:33,149 --> 05:40:36,953
IN, COMPARED TO JUST INFECTION

9058
05:40:36,953 --> 05:40:40,257
ALONE, THIS CORRESPONDS TO

9059
05:40:40,257 --> 05:40:42,092
FREQUENCY OR TOTAL COUNT, TWO

9060
05:40:42,092 --> 05:40:44,427
LOG INCREASE IN LEVEL OF

9061
05:40:44,427 --> 05:40:46,997
EOSINOPHILS IN LOW DOSE

9062
05:40:46,997 --> 05:40:48,098
VACCINATED MICE INFECTED

9063
05:40:48,098 --> 05:40:51,768
COMPARED TO NAIVE INFECTED MICE.

9064
05:40:51,768 --> 05:40:53,970
THESE EOSINOPHILS INVOLVED IN

9065
05:40:53,970 --> 05:40:57,874
TYPE 2 IMMUNITY, KNOWN FOR

9066
05:40:57,874 --> 05:41:00,443
DRIVING LUNG PATHOLOGY DURING

9067
05:41:00,443 --> 05:41:03,046
ASTHMA AND ASSOCIATED DISEASE.

9068
05:41:03,046 --> 05:41:03,713
THERE'S GROWING EVIDENCE

9069
05:41:03,713 --> 05:41:05,248
EOSINOPHILS CAN HAVE A

9070
05:41:05,248 --> 05:41:06,850
PROTECTIVE ROLE AS WELL.

9071
05:41:06,850 --> 05:41:09,252
WE WANTED TO LOOK AT THIS A BIT

9072
05:41:09,252 --> 05:41:10,654
MORE CLOSELY.

9073
05:41:10,654 --> 05:41:12,355
WE PERFORMED SINGLE CELL RNA

9074
05:41:12,355 --> 05:41:14,391
SEQUENCING WHERE IN THIS CASE

9075
05:41:14,391 --> 05:41:19,162
UNLIKE WHAT WE DID BEFORE WE

9076
05:41:19,162 --> 05:41:20,764
PAIRED THIS WITH CITE-SEQ DATA,

9077
05:41:20,764 --> 05:41:23,066
IDENTIFIED CLUSTERS OF IMMUNE

9078
05:41:23,066 --> 05:41:25,769
CELLS, ABLE TO PRECISELY

9079
05:41:25,769 --> 05:41:26,803
IDENTIFY EOSINOPHILS AND

9080
05:41:26,803 --> 05:41:28,405
NEUTROPHILS HERE, AND WE ALSO

9081
05:41:28,405 --> 05:41:29,406
MAPPED THIS TO SARS-COV-2.

9082
05:41:29,406 --> 05:41:32,175
WE WANTED TO SEE WHAT IMMUNE

9083
05:41:32,175 --> 05:41:35,879
CELLS WERE MAPPING OR

9084
05:41:35,879 --> 05:41:40,884
ASSOCIATING WITH VIRAL RNA. 

9085
05:41:40,884 --> 05:41:42,586
WE SEE EOSINOPHIL POPULATION HAS

9086
05:41:42,586 --> 05:41:48,758
LOTS OF VIRAL RNA ASSOCIATED,

9087
05:41:48,758 --> 05:41:50,660
MAY BE COLLECTING DEB RIB OR

9088
05:41:50,660 --> 05:41:54,598
ASSOCIATING WITH DEAD CELL

9089
05:41:54,598 --> 05:41:55,865
DEBRIS OR PHAGOCYTOSING VIRAL

9090
05:41:55,865 --> 05:41:56,032
RNA.

9091
05:41:56,032 --> 05:41:58,068
WE TRIED TO DO IN VITRO

9092
05:41:58,068 --> 05:42:00,804
INFECTIONS, DOESN'T LOOK LIKE

9093
05:42:00,804 --> 05:42:02,772
THEY ARE INFECTIBLE AS PLAYING

9094
05:42:02,772 --> 05:42:05,175
DEVIL'S ADVOCATE THERE, WE DO

9095
05:42:05,175 --> 05:42:06,376
SEE LOTS OF VIRAL RNA.

9096
05:42:06,376 --> 05:42:08,778
THERE'S BEEN QUITE A BIT OF

9097
05:42:08,778 --> 05:42:10,780
LITERATURE WITH MONOCYTES AND

9098
05:42:10,780 --> 05:42:13,116
MACROPHAGES, ASSOCIATING WITH

9099
05:42:13,116 --> 05:42:14,184
VIRAL RNAs QUITE CONTROVERSIAL

9100
05:42:14,184 --> 05:42:16,486
AS TO WHETHER THEY ARE INFECTED

9101
05:42:16,486 --> 05:42:19,456
OR NOT.

9102
05:42:19,456 --> 05:42:21,524
BUT I THINK IT'S RATHER ACCEPTED

9103
05:42:21,524 --> 05:42:24,594
THERE IS VIRAL RNA ASSOCIATED

9104
05:42:24,594 --> 05:42:26,062
WITH THESE IMMUNE CELLS, WE

9105
05:42:26,062 --> 05:42:28,531
CERTAINLY SEE THAT AS WELL, IN

9106
05:42:28,531 --> 05:42:31,267
OUR NAIVE POPULATION AND WITHIN

9107
05:42:31,267 --> 05:42:32,135
OUR VACCINE BREAKTHROUGH

9108
05:42:32,135 --> 05:42:33,336
INFECTED GROUP HERE.

9109
05:42:33,336 --> 05:42:37,173
WE WANTED TO LOOK CLOSELY AT

9110
05:42:37,173 --> 05:42:39,809
THIS, AND ISOLATE THESE

9111
05:42:39,809 --> 05:42:41,011
COMPUTATIONALLY AND RECLUSTER

9112
05:42:41,011 --> 05:42:43,013
THEM BASED ON THIS POPULATION.

9113
05:42:43,013 --> 05:42:45,315
MOCK IS IN GRAY.

9114
05:42:45,315 --> 05:42:47,083
INFECTED GROUP IN BLUE.

9115
05:42:47,083 --> 05:42:48,051
VACCINE BREAKTHROUGH INFECTED

9116
05:42:48,051 --> 05:42:51,421
GROUP IS IN RED.

9117
05:42:51,421 --> 05:42:55,525
YOU CAN SEE EOSINOPHILS ARE

9118
05:42:55,525 --> 05:42:57,027
DIFFERENT TRANSCRIPTIONALLY

9119
05:42:57,027 --> 05:42:58,561
BETWEEN NAIVE INFECTED AND

9120
05:42:58,561 --> 05:43:00,096
VACCINE BREAKTHROUGH GROUPS.

9121
05:43:00,096 --> 05:43:03,299
AND YOU CAN FURTHER SUBCLUSTER

9122
05:43:03,299 --> 05:43:05,135
INTO DIFFERENT POPULATIONS AND

9123
05:43:05,135 --> 05:43:07,837
THESE ARE AGAIN VACCINE

9124
05:43:07,837 --> 05:43:09,639
BREAKTHROUGH GROUPS ARE BOTTOM

9125
05:43:09,639 --> 05:43:11,508
RIGHT-HAND GROUP HERE, WHEREAS

9126
05:43:11,508 --> 05:43:14,577
THE NAIVE ARE PART OF THE

9127
05:43:14,577 --> 05:43:17,814
CLUSTER 3, AND -- SORRY MOCK IN

9128
05:43:17,814 --> 05:43:19,916
CLUSTER 3, NAIVE INFECTED MICE

9129
05:43:19,916 --> 05:43:22,185
IN CLUSTERS 1 AND 2 HERE.

9130
05:43:22,185 --> 05:43:25,088
WE NEXT WANTED TO ASK WHAT KIND

9131
05:43:25,088 --> 05:43:26,256
OF EOSINOPHILS MIGHT BE, THERE'S

9132
05:43:26,256 --> 05:43:28,491
QUITE A BIT OF LITERATURE IN

9133
05:43:28,491 --> 05:43:31,695
TERMS OF AT LEAST IDENTIFYING

9134
05:43:31,695 --> 05:43:32,829
SIGNATURES, WHETHER TYPE 1 OR

9135
05:43:32,829 --> 05:43:34,297
TYPE 2.

9136
05:43:34,297 --> 05:43:37,367
AND SO THERE'S ONE GROUP HERE

9137
05:43:37,367 --> 05:43:38,768
HAD ISOLATED MOUSE EOSINOPHILS

9138
05:43:38,768 --> 05:43:42,372
BUT THEN EX VIVO TREATED WITH

9139
05:43:42,372 --> 05:43:44,708
INTERFERON GAMMA OR IL-4.

9140
05:43:44,708 --> 05:43:46,076
WE TOOK TRANSCRIPTIONAL MODULES

9141
05:43:46,076 --> 05:43:52,248
AND ASK HOW DO OUR DATA COMPARE,

9142
05:43:52,248 --> 05:43:54,217
WITHIN THEIR ASTHMA MODULE IT

9143
05:43:54,217 --> 05:43:56,619
DOESN'T LOOK LIKE ENRICHMENT IN

9144
05:43:56,619 --> 05:43:58,154
TERMS OF DIFFERENCE BETWEEN

9145
05:43:58,154 --> 05:44:02,325
NAIVE AND VACCINE BREAKTHROUGH,

9146
05:44:02,325 --> 05:44:04,928
IL-4 DOESN'T SEEM TO STRONGLY

9147
05:44:04,928 --> 05:44:05,195
INFLUENCE.

9148
05:44:05,195 --> 05:44:08,998
WE DO INSTEAD SEE MORE

9149
05:44:08,998 --> 05:44:09,799
INTERFERON GAMMA-RELATED

9150
05:44:09,799 --> 05:44:11,835
PHENOTYPE, EOSINOPHILS FROM OUR

9151
05:44:11,835 --> 05:44:12,702
VACCINE BREAKTHROUGH INFECTIONS

9152
05:44:12,702 --> 05:44:15,805
SEEM TO BE MORE ENRICHED FOR

9153
05:44:15,805 --> 05:44:17,373
INTERFERON GAMMA SIGNATURES

9154
05:44:17,373 --> 05:44:21,277
COMPARED TO NAIVE INFECTION,

9155
05:44:21,277 --> 05:44:26,583
SUGGESTING IN THE LUNGS AT LEAST

9156
05:44:26,583 --> 05:44:29,219
THERE MAY BE MORE OF INTERFERON

9157
05:44:29,219 --> 05:44:30,353
GAMMA MILIEU, SOMETHING WE'RE

9158
05:44:30,353 --> 05:44:31,354
LOOKING AT IN DETAIL.

9159
05:44:31,354 --> 05:44:35,091
WE WANTED TO ASK THE MORE

9160
05:44:35,091 --> 05:44:36,926
IMPORTANT QUESTION ARE

9161
05:44:36,926 --> 05:44:40,430
EOSINOPHILS PROTECTED?

9162
05:44:40,430 --> 05:44:42,532
WE TOOK ANTIBODY-DEPLETING

9163
05:44:42,532 --> 05:44:45,802
TECHNIQUE, WHICH WE GAVE MICE

9164
05:44:45,802 --> 05:44:49,305
CCR3 ANTIBODY, WHICH IS SPECIFIC

9165
05:44:49,305 --> 05:44:50,940
TO EOSINOPHILS, DEPLETE

9166
05:44:50,940 --> 05:44:51,407
EOSINOPHILS.

9167
05:44:51,407 --> 05:44:53,009
WHEN WE DEPLETE THESE MICE WE

9168
05:44:53,009 --> 05:44:55,678
ENDED UP HAVING TWO GROUPS OF

9169
05:44:55,678 --> 05:44:58,081
DEPLETED MICE, YOU DON'T EVER

9170
05:44:58,081 --> 05:45:01,050
GET PERFECT DEPLETION IN MICE,

9171
05:45:01,050 --> 05:45:02,919
ESPECIALLY WITH EOSINOPHILS.

9172
05:45:02,919 --> 05:45:04,654
WE TRY DIFFERENT TECHNIQUES,

9173
05:45:04,654 --> 05:45:06,422
DIFFERENT DOSES, DIFFERENT

9174
05:45:06,422 --> 05:45:06,790
REGIMENS.

9175
05:45:06,790 --> 05:45:08,458
WE SEEM TO GET TWO GROUPS, ONE

9176
05:45:08,458 --> 05:45:10,894
THAT DOESN'T DEPLETE WELL, ONE

9177
05:45:10,894 --> 05:45:12,228
THAT DEPLETES VERY WELL.

9178
05:45:12,228 --> 05:45:16,299
HERE WE CAN SEE A TWO LOG

9179
05:45:16,299 --> 05:45:18,434
REDUCTION IN EOSINOPHILS, IN THE

9180
05:45:18,434 --> 05:45:19,269
BREAKTHROUGH GROUP.

9181
05:45:19,269 --> 05:45:20,403
WHAT'S INTERESTING IS THAT THE

9182
05:45:20,403 --> 05:45:23,773
GROUP IN WHICH WE SAW GREATER

9183
05:45:23,773 --> 05:45:28,378
THAN FIVE-FOLD DEPLETION OF

9184
05:45:28,378 --> 05:45:32,649
EOSINOPHILS, CONTINUESED TO SHOW

9185
05:45:32,649 --> 05:45:34,851
WEIGHT LOSS, ISOTYPE OR POORLY

9186
05:45:34,851 --> 05:45:35,585
DEPLETED SHOWED BETTER

9187
05:45:35,585 --> 05:45:36,820
PROTECTION IN TERMS OF WEIGHT

9188
05:45:36,820 --> 05:45:38,054
LOSS.

9189
05:45:38,054 --> 05:45:41,825
NEXT ASKED ABOUT VIRAL LOAD,

9190
05:45:41,825 --> 05:45:44,894
INFECTIOUS VIRUS HIGHER LEVELS

9191
05:45:44,894 --> 05:45:48,631
IN MICE THAT WERE EOSINOPHIL

9192
05:45:48,631 --> 05:45:50,133
DEPLETED, CORRELATES COMPARING

9193
05:45:50,133 --> 05:45:52,669
SAMPLES, LOWER -- SORRY, THE

9194
05:45:52,669 --> 05:45:54,504
LOWER NUMBERS OF EOSINOPHILS,

9195
05:45:54,504 --> 05:45:55,471
HIGHER LEVELS OF VIRUS

9196
05:45:55,471 --> 05:45:57,140
REPLICATION, SEEMS TO BE A NICE

9197
05:45:57,140 --> 05:45:59,142
CORRELATION BETWEEN THAT.

9198
05:45:59,142 --> 05:46:02,412
MORE IMPORTANTLY, IF YOU NOW GO

9199
05:46:02,412 --> 05:46:06,249
WITHIN THE HISTOLOGY SAMPLE BETA

9200
05:46:06,249 --> 05:46:09,252
INFECTION IN LARGE AIRWAYS,

9201
05:46:09,252 --> 05:46:10,053
ISOTYPE CONTROLS WE SEE LOTS OF

9202
05:46:10,053 --> 05:46:12,121
VIRUS IN THE LARGE AIRWAY SPACES

9203
05:46:12,121 --> 05:46:13,523
WITH LOTS OF INFLAMMATION

9204
05:46:13,523 --> 05:46:13,790
OCCURRING.

9205
05:46:13,790 --> 05:46:15,658
NOW WHEN YOU GET RID OF

9206
05:46:15,658 --> 05:46:17,360
EOSINOPHILS WHAT YOU SEE IS

9207
05:46:17,360 --> 05:46:21,564
VIRUS SPREADING TO SMALLER

9208
05:46:21,564 --> 05:46:22,632
AIRWAYS, LESS INFLAMMATION

9209
05:46:22,632 --> 05:46:26,069
OVERALL, DON'T SEE LARGE AIRWAYS

9210
05:46:26,069 --> 05:46:30,073
FILLING UP WITH DEBRIS OR CELLS

9211
05:46:30,073 --> 05:46:31,474
SUGGESTING EOSINOPHILS ARE

9212
05:46:31,474 --> 05:46:33,243
HELPING RESTRICT VIRUS

9213
05:46:33,243 --> 05:46:36,179
REPLICATION AND MAY BE CLOGGING

9214
05:46:36,179 --> 05:46:37,380
UP AIRWAYS TO HELP GET RID OF

9215
05:46:37,380 --> 05:46:40,283
CELLS OR GET RID OF INFECTED

9216
05:46:40,283 --> 05:46:43,519
CELLS AND DEBRIS. 

9217
05:46:43,519 --> 05:46:45,722
NONETHELESS IT APPEARS TO

9218
05:46:45,722 --> 05:46:47,724
EOSINOPHILS ARE IN FACT HAVING

9219
05:46:47,724 --> 05:46:49,192
AN ANTI-VIRAL ROLE IN THIS

9220
05:46:49,192 --> 05:46:51,828
VACCINE BREAKTHROUGH INFECTION.

9221
05:46:51,828 --> 05:47:02,305
WE'VE DONE THIS WITH SCP BUT

9222
05:47:06,276 --> 05:47:06,576
 but

9223
05:47:06,576 --> 05:47:08,945
with mRNA VACCINE, WE FOCUSED

9224
05:47:08,945 --> 05:47:11,648
ON MONOCYTES AND MACROPHAGES,

9225
05:47:11,648 --> 05:47:15,585
SIMILAR TO EOSINOPHILS WE GET

9226
05:47:15,585 --> 05:47:17,553
DIFFERENT CLUSTERS, FROM

9227
05:47:17,553 --> 05:47:19,222
INFECTED, NAIVE INFECTED, OR

9228
05:47:19,222 --> 05:47:20,924
VACCINE BREAKTHROUGH INFECTION.

9229
05:47:20,924 --> 05:47:21,624
ONE IMPORTANT MOLECULE THAT

9230
05:47:21,624 --> 05:47:23,826
SEEMS TO BE DIFFERENT BETWEEN

9231
05:47:23,826 --> 05:47:34,304
THESE GROUPS IS EOHTAX IN2,

9232
05:47:35,972 --> 05:47:38,041
IMPORTANT FOR DRIVING EOSINOPHIL

9233
05:47:38,041 --> 05:47:39,542
INTO THE LUNGS.

9234
05:47:39,542 --> 05:47:41,711
TOTAL MONOCYTES IN DEPLETED MICE

9235
05:47:41,711 --> 05:47:43,513
WE SEE SLIGHTLY INCREASED LEVEL

9236
05:47:43,513 --> 05:47:46,015
OF MONOCYTES WITHIN THE LUNGS

9237
05:47:46,015 --> 05:47:47,583
COMPARED TO ISOTYPE CONTROL,

9238
05:47:47,583 --> 05:47:50,586
SUGGESTING THERE MAY BE FEEDBACK

9239
05:47:50,586 --> 05:47:52,689
BETWEEN EOSINOPHILS BEING

9240
05:47:52,689 --> 05:47:53,389
RECRUITED, MONOCYTES DEPLETING

9241
05:47:53,389 --> 05:47:56,626
CCL 24, MAYBE A FEEDBACK ROPE

9242
05:47:56,626 --> 05:47:57,894
BETWEEN THE TWO POPULATIONS,

9243
05:47:57,894 --> 05:47:58,661
SOMETHING WE'RE LOOKING AT MORE

9244
05:47:58,661 --> 05:47:59,963
CLOSELY NOW.

9245
05:47:59,963 --> 05:48:03,032
THIS IS A SUMMARY OF THE

9246
05:48:03,032 --> 05:48:04,567
DIFFERENCE BETWEEN NAIVE

9247
05:48:04,567 --> 05:48:06,135
INFECTION AND VACCINATED

9248
05:48:06,135 --> 05:48:07,603
BREAKTHROUGH INFECTION.

9249
05:48:07,603 --> 05:48:09,739
WE THINK THERE'S CERTAINLY A

9250
05:48:09,739 --> 05:48:11,307
POSITIVE ROLE IN TERMS OF

9251
05:48:11,307 --> 05:48:14,110
EOSINOPHILS DRIVING PROTECTION.

9252
05:48:14,110 --> 05:48:16,045
THESE ARE RECRUITED POSSIBLY BY

9253
05:48:16,045 --> 05:48:17,947
MONOCYTES, SEEM TO HELP CONTROL

9254
05:48:17,947 --> 05:48:19,048
VIRUS REPLICATION.

9255
05:48:19,048 --> 05:48:21,451
I HOPE I'VE SHOWN AT LEAST THREE

9256
05:48:21,451 --> 05:48:24,287
VERSIONS WHETHER WE LOOK AT THE

9257
05:48:24,287 --> 05:48:25,855
INNATE IMMUNE RESPONSE IN THE

9258
05:48:25,855 --> 05:48:27,824
CONTEXT OF NAIVE INFECTION

9259
05:48:27,824 --> 05:48:29,359
TRYING TO DISSECT WHAT'S GOING

9260
05:48:29,359 --> 05:48:34,397
ON, WE'RE NOW LOOKING AT UPPER

9261
05:48:34,397 --> 05:48:36,766
VERSUS LOWER RESPIRATORY TRACT,

9262
05:48:36,766 --> 05:48:39,102
WHAT ROLE T CELLS PLAY AND

9263
05:48:39,102 --> 05:48:40,436
CONTEXT OF BREAKTHROUGH

9264
05:48:40,436 --> 05:48:40,703
INFECTION.

9265
05:48:40,703 --> 05:48:42,305
SEVERAL PEOPLE I'D LIKE TO

9266
05:48:42,305 --> 05:48:44,707
THANK, I'LL POINT OUT A FEW THAT

9267
05:48:44,707 --> 05:48:50,079
HAVE WORKED HARD IN THE

9268
05:48:50,079 --> 05:48:53,349
LABORATORY, WORKING ON THE

9269
05:48:53,349 --> 05:48:59,956
VACCINE BREAKTHROUGH MODEL.

9270
05:48:59,956 --> 05:49:01,657
AND MEENAKSHI KAR, ABIGAIL WHEN

9271
05:49:01,657 --> 05:49:03,126
WE FIRST STARTED THE MOUSE WORK

9272
05:49:03,126 --> 05:49:06,496
IN THE LABORATORY HAD UNDERTAKEN

9273
05:49:06,496 --> 05:49:11,100
SOME WORK WITH CCR 2 AND SEVERAL

9274
05:49:11,100 --> 05:49:14,270
COLLABORATORS ACROSS EMORY

9275
05:49:14,270 --> 05:49:22,478
UNIVERSITY AND OTHER PLACES,

9276
05:49:22,478 --> 05:49:27,417
VINEET IS NOW AT EMORY.

9277
05:49:27,417 --> 05:49:29,719
I HAVE HIM MISLABELED AT

9278
05:49:29,719 --> 05:49:29,986
GALVESTON.

9279
05:49:29,986 --> 05:49:31,254
>> I HAVE A QUESTION ABOUT

9280
05:49:31,254 --> 05:49:31,921
EOSINOPHIL AND VACCINE

9281
05:49:31,921 --> 05:49:33,089
BREAKTHROUGH.

9282
05:49:33,089 --> 05:49:34,657
DO YOU THINK THAT THE EOSINOPHIL

9283
05:49:34,657 --> 05:49:39,562
THAT YOU'RE SEEING IS AT ALL DUE

9284
05:49:39,562 --> 05:49:41,731
TO SLIGHTLY HETEROLOGOUS

9285
05:49:41,731 --> 05:49:42,498
CHALLENGE VIRUS SKEWING THINGS

9286
05:49:42,498 --> 05:49:45,401
MORE Th2 OR DO YOU THINK THAT

9287
05:49:45,401 --> 05:49:46,769
IT'S JUST AN INSUFFICIENT

9288
05:49:46,769 --> 05:49:49,705
ANTIBODY, LIKE A BINDING

9289
05:49:49,705 --> 05:49:50,206
NON-NEUTRALIZING OR NOT

9290
05:49:50,206 --> 05:49:50,873
SUFFICIENT NEUTRALIZING?

9291
05:49:50,873 --> 05:49:53,776
>> I THINK IT HAS MORE TO
DO

9292
05:49:53,776 --> 05:49:54,977
WITH VIRUS INFECTION OF THE

9293
05:49:54,977 --> 05:49:55,211
LUNG.

9294
05:49:55,211 --> 05:49:56,946
IF THE VIRUS CAN GET INTO THE

9295
05:49:56,946 --> 05:49:58,848
LUNGS YOU'RE GOING TO GET

9296
05:49:58,848 --> 05:50:00,283
INFECTION OF CELLS, IMMEDIATE

9297
05:50:00,283 --> 05:50:01,017
ANTIBODY.

9298
05:50:01,017 --> 05:50:05,288
THIS IS MY -- WE HAVE NOT

9299
05:50:05,288 --> 05:50:07,356
TESTED, TESTED AGAINST GAMMA

9300
05:50:07,356 --> 05:50:08,357
RECEPTOR KNOCKOUT MICE, GETTING

9301
05:50:08,357 --> 05:50:08,825
ANTIBODY BINDING.

9302
05:50:08,825 --> 05:50:12,528
WHEN YOU LOOK AT BINDING VERSUS

9303
05:50:12,528 --> 05:50:23,072
NUTES, THERE'S A LOT OF  BINDING

9304
05:50:26,542 --> 05:50:28,344
COMPARED TO ANTIBODIES.

9305
05:50:28,344 --> 05:50:31,814
THE MOUSE ADAPTIVE STRAIN IS

9306
05:50:31,814 --> 05:50:32,815
SIMILAR TO TRIMERIC, THE

9307
05:50:32,815 --> 05:50:35,918
PROTEIN, WE SEE THE SAME THING. 

9308
05:50:35,918 --> 05:50:38,888
AS LONG AS YOU OVERCOME WHATEVER

9309
05:50:38,888 --> 05:50:39,989
PROTECTIVE IMMUNITY THERE IS TO

9310
05:50:39,989 --> 05:50:42,925
NOT GET THE VIRUS IN THE LUNGS,

9311
05:50:42,925 --> 05:50:45,228
IF THE VIRUS GETS IN THE LUNGS

9312
05:50:45,228 --> 05:50:46,863
YOU'RE GETTING INFLAMMATORY

9313
05:50:46,863 --> 05:50:47,463
RESPONSE.

9314
05:50:47,463 --> 05:50:53,202
TIME 1 VERSUS TYPE 2 I DON'T

9315
05:50:53,202 --> 05:50:54,837
THINK THERE'S STRONG EVIDENCE IN

9316
05:50:54,837 --> 05:50:57,140
HUMANS THERE'S STRONG TYPE 2

9317
05:50:57,140 --> 05:50:57,406
RESPONSE.

9318
05:50:57,406 --> 05:50:59,542
I THINK THIS TYPE 1 VERSUS TYPE

9319
05:50:59,542 --> 05:51:02,512
2, I'M NOT QUITE SURE THAT THIS

9320
05:51:02,512 --> 05:51:08,117
NECESSARILY FITS THAT BILL

9321
05:51:08,117 --> 05:51:08,784
COMPLETELY.

9322
05:51:08,784 --> 05:51:14,056
>> CURIOUS ABOUT THE SARS
2 IN

9323
05:51:14,056 --> 05:51:16,492
PHAGOCYTIC CELLS, DIFFICULT TO

9324
05:51:16,492 --> 05:51:16,792
DISENTANGLE.

9325
05:51:16,792 --> 05:51:19,896
DO YOU FIND LOW LEVEL READS FOR

9326
05:51:19,896 --> 05:51:21,898
EPITHELIAL-SPECIFIC MARKERS

9327
05:51:21,898 --> 05:51:22,999
SUGGESTING THEY DID PHAGOCYTOSE.

9328
05:51:22,999 --> 05:51:25,501
>> WE HAVEN'T GONE TO THAT
DEEP

9329
05:51:25,501 --> 05:51:26,002
LEVEL.

9330
05:51:26,002 --> 05:51:33,242
THERE'S BEEN SOME STUDIES THAT

9331
05:51:33,242 --> 05:51:35,945
TRIED TO FLOW SOURCE, MACROPHAGE

9332
05:51:35,945 --> 05:51:41,551
POPULATIONS IN CULTURE FOR

9333
05:51:41,551 --> 05:51:42,151
HOURS, SHOWING POSITIVE VIRUS

9334
05:51:42,151 --> 05:51:45,555
REPLICATION, IT'S STUFF TO STATE

9335
05:51:45,555 --> 05:51:46,289
THERE'S VIRUS REPLICATION.

9336
05:51:46,289 --> 05:51:47,957
EVEN IF YOU TRY TO IDENTIFY I

9337
05:51:47,957 --> 05:51:50,660
STILL DON'T THINK ONE CAN SAY

9338
05:51:50,660 --> 05:51:53,496
IT'S VIRUS REPLICATION VERSUS

9339
05:51:53,496 --> 05:51:58,568
EATING DEAD CELL DEBRIS.

9340
05:51:58,568 --> 05:51:59,969
>> YES, SUPER NICE WORK.

9341
05:51:59,969 --> 05:52:05,942
I WAS WONDERING DO YOU THINK THE

9342
05:52:05,942 --> 05:52:09,712
VIRUS RESTRICTION BY EOSINOPHILS

9343
05:52:09,712 --> 05:52:12,448
IS DIRECT RESPONSE OR SOMETHING

9344
05:52:12,448 --> 05:52:13,649
OTHER, ANOTHER FUNCTION.

9345
05:52:13,649 --> 05:52:15,051
>> WE HAVE A COUPLE
CANDIDATE

9346
05:52:15,051 --> 05:52:16,419
GENES WE'RE LOOKING AT.

9347
05:52:16,419 --> 05:52:21,390
ONE THAT SEEMS TO BE QUITE

9348
05:52:21,390 --> 05:52:26,062
INTERESTING THAT EOSINOPHILS MAY

9349
05:52:26,062 --> 05:52:26,395
BE SECRETING.

9350
05:52:26,395 --> 05:52:28,965
THERE'S NOT A LOT OF EOSINOPHIL

9351
05:52:28,965 --> 05:52:29,232
REAGENTS.

9352
05:52:29,232 --> 05:52:30,700
THAT'S THE PAUSE I HAVE IN TERMS

9353
05:52:30,700 --> 05:52:34,670
OF BEING ABLE TO LOOK AT

9354
05:52:34,670 --> 05:52:35,404
CONDITIONAL KNOCKOUTS, TAKING

9355
05:52:35,404 --> 05:52:36,239
OUT CERTAIN MOLECULES.

9356
05:52:36,239 --> 05:52:38,674
JUST SHORT OF BEING ABLE TO

9357
05:52:38,674 --> 05:52:39,875
ISOLATE EOSINOPHILS FROM MICE,

9358
05:52:39,875 --> 05:52:42,011
WHICH IS STILL VERY TOUGH TO BE

9359
05:52:42,011 --> 05:52:44,513
ABLE TO SORT THOSE WITHOUT

9360
05:52:44,513 --> 05:52:44,914
KILLING THEM.

9361
05:52:44,914 --> 05:52:45,815
AND TRANSFERRING THEM.

9362
05:52:45,815 --> 05:52:50,052
WE'RE NOT ABLE TO SPECIFICALLY

9363
05:52:50,052 --> 05:52:51,721
DISSECT DIRECT ANTI-VIRAL

9364
05:52:51,721 --> 05:52:58,461
SECRETION OF ENZYME OR CYTOKINE,

9365
05:52:58,461 --> 05:52:59,228
FROM BY STANDARD EFFECT.

9366
05:52:59,228 --> 05:53:04,767
>> WERE YOU ABLE TO STAIN
FOR

9367
05:53:04,767 --> 05:53:06,369
VIRAL PROTEIN IN EOSINOPHILS?

9368
05:53:06,369 --> 05:53:08,137
>> WE'VE NOT DONE THAT.

9369
05:53:08,137 --> 05:53:10,506
IT'S ONLY BY SORT OF EYE IN

9370
05:53:10,506 --> 05:53:11,741
TERMS OF WHEN WE DEPLETE

9371
05:53:11,741 --> 05:53:14,710
EOSINOPHILS WE NO LONGER GET

9372
05:53:14,710 --> 05:53:16,879
THIS MASSIVE POPULATION THAT'S

9373
05:53:16,879 --> 05:53:20,016
WITHIN THAT AIRWAY SPACE,

9374
05:53:20,016 --> 05:53:21,117
WHETHER OUR COMPUTATIONAL STUFF

9375
05:53:21,117 --> 05:53:24,954
FOR RNAseq SHOWING A LOT OF

9376
05:53:24,954 --> 05:53:27,023
VIRAL RNA ASSOCIATED WITH THOSE

9377
05:53:27,023 --> 05:53:28,190
CELLS.

9378
05:53:28,190 --> 05:53:29,692
>> I HAD A QUESTION.

9379
05:53:29,692 --> 05:53:33,329
IN PATIENTS WHO DIED EARLY IN

9380
05:53:33,329 --> 05:53:38,934
THE PANDEMIC, WITH LOTS OF

9381
05:53:38,934 --> 05:53:41,470
EOSINOPHILS IN THE LUNGS --

9382
05:53:41,470 --> 05:53:42,838
>> THEY WERE NEUTROPHIL

9383
05:53:42,838 --> 05:53:45,808
DOMINATED IN TERMS OF NAIVE

9384
05:53:45,808 --> 05:53:48,411
INFECTION. 

9385
05:53:48,411 --> 05:53:49,245
FROM VACCINE BREAKTHROUGH

9386
05:53:49,245 --> 05:53:49,845
INFECTIONS, WHICH INDIVIDUALS

9387
05:53:49,845 --> 05:53:51,614
MAY HAVE GONE TO THE HOSPITAL,

9388
05:53:51,614 --> 05:53:52,948
HAD SEVERE DISEASE, WE'VE TRIED

9389
05:53:52,948 --> 05:53:55,718
TO LOOK IN THE LITERATURE.

9390
05:53:55,718 --> 05:53:59,121
THERE'S NOT A LOT OF DATA TO GET

9391
05:53:59,121 --> 05:54:03,059
THIS TRYING TO GET FLUID FROM

9392
05:54:03,059 --> 05:54:05,161
INFECTED INDIVIDUALS IS TOUGH,

9393
05:54:05,161 --> 05:54:06,362
ESPECIALLY WITH SHORT-LIVED

9394
05:54:06,362 --> 05:54:07,363
CELLS LIKE EOSINOPHILS, TIMING

9395
05:54:07,363 --> 05:54:08,864
IS IMPORTANT WHEN YOU COLLECT

9396
05:54:08,864 --> 05:54:14,136
THOSE SAMPLES AS WELL.

9397
05:54:14,136 --> 05:54:14,804
>> THIS QUESTION WAS
SUBMITTED

9398
05:54:14,804 --> 05:54:16,605
AT THE BEGINNING OF THE TALK.

9399
05:54:16,605 --> 05:54:18,507
WOULD IT BE IMPORTANT TO SHOW

9400
05:54:18,507 --> 05:54:22,078
THE STRENGTH OF RESPONSE IN

9401
05:54:22,078 --> 05:54:23,946
SHOWING MEDIAN FLUORESCENT

9402
05:54:23,946 --> 05:54:28,117
INTENSITY OF PERCENT POSITIVE

9403
05:54:28,117 --> 05:54:31,654
ANTIGEN SPECIFIC T CELL?

9404
05:54:31,654 --> 05:54:35,891
>> WE HAVE LOOKED AT IN
TERMS OF

9405
05:54:35,891 --> 05:54:36,959
INTERFERON GAMMA STAGE, TNF

9406
05:54:36,959 --> 05:54:40,296
ALPHA STAINING, WE DON'T SEE

9407
05:54:40,296 --> 05:54:41,597
DIFFERENCE IN INTENSITY.

9408
05:54:41,597 --> 05:54:47,837
NO MAJOR SHIFT EITHER POSITIVE

9409
05:54:47,837 --> 05:54:49,038
OR NEGATIVE.

9410
05:54:49,038 --> 05:54:52,408
>> EOSINOPHIL HAPPEN IN

9411
05:54:52,408 --> 05:54:53,876
BREAKTHROUGH INFECTION, LOOKS

9412
05:54:53,876 --> 05:54:57,480
LIKE ANIMAL GET PRIME BY

9413
05:54:57,480 --> 05:54:59,548
INFECTION OR VACCINE, IN THAT

9414
05:54:59,548 --> 05:55:03,552
CASE, SO WHY ONLY THE

9415
05:55:03,552 --> 05:55:04,153
BREAKTHROUGH INFECTION YOU SEE

9416
05:55:04,153 --> 05:55:04,286
--

9417
05:55:04,286 --> 05:55:05,788
>> I THINK IN TERMS OF

9418
05:55:05,788 --> 05:55:08,057
BREAKTHROUGH INFECTION THE LUNG

9419
05:55:08,057 --> 05:55:10,493
IS BATHED IN ANTIBODIES.

9420
05:55:10,493 --> 05:55:11,861
WHEREAS NAIVE MICE DON'T HAVE

9421
05:55:11,861 --> 05:55:12,361
THOSE.

9422
05:55:12,361 --> 05:55:14,296
I THINK IT HAS A LOT TO DO WITH

9423
05:55:14,296 --> 05:55:14,630
ANTIBODIES.

9424
05:55:14,630 --> 05:55:17,967
I THINK IN THE SHORT WINDOW OF

9425
05:55:17,967 --> 05:55:19,668
DAY 3 POST-INFECTION, WE HAVE

9426
05:55:19,668 --> 05:55:22,705
HAVEN'T FORMALLY TESTED ROLE OF

9427
05:55:22,705 --> 05:55:24,774
T CELLS BUT CERTAINLY THE LUNG

9428
05:55:24,774 --> 05:55:28,878
AND LOTS OF BINDING ANTIBODIES.

9429
05:55:28,878 --> 05:55:32,348
>> IF YOU USE KNOCKOUT
MICE,

9430
05:55:32,348 --> 05:55:35,084
WHAT WOULD YOU EXPECT?

9431
05:55:35,084 --> 05:55:37,153
>> B CELL KNOCKOUTS ARE
MORE

9432
05:55:37,153 --> 05:55:38,387
COMPLEX, IMMUNOLOGICALLY NOT THE

9433
05:55:38,387 --> 05:55:40,089
SAME AS NAIVE MICE.

9434
05:55:40,089 --> 05:55:41,457
IT'S NOT JUST SIMPLY YOU REMOVE

9435
05:55:41,457 --> 05:55:43,526
B CELLS FROM THEM.

9436
05:55:43,526 --> 05:55:45,995
I THINK THE BETTER EXPERIMENT

9437
05:55:45,995 --> 05:55:49,131
WHICH I'VE ASKED MY FOLKS TO DO

9438
05:55:49,131 --> 05:55:50,866
IS DEPLETE T CELLS AND ASK WHAT

9439
05:55:50,866 --> 05:55:54,270
HAPPENS IN THAT CONTEXT.

9440
05:55:54,270 --> 05:55:55,337
>> I GUESS ON A SIMILAR
NOTE

9441
05:55:55,337 --> 05:55:59,074
HAVE YOU BEEN ABLE TO GIVE

9442
05:55:59,074 --> 05:56:01,277
IMMUNE SERA FROM RECOVERED

9443
05:56:01,277 --> 05:56:02,511
HAMSTERS, SORRY, FOR RECOVERED

9444
05:56:02,511 --> 05:56:09,151
MICE, IS THAT SIGNIFICANT ENOUGH

9445
05:56:09,151 --> 05:56:10,052
TO INDUCE EOSINOPHILS?

9446
05:56:10,052 --> 05:56:12,321
>> WE'VE BEEN WORKING
TRYING TO

9447
05:56:12,321 --> 05:56:13,889
GET THE RIGHT DOSE, RIGHT AMOUNT

9448
05:56:13,889 --> 05:56:15,825
OF ANTIBODIES, RIGHT TIMING OF

9449
05:56:15,825 --> 05:56:16,425
INFECTION, HASN'T BEEN

9450
05:56:16,425 --> 05:56:17,126
SUCCESSFUL YET.

9451
05:56:17,126 --> 05:56:20,729
IT HAS MORE TO DO WITH TECHNICAL

9452
05:56:20,729 --> 05:56:21,430
THAN ACTUAL PHENOTYPE.

9453
05:56:21,430 --> 05:56:23,599
ONE OF THE THINGS WE WANTED TO

9454
05:56:23,599 --> 05:56:26,001
DO WAS TAKE THAT PASSIVE IMMUNE

9455
05:56:26,001 --> 05:56:29,405
TRANSFER AND PERFORM THAT

9456
05:56:29,405 --> 05:56:30,840
RECEPTOR KNOCKOUT MICE TO

9457
05:56:30,840 --> 05:56:33,042
DEMONSTRATE FC GAMMA DEPENDENT

9458
05:56:33,042 --> 05:56:36,512
SIGNALING THAT'S DRIVING THAT.

9459
05:56:36,512 --> 05:56:39,148
>> IF NO MORE QUESTIONS WE
CAN

9460
05:56:39,148 --> 05:56:40,583
HAVE OUR PANEL DISCUSSION.

9461
05:56:40,583 --> 05:56:41,283
>> ONE MORE QUESTION.

9462
05:56:41,283 --> 05:56:45,588
IN TERMS OF THE VIRAL PERSISTENT

9463
05:56:45,588 --> 05:56:48,090
STORY, I'M NOT CLEAR ON THE

9464
05:56:48,090 --> 05:56:49,425
EVIDENCE FOR HOW STRONG IT IS

9465
05:56:49,425 --> 05:56:52,161
FOR THE IDEA OF PERSISTENCE IN

9466
05:56:52,161 --> 05:56:52,661
HUMANS.

9467
05:56:52,661 --> 05:56:56,432
IS THAT STRONGER DATA NOW?

9468
05:56:56,432 --> 05:56:57,199
>> YEAH, SO
IMMUNOCOMPROMISED

9469
05:56:57,199 --> 05:56:59,268
INDIVIDUALS I THINK IT'S QUITE

9470
05:56:59,268 --> 05:57:00,236
COMPELLING THAT INDIVIDUALS THAT

9471
05:57:00,236 --> 05:57:03,239
ARE EITHER ON B CELL THERAPY,

9472
05:57:03,239 --> 05:57:06,275
T-CELL THERAPY, THEY DO HAVE

9473
05:57:06,275 --> 05:57:08,677
PERSISTENT VIRAL INFECTION.

9474
05:57:08,677 --> 05:57:09,778
IMMUNE COMPROMISED INDIVIDUALS,

9475
05:57:09,778 --> 05:57:10,980
ESPECIALLY CANCER INDIVIDUALS,

9476
05:57:10,980 --> 05:57:13,415
THERE'S LOTS OF EVIDENCE OUT

9477
05:57:13,415 --> 05:57:14,283
THERE SHOWING VIRUS CAN PERSIST

9478
05:57:14,283 --> 05:57:16,485
FOR MONTHS ON END IN THEIR UPPER

9479
05:57:16,485 --> 05:57:17,119
RESPIRATORY TRACT, AS A MATTER

9480
05:57:17,119 --> 05:57:20,556
OF FACT I KNOW ONE OF OUR

9481
05:57:20,556 --> 05:57:23,259
CLINICIANS WORKING AT THE CANCER

9482
05:57:23,259 --> 05:57:26,228
CENTER AS PART OF OUR U54 GRANT

9483
05:57:26,228 --> 05:57:28,464
WOULD COMPLAIN HIS PATIENTS

9484
05:57:28,464 --> 05:57:29,365
WEREN'T COMING TO THE CLINIC

9485
05:57:29,365 --> 05:57:30,566
EARLY DURING THE PANDEMIC

9486
05:57:30,566 --> 05:57:34,069
BECAUSE THEY WOULD TEST POSITIVE

9487
05:57:34,069 --> 05:57:35,671
IN THE UPPER RESPIRATORY TRACT,

9488
05:57:35,671 --> 05:57:39,475
MANY WOULD MISTREATMENT  MISS -E

9489
05:57:39,475 --> 05:57:40,643
TREATMENT THEY ARE SUPPOSED TO

9490
05:57:40,643 --> 05:57:43,379
GET.

9491
05:57:43,379 --> 05:57:44,713
 

9492
05:57:44,713 --> 05:57:53,155
THANK YOU. 

9493
05:57:53,155 --> 05:57:53,522
>> OKAY.

9494
05:57:53,522 --> 05:57:58,060
SO NOW WE HAVE OUR PANEL

9495
05:57:58,060 --> 05:57:59,995
DISCUSSION.

9496
05:57:59,995 --> 05:58:10,039
 

9497
05:58:14,143 --> 05:58:24,119
 

9498
05:58:27,389 --> 05:58:28,724
>> DOES ANYONE HAVE
QUESTIONS

9499
05:58:28,724 --> 05:58:29,091
FOR THE PANEL?

9500
05:58:29,091 --> 05:58:30,593
>> I HAVE A QUESTION.

9501
05:58:30,593 --> 05:58:31,927
WE'RE DISCUSSING DURING THE

9502
05:58:31,927 --> 05:58:34,563
BREAK, IN TERMS OF MUCOSAL

9503
05:58:34,563 --> 05:58:36,098
IMMUNITY IN THE SMALL ANIMAL

9504
05:58:36,098 --> 05:58:39,134
MODEL, ARE WE GOING TO NEAT

9505
05:58:39,134 --> 05:58:41,637
ADJUVANTS, ARE THERE POTENTIAL

9506
05:58:41,637 --> 05:58:42,838
WITHDRAWAL EFFECTS OF USING

9507
05:58:42,838 --> 05:58:44,540
ADJUVANTS IN ANIMAL MODELS AND

9508
05:58:44,540 --> 05:58:46,241
IN TRYING TO TRANSLATE THAT TO

9509
05:58:46,241 --> 05:58:50,312
HUMANS, SO DO WE NEED ADJUVANTS?

9510
05:58:50,312 --> 05:58:51,714
ARE THERE MUTUAL SIDE EFFECTS

9511
05:58:51,714 --> 05:58:57,252
WHEN WE MOVE TO HUMANS? 

9512
05:58:57,252 --> 05:58:59,588
WHAT ARE THE PANELIST FEELINGS?

9513
05:58:59,588 --> 05:59:00,889
>> I CAN TAKE THE
QUESTION.

9514
05:59:00,889 --> 05:59:05,227
WE HAVE TO START SEVERAL

9515
05:59:05,227 --> 05:59:06,095
ADJUVANTS FOR MUCOSAL AND

9516
05:59:06,095 --> 05:59:06,962
MUSCULAR VACCINATION, AND IN

9517
05:59:06,962 --> 05:59:09,798
MICE WE HAVE SEEN IF WE GIVE

9518
05:59:09,798 --> 05:59:10,432
RECOMBINANT PROTEIN NOT MUCH

9519
05:59:10,432 --> 05:59:16,472
HAPPENS IN TERMS OF SERUM,

9520
05:59:16,472 --> 05:59:21,210
ANTIBODY INDUCTION,  MEASURING

9521
05:59:21,210 --> 05:59:22,277
SERUM OR MUCOSA.

9522
05:59:22,277 --> 05:59:27,216
ON THE HAMSTER WE SEE GOOD IgA

9523
05:59:27,216 --> 05:59:28,884
AND SEER INDUCTION, SEEMS TO BE

9524
05:59:28,884 --> 05:59:31,253
A DIFFERENCE IN MICE OR BIG OR

9525
05:59:31,253 --> 05:59:32,554
SMALL ANIMALS.

9526
05:59:32,554 --> 05:59:34,423
THAT BEING SAID, IF WE USE MICE

9527
05:59:34,423 --> 05:59:36,659
FOR MUCOSAL VACCINATION WE ALSO

9528
05:59:36,659 --> 05:59:40,396
HAVE TO PUT SOME GOOD ADJUVANTS,

9529
05:59:40,396 --> 05:59:43,298
BUT WE HAVE TO BE CAREFUL

9530
05:59:43,298 --> 05:59:48,537
BECAUSE THE RANGE OF TOXICITY IS

9531
05:59:48,537 --> 05:59:49,738
VERY SMALL.

9532
05:59:49,738 --> 05:59:55,978
SO, FOR EXAMPLE, AGONISTS WE'VE

9533
05:59:55,978 --> 05:59:57,413
TESTED WAS TOXICS, SMALLER WERE

9534
05:59:57,413 --> 05:59:58,781
ACTUALLY VERY SAFE.

9535
05:59:58,781 --> 05:59:59,682
>> A QUICK COMMENT.

9536
05:59:59,682 --> 06:00:02,251
AS FAR AS I'M AWARE, CORRECT ME

9537
06:00:02,251 --> 06:00:07,723
IF I'M WRONG, NO SMALL ANIMAL

9538
06:00:07,723 --> 06:00:08,924
MODEL RECAPITULATES

9539
06:00:08,924 --> 06:00:09,825
REACTIGENICITY, FOR SOME HUMANS

9540
06:00:09,825 --> 06:00:12,528
HAVE IT BUT NOT ALL.

9541
06:00:12,528 --> 06:00:17,433
IT'S A HUGE DRAWBACK IN THE

9542
06:00:17,433 --> 06:00:19,234
VACCINE FIELD BECAUSE PEOPLE

9543
06:00:19,234 --> 06:00:25,874
THINK  REACTIGENICITY, PREDICTIG

9544
06:00:25,874 --> 06:00:27,076
WHO MAY GET REACTIGENICITY,

9545
06:00:27,076 --> 06:00:28,243
PREVENTING REACTIGENICITY WOULD

9546
06:00:28,243 --> 06:00:31,580
BE A HUGE DEAL.

9547
06:00:31,580 --> 06:00:33,549
WE'VE TRIED, WITH A FEW

9548
06:00:33,549 --> 06:00:36,218
ADJUVANTS WE HAVE YET TO SEE IT.

9549
06:00:36,218 --> 06:00:41,623
WE WOULD LIKE TO FIND A MODEL

9550
06:00:41,623 --> 06:00:45,661
FOR REACTIGENICITY.

9551
06:00:45,661 --> 06:00:49,732
>> YOUR DIRTY MICE MODEL
DOES

9552
06:00:49,732 --> 06:00:54,636
YOUR ADJUVANT STEAL ADJUVANT. 

9553
06:00:54,636 --> 06:00:56,505
>> YOU NEED IT.

9554
06:00:56,505 --> 06:00:58,807
THE ADJUVANT IS QUITE CRITICAL

9555
06:00:58,807 --> 06:01:01,977
IN DIRTY MICE JUST LIKE HUMANS

9556
06:01:01,977 --> 06:01:02,911
WHERE IT'S QUITE CRITICAL.

9557
06:01:02,911 --> 06:01:04,613
>> ANOTHER PROBLEM IN MICE
IS

9558
06:01:04,613 --> 06:01:06,381
THE VOLUME FOR MUCOSAL

9559
06:01:06,381 --> 06:01:08,484
ADJUVANTS, VERY SMALL VOLUMES IF

9560
06:01:08,484 --> 06:01:09,451
YOU WANT TO PREVENT FROM GOING

9561
06:01:09,451 --> 06:01:19,695
TO THE LUNGS.

9562
06:01:20,362 --> 06:01:24,967
>> I HAVE A QUESTION, MORE

9563
06:01:24,967 --> 06:01:26,034
GENERAL QUESTION.

9564
06:01:26,034 --> 06:01:28,403
NATURAL INFECTION DOESN'T SEEM

9565
06:01:28,403 --> 06:01:30,205
TO INDUCE MUCOSAL IMMUNITY, AT

9566
06:01:30,205 --> 06:01:31,306
LEAST WITH PROTECTIVE EXTENT.

9567
06:01:31,306 --> 06:01:33,342
WHAT DO YOU THINK WE'RE DOING

9568
06:01:33,342 --> 06:01:38,347
DIFFERENTLY THAT WILL HELP GET

9569
06:01:38,347 --> 06:01:41,483
AROUND THAT PROBLEM?

9570
06:01:41,483 --> 06:01:46,421
>> I MEAN, I THINK WE
DON'T

9571
06:01:46,421 --> 06:01:48,624
FULLY UNDERSTAND WHAT IS BEING

9572
06:01:48,624 --> 06:01:50,159
INDUCED WHEN PEOPLE ARE INFECTED

9573
06:01:50,159 --> 06:01:51,226
WITH SARS-COV-2, WHETHER THAT

9574
06:01:51,226 --> 06:01:54,329
COMPARES TO WHAT WE INDUCE WITH

9575
06:01:54,329 --> 06:01:55,430
INTRANASAL VACCINATION, MUCOSAL

9576
06:01:55,430 --> 06:01:56,131
VACCINATION.

9577
06:01:56,131 --> 06:01:58,133
SO THAT'S AN INCREDIBLY

9578
06:01:58,133 --> 06:02:00,235
IMPORTANT QUESTION TO TRY AND

9579
06:02:00,235 --> 06:02:02,538
UNDERSTAND BETTER BECAUSE

9580
06:02:02,538 --> 06:02:07,342
CLEARLY WE'RE GETTING THE

9581
06:02:07,342 --> 06:02:11,580
INFECTED AND WOULD IDEALLY HAVE

9582
06:02:11,580 --> 06:02:12,447
VACCINE THAT LIFELONG PROTECTION

9583
06:02:12,447 --> 06:02:14,449
WOULD BE GREAT BUT I DON'T WE'RE

9584
06:02:14,449 --> 06:02:19,388
GOING TO GET THERE. 

9585
06:02:19,388 --> 06:02:20,789
EITHER WITH VIRUS INFECTION, NOT

9586
06:02:20,789 --> 06:02:23,992
BEING INDUCED OR OVER TIME GO

9587
06:02:23,992 --> 06:02:26,962
AWAY AND YOU'RE SUSCEPTIBLE

9588
06:02:26,962 --> 06:02:27,162
AGAIN.

9589
06:02:27,162 --> 06:02:29,031
>> ARE YOU SPECIFICALLY
ASKING

9590
06:02:29,031 --> 06:02:32,067
PROTECTION IN THE UPPER?

9591
06:02:32,067 --> 06:02:36,271
>> YEAH, I THINK IT'S VERY
HARD

9592
06:02:36,271 --> 06:02:37,906
TO DRIVE STERILIZING IMMUNITY IN

9593
06:02:37,906 --> 06:02:39,007
THE UPPER RESPIRATORY TRACT.

9594
06:02:39,007 --> 06:02:41,944
EVEN IF YOU HAVE A HOMOLOGOUS

9595
06:02:41,944 --> 06:02:45,881
INFECTION YOU CAN STILL GET --

9596
06:02:45,881 --> 06:02:46,849
HOMOLOGOUS VIRUS, COULD STILL

9597
06:02:46,849 --> 06:02:48,550
GET GOOD REPLICATION OF THE

9598
06:02:48,550 --> 06:02:49,618
UPPER TRACT BUT DO GOT STRONG

9599
06:02:49,618 --> 06:02:51,920
PROTECTION IN THE LOWER TRACT,

9600
06:02:51,920 --> 06:02:53,455
WE NEED A DIVERGENT VARIANT,

9601
06:02:53,455 --> 06:02:55,991
THAT'S WHERE YOU GET INFECTION

9602
06:02:55,991 --> 06:02:56,525
OF THE LUNGS.

9603
06:02:56,525 --> 06:02:58,927
>> IT'S ONE OF THE KEY
QUESTIONS

9604
06:02:58,927 --> 06:03:00,896
BECAUSE WE DO GET REINFECTED,

9605
06:03:00,896 --> 06:03:05,467
PEOPLE ARE NOT GOING TO THE

9606
06:03:05,467 --> 06:03:08,003
HOSPITAL, TO SUBSTANTIAL EFFECT,

9607
06:03:08,003 --> 06:03:08,637
UNLESS THEY ARE

9608
06:03:08,637 --> 06:03:09,805
IMMUNOCOMPROMISED OR QUITE AGED

9609
06:03:09,805 --> 06:03:11,173
IN NURSING HOMES.

9610
06:03:11,173 --> 06:03:15,878
THE GOAL OF MUCOSAL IMMUNITY IS

9611
06:03:15,878 --> 06:03:16,879
PREVENT INFECTION, YOU'RE SAYING

9612
06:03:16,879 --> 06:03:19,281
THAT MAY BE VERY TYPICAL.

9613
06:03:19,281 --> 06:03:23,785
IS IT WORTH FOCUSING ON MUCOSAL

9614
06:03:23,785 --> 06:03:25,187
IMMUNITY AS OPPOSED TO OTHER

9615
06:03:25,187 --> 06:03:29,024
METHODS OF VACCINATION.

9616
06:03:29,024 --> 06:03:31,426
>> SO I THINK FROM WHAT WE
KNOW

9617
06:03:31,426 --> 06:03:36,031
IN SARS-COV-2 HYBRID IMMUNITY, A

9618
06:03:36,031 --> 06:03:36,999
COMBINATION OF VACCINATION,

9619
06:03:36,999 --> 06:03:39,434
COMBINATION OF INFECTION OF

9620
06:03:39,434 --> 06:03:40,936
MUCOSA, GIVING SUPERIOR

9621
06:03:40,936 --> 06:03:44,473
PROTECTION BUT ALSO IT SEEMS

9622
06:03:44,473 --> 06:03:46,541
THAT MEMORY AT MUCOSAL SITES IS

9623
06:03:46,541 --> 06:03:49,578
NOT AS STRONG AS PERIPHERY.

9624
06:03:49,578 --> 06:03:51,146
WE THEY FOCUS IF RECALL OR

9625
06:03:51,146 --> 06:03:54,216
MEMORY IS NOT IN THE PERIPHERY,

9626
06:03:54,216 --> 06:03:56,618
HAS TO BE RECRUITED TO THE

9627
06:03:56,618 --> 06:03:59,788
MUCOSA, HAVE TO CHECK IF WE CAN

9628
06:03:59,788 --> 06:04:04,493
FACILITATE OR MAKE THIS GO

9629
06:04:04,493 --> 06:04:04,793
FASTER.

9630
06:04:04,793 --> 06:04:07,429
FOCUSING ON INDUCING MEMORY AT

9631
06:04:07,429 --> 06:04:08,997
MUCOSAL SITES THEMSELVES.

9632
06:04:08,997 --> 06:04:11,166
PERIPHERY MIGHT BE THE MEMORY

9633
06:04:11,166 --> 06:04:14,803
COMPARTMENT FOR THE MUCOSAL

9634
06:04:14,803 --> 06:04:15,037
SITE.

9635
06:04:15,037 --> 06:04:16,638
>> WE DON'T KNOW ENOUGH
ABOUT

9636
06:04:16,638 --> 06:04:19,441
THE UPPER RESPIRATORY TRACT

9637
06:04:19,441 --> 06:04:24,179
COMPARED TO THE LUNG.

9638
06:04:24,179 --> 06:04:27,382
>> SORRY, YEAH, I WANT TO
SORT

9639
06:04:27,382 --> 06:04:33,588
OF MORE BROADLY TALK ABOUT WE'VE

9640
06:04:33,588 --> 06:04:35,223
BEEN FOCUSED ON VACCINATION,

9641
06:04:35,223 --> 06:04:38,160
LETHALITY OF DISEASE OR

9642
06:04:38,160 --> 06:04:39,895
REPLICATION, HOPEFULLY

9643
06:04:39,895 --> 06:04:40,929
ADMINISTERED OR SYSTEMICALLY

9644
06:04:40,929 --> 06:04:42,731
ADMINISTERED BUT WHAT ABOUT

9645
06:04:42,731 --> 06:04:43,498
TRANSMISSION AND NATURAL

9646
06:04:43,498 --> 06:04:46,435
INFECTION, CAN WE TALK ABOUT

9647
06:04:46,435 --> 06:04:49,571
WHAT BARRIERS ARE, DOVETAILING

9648
06:04:49,571 --> 06:04:50,806
WITH TOMORROW'S SESSION, WHERE

9649
06:04:50,806 --> 06:04:55,243
DO WE NEED TO GO, RIGHT, AS A

9650
06:04:55,243 --> 06:04:58,347
FIELD TO REALLY THINK ABOUT HOW

9651
06:04:58,347 --> 06:05:01,049
VACCINATION CAN COMBAT NATURAL

9652
06:05:01,049 --> 06:05:01,850
INFECTIONS AND BE SORT OF WHAT

9653
06:05:01,850 --> 06:05:07,856
WE BILL IT TO BE?

9654
06:05:07,856 --> 06:05:07,990
 

9655
06:05:07,990 --> 06:05:09,524
>> YEAH, I'M GOING TO
ACTUALLY

9656
06:05:09,524 --> 06:05:11,994
GO BACK AND SAY I DO THINK

9657
06:05:11,994 --> 06:05:14,196
MUCOSAL IMMUNITY IS SOMETHING WE

9658
06:05:14,196 --> 06:05:17,299
SHOULD FOCUS ON BECAUSE STRAIGHT

9659
06:05:17,299 --> 06:05:18,800
AFTER INFECTION PEOPLE OFTEN ARE

9660
06:05:18,800 --> 06:05:20,335
PROTECTED, I THINK THAT ALSO

9661
06:05:20,335 --> 06:05:21,970
GOES INTO TRANSMISSION AS WELL,

9662
06:05:21,970 --> 06:05:25,407
WHAT WE LIKELY NEED IN UPPER

9663
06:05:25,407 --> 06:05:30,946
RESPIRATORY TRACT IS ANTIBODY

9664
06:05:30,946 --> 06:05:32,814
PROTECTION BY CELLS, SO IT'S NOT

9665
06:05:32,814 --> 06:05:37,786
EVEN NECESSARILY JUST THAT YOU

9666
06:05:37,786 --> 06:05:41,256
GET STABLE PROTECTION OF UPPER

9667
06:05:41,256 --> 06:05:44,359
TRACT BUT ANTIBODIES,

9668
06:05:44,359 --> 06:05:45,994
POTENTIALLY REDUCING ACTUAL

9669
06:05:45,994 --> 06:05:48,397
EFFECTIVENESS OF TRANSMISSION.

9670
06:05:48,397 --> 06:05:50,932
SO I THINK WE NEED A LITTLE BIT

9671
06:05:50,932 --> 06:05:53,368
MORE THAN JUST WE NEED TO

9672
06:05:53,368 --> 06:05:56,705
UNDERSTAND WHETHER ANTIBODIES IN

9673
06:05:56,705 --> 06:05:58,373
THE UPPER TRACT ARE ABLE TO DO

9674
06:05:58,373 --> 06:05:59,708
THAT.

9675
06:05:59,708 --> 06:06:02,711
WHEN WE DO TRANSMISSION STUDIES

9676
06:06:02,711 --> 06:06:04,679
WE ONLY VACCINATE SENTINEL, WE

9677
06:06:04,679 --> 06:06:05,914
STILL GET TRANSMISSION OF THE

9678
06:06:05,914 --> 06:06:09,818
VIRUS, FROM THE DONOR ANIMALS,

9679
06:06:09,818 --> 06:06:13,555
TO THE SENTINELS EVEN THOUGH

9680
06:06:13,555 --> 06:06:15,424
THEY ARE PROTECTED, YOU STILL

9681
06:06:15,424 --> 06:06:16,625
GET INFECTION OF UPPER

9682
06:06:16,625 --> 06:06:20,328
RESPIRATORY TRACT.

9683
06:06:20,328 --> 06:06:21,029
DONOR ANIMALS VACCINATED,

9684
06:06:21,029 --> 06:06:22,864
INTRAMUSCULAR, WE GET LESS

9685
06:06:22,864 --> 06:06:23,865
TRANSMISSION OR ABSOLUTELY NO

9686
06:06:23,865 --> 06:06:25,200
TRANSMISSION AT ALL, THAT HAS TO

9687
06:06:25,200 --> 06:06:27,702
DO WITH COATING OF THE VIRUS BY

9688
06:06:27,702 --> 06:06:28,236
ANTIBODIES.

9689
06:06:28,236 --> 06:06:32,374
SO I THINK THAT TO LOOK AT

9690
06:06:32,374 --> 06:06:33,542
TRANSMISSION, PREVENTION

9691
06:06:33,542 --> 06:06:35,544
TRANSMISSION, KEY QUESTION, HOW

9692
06:06:35,544 --> 06:06:39,414
CAN WE INDUCE BY VACCINATION.

9693
06:06:39,414 --> 06:06:40,949
>> A SMALL ANIMAL MODEL

9694
06:06:40,949 --> 06:06:43,251
WORKSHOP, I'LL PLUG WE NEED MORE

9695
06:06:43,251 --> 06:06:46,054
MODELS TO STUDY THIS EXACT

9696
06:06:46,054 --> 06:06:49,357
THING, NEED MORE TRANSMISSION

9697
06:06:49,357 --> 06:06:50,192
MODELS.

9698
06:06:50,192 --> 06:06:51,426
A MODEL ABOUT ANOTHER

9699
06:06:51,426 --> 06:06:53,061
TRANSMISSION MODEL, THE MORE WE

9700
06:06:53,061 --> 06:06:55,797
HAVE WITH DIFFERENT MODELS,

9701
06:06:55,797 --> 06:06:56,498
STRENGTHS, WEAKNESSES, TOOLS,

9702
06:06:56,498 --> 06:06:59,067
THE BETTER TO ADDRESS THE

9703
06:06:59,067 --> 06:06:59,501
QUESTIONS.

9704
06:06:59,501 --> 06:07:00,402
IT'S HARD, TRANSMISSION MODELS

9705
06:07:00,402 --> 06:07:02,237
ARE NOT EASY.

9706
06:07:02,237 --> 06:07:11,012
WE CLEARLY NEED MORE.

9707
06:07:11,012 --> 06:07:14,149
>> I WAS GOING TO CALL ON
DAVID

9708
06:07:14,149 --> 06:07:18,253
MARTINEZ ON ZOOM TO UNMUTE.

9709
06:07:18,253 --> 06:07:25,894
>> YEAH, I HAVE A QUESTION
FOR

9710
06:07:25,894 --> 06:07:29,397
ANNELTJE IN PARTICULAR, ABOUT

9711
06:07:29,397 --> 06:07:30,665
YOUR CHADOX DATA.

9712
06:07:30,665 --> 06:07:34,569
THE VECTOR IS REMARKABLE AT

9713
06:07:34,569 --> 06:07:36,371
ELICITING TISSUE RESIDENT T-CELL

9714
06:07:36,371 --> 06:07:38,006
RESPONSES AND IgA RESPONSES IN

9715
06:07:38,006 --> 06:07:40,108
ANIMAL MODELS.

9716
06:07:40,108 --> 06:07:42,043
HOWEVER, THAT CHADOX VACCINE IN

9717
06:07:42,043 --> 06:07:43,912
HUMANS IN A PAPER PUBLISHED

9718
06:07:43,912 --> 06:07:46,848
MAYBE OVER A YEAR AGO SHOWED IT

9719
06:07:46,848 --> 06:07:48,049
WAS LACKLUSTER.

9720
06:07:48,049 --> 06:07:49,384
SO I WAS WONDERING IF YOU COULD

9721
06:07:49,384 --> 06:07:50,819
COMMENT ON WHY PERHAPS THERE'S

9722
06:07:50,819 --> 06:07:52,787
SUCH A DISCONNECT IN THE ANIMAL

9723
06:07:52,787 --> 06:07:54,189
MODEL THAT YOU'RE USING COMPARED

9724
06:07:54,189 --> 06:07:57,025
TO WHAT THE DATA THAT WAS SHOWN

9725
06:07:57,025 --> 06:08:03,098
IN HUMANS, I THINK BY

9726
06:08:03,098 --> 06:08:03,632
ASTRAZENECA.

9727
06:08:03,632 --> 06:08:04,533
>> YES, A FANTASTIC
QUESTION.

9728
06:08:04,533 --> 06:08:07,102
IT GOES BACK TO THE MODELS WE'RE

9729
06:08:07,102 --> 06:08:12,274
USING IN THE MOUSE, NOT THE

9730
06:08:12,274 --> 06:08:15,877
HUMAN, NEITHER THE HAMSTER OR

9731
06:08:15,877 --> 06:08:16,178
FERRET.

9732
06:08:16,178 --> 06:08:18,079
HOW THEY ADMINISTER, THEY USE

9733
06:08:18,079 --> 06:08:21,349
THE SAME NEBULIZER AS WE USED IN

9734
06:08:21,349 --> 06:08:22,551
NON-HUMAN PRIMATES, WE CAN'T USE

9735
06:08:22,551 --> 06:08:24,886
THAT IN A HAMSTER BECAUSE IT'S

9736
06:08:24,886 --> 06:08:28,557
TOO LARGE BUT BASICALLY CREATING

9737
06:08:28,557 --> 06:08:31,426
A CLOUD OF AEROSOLS, VACCINES

9738
06:08:31,426 --> 06:08:33,361
THE ANIMALS BREATHE IN.

9739
06:08:33,361 --> 06:08:35,830
IT DIDN'T INUSE THE SAME IMMUNE

9740
06:08:35,830 --> 06:08:36,097
RESPONSE.

9741
06:08:36,097 --> 06:08:37,866
OUR COMPANIES USING DIFFERENT

9742
06:08:37,866 --> 06:08:39,434
WAYS OF VACCINATION AND IN CHINA

9743
06:08:39,434 --> 06:08:41,703
THEY ARE ACTUALLY DOING A CORE

9744
06:08:41,703 --> 06:08:43,805
THING CREATING A CLOUD OF

9745
06:08:43,805 --> 06:08:45,607
AEROSOLS, SORT OF INHALE THAT,

9746
06:08:45,607 --> 06:08:48,743
IT GOES MORE INTO THE LUNGS.

9747
06:08:48,743 --> 06:08:51,713
I THINK THAT MAY BE BETTER WAY

9748
06:08:51,713 --> 06:08:53,415
OF GETTING MUCOSAL IMMUNITY, IN

9749
06:08:53,415 --> 06:08:54,349
THE NOSE WE DON'T ACTUALLY

9750
06:08:54,349 --> 06:08:56,851
INDUCE IT IN THE SAME WAY.

9751
06:08:56,851 --> 06:08:59,487
THIS IS WHAT I TRIED TO SAY

9752
06:08:59,487 --> 06:09:02,157
DURING MY PRESENTATION, MODELING

9753
06:09:02,157 --> 06:09:03,625
IN ANIMALS IS INCREDIBLY

9754
06:09:03,625 --> 06:09:04,125
IMPORTANT TO UNDERSTAND

9755
06:09:04,125 --> 06:09:06,328
MECHANISMS LIKE HOW DO WE INDUCE

9756
06:09:06,328 --> 06:09:07,929
IMMUNITY BUT THEN I THINK WE

9757
06:09:07,929 --> 06:09:09,965
NEED TO TAKE IT TO HUMANS AND

9758
06:09:09,965 --> 06:09:12,367
SEE WHAT WE SEE IN ANIMALS IS

9759
06:09:12,367 --> 06:09:13,134
THAT ACTUALLY HAPPENING IN

9760
06:09:13,134 --> 06:09:22,777
HUMANS AS WELL. 

9761
06:09:22,777 --> 06:09:24,713
>> OTHER QUESTIONS?

9762
06:09:24,713 --> 06:09:27,916
>> YEAH, I HAVE ANOTHER
FROM THE

9763
06:09:27,916 --> 06:09:28,083
Q&A.

9764
06:09:28,083 --> 06:09:34,356
BRIAN SAYS AGREE WITH THE PANEL,

9765
06:09:34,356 --> 06:09:35,991
UPPER RESPIRATORY TRACT, MUCOSAL

9766
06:09:35,991 --> 06:09:38,393
IMMUNITY IS MEMORY.

9767
06:09:38,393 --> 06:09:42,330
WOULD THE GOAL BE PROPHYLACTIC

9768
06:09:42,330 --> 06:09:44,766
ATTACKS AT SEASONAL COMMISSION,

9769
06:09:44,766 --> 06:09:46,101
EPIKINETICS OF SEASONAL DISEASE

9770
06:09:46,101 --> 06:09:48,703
AND POPULATION?

9771
06:09:48,703 --> 06:09:53,108
 

9772
06:09:53,108 --> 06:09:54,709
IT'S EASIER WHEN SOMEONE COMES

9773
06:09:54,709 --> 06:09:59,114
OFF MUTE AND ASKS. 

9774
06:09:59,114 --> 06:10:02,317
>> DO YOU WANT THE
QUESTION

9775
06:10:02,317 --> 06:10:02,884
REPEATED?

9776
06:10:02,884 --> 06:10:05,587
COULD YOU REPEAT IT?

9777
06:10:05,587 --> 06:10:10,659
 

9778
06:10:10,659 --> 06:10:14,062
>> BRIAN?

9779
06:10:14,062 --> 06:10:17,465
 

9780
06:10:17,465 --> 06:10:21,169
WE CAN GO ON TO STEPHANIE.

9781
06:10:21,169 --> 06:10:23,138
>> YES, THANK YOU.

9782
06:10:23,138 --> 06:10:24,339
THIS IS FOLLOW-UP.

9783
06:10:24,339 --> 06:10:27,876
FOLLOWING UP WITH WHAT DAVID WAS

9784
06:10:27,876 --> 06:10:31,212
SAYING CURIOUS ABOUT DIFFERENCES

9785
06:10:31,212 --> 06:10:33,748
IN OUR SERONEGATIVE ANIMAL

9786
06:10:33,748 --> 06:10:36,384
MODELS TO HUMAN, EVEN THOUGH

9787
06:10:36,384 --> 06:10:38,253
SCREENED SERONEGATIVE FOR

9788
06:10:38,253 --> 06:10:39,354
SARS-COV-2 MAYBE OTHER

9789
06:10:39,354 --> 06:10:40,989
CORONAVIRUSES, THEY COULD BE

9790
06:10:40,989 --> 06:10:43,591
ASYMPTOMATICALLY INFECTED WITH

9791
06:10:43,591 --> 06:10:45,126
OTHER RESPIRATORY VIRUSES, COULD

9792
06:10:45,126 --> 06:10:46,027
BE SMOKERS, COULD HAVE

9793
06:10:46,027 --> 06:10:49,497
POLLUTANTS IN THE HOME SHOWN TO

9794
06:10:49,497 --> 06:10:51,499
REDUCE IgA RESPONSES, CURIOUS

9795
06:10:51,499 --> 06:10:54,002
YOUR THOUGHTS ABOUT TRANSLATING

9796
06:10:54,002 --> 06:10:57,272
TO HUMANS WHICH FOR MUCOSAL

9797
06:10:57,272 --> 06:11:05,814
IMMUNITY MAY BE MORE

9798
06:11:05,814 --> 06:11:07,015
COMPLICATED.

9799
06:11:07,015 --> 06:11:08,383
>> THERE ARE SO MANY
VARIABLES

9800
06:11:08,383 --> 06:11:10,585
WE NEED TO THINK ABOUT.

9801
06:11:10,585 --> 06:11:11,953
I HONESTLY THING THE MOUSE MODEL

9802
06:11:11,953 --> 06:11:14,489
WOULD BE WHERE I WOULD LIKE TO

9803
06:11:14,489 --> 06:11:21,529
GO FIRST BECAUSE I THINK ABOUT

9804
06:11:21,529 --> 06:11:23,732
ACCESSING SO MANY OTHER THINGS.

9805
06:11:23,732 --> 06:11:24,899
>> FOR SURE.

9806
06:11:24,899 --> 06:11:31,139
>> I THINK IT'S SO
DIFFICULT  TO

9807
06:11:31,139 --> 06:11:32,140
MODEL ALL THEY THINGS, AT WHAT

9808
06:11:32,140 --> 06:11:33,575
POINT ARE YOU ASKING TOO MUCH

9809
06:11:33,575 --> 06:11:35,443
FOR ONE STUDY?

9810
06:11:35,443 --> 06:11:37,746
>> YEAH, FOR SURE.

9811
06:11:37,746 --> 06:11:44,319
>> MY APOLOGIES FOR
MISSING IT

9812
06:11:44,319 --> 06:11:46,921
BUT HAS ANYONE DONE THE DIRTY

9813
06:11:46,921 --> 06:11:54,062
EXPERIMENT FOR FERRETS? 

9814
06:11:54,062 --> 06:11:56,898
MAKING FERRETS DIRTY?

9815
06:11:56,898 --> 06:11:58,733
>> YOU DON'T THINK THEY
ARE

9816
06:11:58,733 --> 06:12:00,168
SPECIFIC PATHOGEN FREE?

9817
06:12:00,168 --> 06:12:03,138
THEY ARE NOT OUTBRED DIRTY BUT

9818
06:12:03,138 --> 06:12:07,842
WILD DIRTY.

9819
06:12:07,842 --> 06:12:09,511
>> THE FACILITIES ARE
FAIRLY

9820
06:12:09,511 --> 06:12:10,445
CLEAN.

9821
06:12:10,445 --> 06:12:13,548
THEY TRY KEEP FLU-FREE COLONIES

9822
06:12:13,548 --> 06:12:18,119
BECAUSE FLU RESEARCHERS ARE THE

9823
06:12:18,119 --> 06:12:18,953
HIGHEST CONSUMERS I THINK, IF

9824
06:12:18,953 --> 06:12:21,956
YOU WOULD AGREE WITH ME, STACY,

9825
06:12:21,956 --> 06:12:23,591
HERE, OF THE FERRETS.

9826
06:12:23,591 --> 06:12:26,194
WITH THAT, THEY DEFINITELY HAVE

9827
06:12:26,194 --> 06:12:30,231
A LOT OF PATHOGENS.

9828
06:12:30,231 --> 06:12:32,767
ENTERIC VIRUSES, CORONAVIRUSES

9829
06:12:32,767 --> 06:12:36,838
THAT ARE ENTERIC, SOME HAVE

9830
06:12:36,838 --> 06:12:38,339
DIARRHEA SOMETIMES, THEY

9831
06:12:38,339 --> 06:12:40,308
DEFINITELY HAVE LOTS OF OTHER --

9832
06:12:40,308 --> 06:12:46,915
YEAH, WE HAVEN'T DONE THE SAME

9833
06:12:46,915 --> 06:12:47,882
SORT OF VIRUM SEQUENCES, I DON'T

9834
06:12:47,882 --> 06:12:50,552
KNOW IF THEY ARE KEPT CLEAN.

9835
06:12:50,552 --> 06:12:52,787
>> I THINK CLEANER THAN A
PET

9836
06:12:52,787 --> 06:12:57,091
STORE FERRET FOR SURE.

9837
06:12:57,091 --> 06:12:58,827
THE SAME BLEEDER, TRIPLE F AS

9838
06:12:58,827 --> 06:13:02,130
WELL BUT GETTING INTO A BL 2

9839
06:13:02,130 --> 06:13:06,701
FACILITY WHERE WE GOWN UP AND GO

9840
06:13:06,701 --> 06:13:08,036
IN IS DIFFERENT THAN A PET STORE

9841
06:13:08,036 --> 06:13:09,704
WITH A HIGH SCHOOL KID CLEANING

9842
06:13:09,704 --> 06:13:11,639
THE BIRD CAGES, HAVING POP ON

9843
06:13:11,639 --> 06:13:13,575
THEIR HANDS, CLEANING THE FERRET

9844
06:13:13,575 --> 06:13:14,175
CAGES.

9845
06:13:14,175 --> 06:13:17,212
I THINK THEY ARE CLEANER THAN

9846
06:13:17,212 --> 06:13:20,849
YOU THINK THEY ARE BUT THEY ARE

9847
06:13:20,849 --> 06:13:22,217
DEFINITELY NOT CLEAN-CLEAN.

9848
06:13:22,217 --> 06:13:25,820
OURS COME IN, THEY ARE PRETTY

9849
06:13:25,820 --> 06:13:26,721
CLEAN.

9850
06:13:26,721 --> 06:13:28,156
WE'VE DONE VIRUM INFORMANT.

9851
06:13:28,156 --> 06:13:29,791
SOMEBODY RON USED TO TALK ABOUT

9852
06:13:29,791 --> 06:13:33,728
ALL THE TIME, YOU HAVE TO BE

9853
06:13:33,728 --> 06:13:38,132
CAREFUL, FERRETS DON'T HAVE

9854
06:13:38,132 --> 06:13:38,900
CORONAVIRUSES, BECAUSE IT CAN

9855
06:13:38,900 --> 06:13:43,137
INFLUENCE WHAT WE DO WITH THE

9856
06:13:43,137 --> 06:13:45,006
FLU BUT WE'VE SEEN WORMS

9857
06:13:45,006 --> 06:13:46,307
OCCASIONALLY, THINGS TO GET

9858
06:13:46,307 --> 06:13:49,344
TREATED WITH ANTIBIOTICS BUT

9859
06:13:49,344 --> 06:13:49,944
NOTHING DRAMATIC.

9860
06:13:49,944 --> 06:13:51,579
>> WE'VE LOOKED AT LIKE --
WE'VE

9861
06:13:51,579 --> 06:13:59,988
HAD  ENTERIC CORONAVIRUSES, IN

9862
06:13:59,988 --> 06:14:03,591
THE FERRETS, THEY HAVE COMMON

9863
06:14:03,591 --> 06:14:04,092
COLD CAUSING CORONAVIRUS

9864
06:14:04,092 --> 06:14:04,392
ANTIBODIES.

9865
06:14:04,392 --> 06:14:05,460
I DON'T KNOW.

9866
06:14:05,460 --> 06:14:09,831
WE HAVEN'T DONE A DEEPER DIVE ON

9867
06:14:09,831 --> 06:14:12,233
ALL THE ANIMALS, YEAH, I'D SAY

9868
06:14:12,233 --> 06:14:13,101
SEMI DIRTY.

9869
06:14:13,101 --> 06:14:17,739
CAN I SAY SEMI DIRTY?

9870
06:14:17,739 --> 06:14:20,141
>> WITH BANK THE SERUM --

9871
06:14:20,141 --> 06:14:21,676
>> WE'VE TALKED ABOUT
THIS.

9872
06:14:21,676 --> 06:14:22,677
>> IT WOULD BE AMAZING,
REALLY

9873
06:14:22,677 --> 06:14:23,278
COOL.

9874
06:14:23,278 --> 06:14:25,313
WE SHOULD DO IT.

9875
06:14:25,313 --> 06:14:28,016
WE SHOULD COLLABORATE, ALL YOU

9876
06:14:28,016 --> 06:14:29,117
FERRET PEOPLE.

9877
06:14:29,117 --> 06:14:31,786
>> YOU COULD DO THIS STUDY
THAT

9878
06:14:31,786 --> 06:14:39,394
PET STORE FERRETS, COMPARE IT. 

9879
06:14:39,394 --> 06:14:41,896
>> MICHELLE'S POINT THERE
ARE

9880
06:14:41,896 --> 06:14:43,698
IMMUNE EXPERIENCED, NOT BRED TO

9881
06:14:43,698 --> 06:14:46,100
BE PATHOGEN FREE ALTHOUGH

9882
06:14:46,100 --> 06:14:50,004
HAMSTERS ARE, IS THAT RIGHT?

9883
06:14:50,004 --> 06:14:50,505
HAMSTERS ARE SPF?

9884
06:14:50,505 --> 06:14:53,174
>> THEY ARE SUPPOSED TO
BE.

9885
06:14:53,174 --> 06:14:55,944
I DON'T KNOW IF ANYBODY HAS TO

9886
06:14:55,944 --> 06:14:56,911
TRIPLE F.

9887
06:14:56,911 --> 06:14:58,212
THEY ARE NEVER COMPLETELY CLEAN,

9888
06:14:58,212 --> 06:15:00,815
I'LL LEAVE IT AT THAT.

9889
06:15:00,815 --> 06:15:03,217
>> IF YOU CONSIDER FERRET
VERSUS

9890
06:15:03,217 --> 06:15:06,120
HAMSTERS, THE CARETAKERS ARE WAY

9891
06:15:06,120 --> 06:15:08,723
MORE INTERACTING WITH THE

9892
06:15:08,723 --> 06:15:12,327
FERRETS, VERY CLOSED, IT'S LIKE

9893
06:15:12,327 --> 06:15:13,728
PETS.

9894
06:15:13,728 --> 06:15:16,664
HAMSTERS YOU CAN STILL HOLD, THE

9895
06:15:16,664 --> 06:15:17,899
FERRETS THE INTERACTION IS MORE

9896
06:15:17,899 --> 06:15:18,132
INTENSE.

9897
06:15:18,132 --> 06:15:21,869
THE CHANCE THEY ARE GOING TO GET

9898
06:15:21,869 --> 06:15:24,205
MICROBIOMES FROM THE CARETAKERS

9899
06:15:24,205 --> 06:15:29,644
IS BIGGER.

9900
06:15:29,644 --> 06:15:31,746
>> SPF ANIMALS AREN'T
COMPLETELY

9901
06:15:31,746 --> 06:15:32,780
FREE OF ANY INFECTION, HOW MUCH

9902
06:15:32,780 --> 06:15:37,952
DO THEY NEED TO BE EXPOSED, TO

9903
06:15:37,952 --> 06:15:38,987
BE LIKE DIRTY MICE?

9904
06:15:38,987 --> 06:15:40,588
>> IT'S A GREAT QUESTION.

9905
06:15:40,588 --> 06:15:43,324
PROBABLY NOT A LOT, TO BE

9906
06:15:43,324 --> 06:15:43,558
HONEST.

9907
06:15:43,558 --> 06:15:45,493
THE PET STORE CO-HOUSING IS NOT

9908
06:15:45,493 --> 06:15:46,160
NECESSARY BUT THERE'S OTHER

9909
06:15:46,160 --> 06:15:47,428
THINGS THAT CAN BE LEARNED.

9910
06:15:47,428 --> 06:15:48,963
THERE'S A LOT OF WAYS TO ATTACK

9911
06:15:48,963 --> 06:15:50,365
THE SAME QUESTION.

9912
06:15:50,365 --> 06:15:51,566
SOME IMMUNE EXPERIENCE IS BETTER

9913
06:15:51,566 --> 06:15:52,333
THAN NONE.

9914
06:15:52,333 --> 06:15:54,936
BASED ON WHAT SEEMA IS SAYING,

9915
06:15:54,936 --> 06:15:56,504
SUFFICIENT AMOUNT OF IMMUNE

9916
06:15:56,504 --> 06:15:58,072
EXPERIENCE IN FERRETS TO AT

9917
06:15:58,072 --> 06:16:03,044
LEAST MAKE THEM MORE HUMAN-LIKE.

9918
06:16:03,044 --> 06:16:04,479
>> ASTRO-1, YOU DO FIND IT
IN

9919
06:16:04,479 --> 06:16:05,780
SOME OF YOUR MICE.

9920
06:16:05,780 --> 06:16:10,184
BUT YOU DON'T KNOW YET --

9921
06:16:10,184 --> 06:16:17,592
>> I DON'T WANT TO SPEAK,
BUT I

9922
06:16:17,592 --> 06:16:19,427
AGREE ASTRO-1 MAY BE COMMENSAL,

9923
06:16:19,427 --> 06:16:23,297
MAYBE NOT DOING THE SAME THINGS

9924
06:16:23,297 --> 06:16:25,900
AN ACUTE CORONAVIRUS WOULD DO SO

9925
06:16:25,900 --> 06:16:28,002
ASTRO IS A UNIQUE SITUATION.

9926
06:16:28,002 --> 06:16:30,738
I DON'T THINK IF THAT'S GOING TO

9927
06:16:30,738 --> 06:16:35,109
END UP BEING TRUE BUT THAT'S

9928
06:16:35,109 --> 06:16:35,677
INTERESTING.

9929
06:16:35,677 --> 06:16:36,678
MAYBE THE MOUSE AND YELLOW

9930
06:16:36,678 --> 06:16:38,079
VIRUS, I DON'T KNOW.

9931
06:16:38,079 --> 06:16:39,847
MAYBE STACY HAS THOUGHTS ON

9932
06:16:39,847 --> 06:16:40,048
THAT.

9933
06:16:40,048 --> 06:16:42,350
>> BE CAREFUL WHEN THEY
GET

9934
06:16:42,350 --> 06:16:42,984
IMMUNOCOMPROMISED, IT WILL GO

9935
06:16:42,984 --> 06:16:44,886
STRAIGHT TO THE BRAINS.

9936
06:16:44,886 --> 06:16:46,487
WE'VE LOOKED FOR ASTRO IN

9937
06:16:46,487 --> 06:16:47,822
FERRETS BECAUSE WE WANTED TO

9938
06:16:47,822 --> 06:16:50,758
FIND IT SINCE WE WORK ON ASTRO

9939
06:16:50,758 --> 06:16:51,426
VIRUS, NOTHING TO DATE

9940
06:16:51,426 --> 06:16:59,500
UNFORTUNATELY. 

9941
06:16:59,500 --> 06:17:04,939
 

9942
06:17:04,939 --> 06:17:07,742
>> I WANT TO RETURN TO THE
NEED

9943
06:17:07,742 --> 06:17:09,811
FOR BETTER MOUSE ADAPTED STRAINS

9944
06:17:09,811 --> 06:17:10,578
FOR FLU.

9945
06:17:10,578 --> 06:17:13,514
HOW DO WE GO ABOUT IDENTIFYING

9946
06:17:13,514 --> 06:17:13,715
THESE?

9947
06:17:13,715 --> 06:17:19,320
IS THIS JUST LIKE A MASSIVE

9948
06:17:19,320 --> 06:17:20,354
SCREENING -- OKAY.

9949
06:17:20,354 --> 06:17:21,723
>> DO YOU WANT TO TAKE IT?

9950
06:17:21,723 --> 06:17:28,062
WHAT WE DID IN THE PAST, YOU CAN

9951
06:17:28,062 --> 06:17:30,832
DO SERIAL PASSAGING LIKE MICE,

9952
06:17:30,832 --> 06:17:32,366
IT STARTS WITH MICE START TO

9953
06:17:32,366 --> 06:17:33,701
LOSE WEIGHT.

9954
06:17:33,701 --> 06:17:35,236
YEAH, YOU MAY HAVE TO TRY THAT

9955
06:17:35,236 --> 06:17:37,405
WITH A LOT OF VIRUSES, A LOT OF

9956
06:17:37,405 --> 06:17:40,374
MONEY AND A LOT OF WORK.

9957
06:17:40,374 --> 06:17:41,142
MAYBE IF WE COORDINATE THAT

9958
06:17:41,142 --> 06:17:42,977
WOULD BE VERY GOOD.

9959
06:17:42,977 --> 06:17:46,147
>> IS THERE A
COMPUTATIONAL WAY

9960
06:17:46,147 --> 06:17:48,349
TO SORT OF STRATEGIZE ABOUT

9961
06:17:48,349 --> 06:17:48,549
THIS?

9962
06:17:48,549 --> 06:17:52,286
LIKE BEST -- I DON'T KNOW.

9963
06:17:52,286 --> 06:17:54,922
>> MULTIPLE FACTORS WITH
MOUSE

9964
06:17:54,922 --> 06:17:59,360
ADAPTIVE VIRUS, THERE'S RECEPTOR

9965
06:17:59,360 --> 06:18:00,194
BINDING, INTERFERON ANTAGONISM,

9966
06:18:00,194 --> 06:18:04,732
CAN YOU MODEL FOR SURE BUT IN

9967
06:18:04,732 --> 06:18:06,200
THE END MANY MODELS, FOR EXAMPLE

9968
06:18:06,200 --> 06:18:08,136
PLEA TICKETED HIGHER AFFINITY

9969
06:18:08,136 --> 06:18:11,773
FOR RECEPTOR BINDING BUT NOT

9970
06:18:11,773 --> 06:18:12,840
THAT'S NOT THE CRUCIAL POINT.

9971
06:18:12,840 --> 06:18:14,842
SO MANY FACTORS YOU CAN MODEL

9972
06:18:14,842 --> 06:18:20,748
BUT IN THE ENDS YOU HAVE TO TEST

9973
06:18:20,748 --> 06:18:21,883
SEVERAL VIRUSES, WHICH MEANS A

9974
06:18:21,883 --> 06:18:23,718
LOT OF ANIMALS, A LOT OF MONEY

9975
06:18:23,718 --> 06:18:29,924
BUT WORTH IT TO COORDINATE SUCH

9976
06:18:29,924 --> 06:18:30,725
AN EFFORT.

9977
06:18:30,725 --> 06:18:31,559
>> THE COMPUTATIONAL IDEA
IS

9978
06:18:31,559 --> 06:18:34,495
FUN, THE IDEA OF PUTTING IN

9979
06:18:34,495 --> 06:18:37,398
FEATURES YOU KNOW CAUSING

9980
06:18:37,398 --> 06:18:38,866
PATHOGENESIS IN MICE, FEEDING

9981
06:18:38,866 --> 06:18:41,435
SOME A.I., WHAT WOULD THE NIH

9982
06:18:41,435 --> 06:18:44,305
SAY ABOUT MAKING THOSE UNKNOWN

9983
06:18:44,305 --> 06:18:45,306
MUTATIONS WHICH MAY POTENTIALLY

9984
06:18:45,306 --> 06:18:47,475
GAIN A FUNCTION AND HOW WE GO

9985
06:18:47,475 --> 06:18:47,875
ABOUT DOING THAT.

9986
06:18:47,875 --> 06:18:51,112
I THINK THIS IS A SIGNIFICANCE

9987
06:18:51,112 --> 06:18:55,016
ISSUE, TAKING ON ANY HUMAN VIRUS

9988
06:18:55,016 --> 06:18:56,117
DIRECTLY, DOING PATHOGEN

9989
06:18:56,117 --> 06:18:58,419
EXPERIMENTS, I THINK A LOT OF US

9990
06:18:58,419 --> 06:19:02,890
ARE QUITE GUN SHY IN THE SPACE.

9991
06:19:02,890 --> 06:19:04,192
EXPERIMENTS ARE INCREDIBLY

9992
06:19:04,192 --> 06:19:05,560
IMPORTANT AND EXPERIENCES FOLK

9993
06:19:05,560 --> 06:19:07,595
ON THE STAGE DID EARLY IN THE

9994
06:19:07,595 --> 06:19:09,263
PANDEMIC WITH SARS WERE

9995
06:19:09,263 --> 06:19:11,666
ESSENTIAL TO GETTING US OUT OF

9996
06:19:11,666 --> 06:19:12,767
THE DEEPEST DARKEST PLACE.

9997
06:19:12,767 --> 06:19:14,936
AND WHAT HAPPENED IN THE NEXT

9998
06:19:14,936 --> 06:19:18,806
PANDEMIC WHEN THE RULES ARE

9999
06:19:18,806 --> 06:19:19,841
UNCLEAR, WHEN THE FUNDING SPACE

10000
06:19:19,841 --> 06:19:20,875
FOR THIS IS UNCLEAR.

10001
06:19:20,875 --> 06:19:22,944
I THINK THIS ISSUE OF HOW TO

10002
06:19:22,944 --> 06:19:25,446
MAKE BETTER MODELS FOR HUMAN

10003
06:19:25,446 --> 06:19:27,782
VIRUSES HAS BEEN SIGNIFICANTLY

10004
06:19:27,782 --> 06:19:30,184
MUDDIED IN THE CURRENT POLITICAL

10005
06:19:30,184 --> 06:19:30,451
CLIMATE.

10006
06:19:30,451 --> 06:19:31,185
>> I AGREE.

10007
06:19:31,185 --> 06:19:33,588
THAT'S GOING TO GET A LITTLE BIT

10008
06:19:33,588 --> 06:19:35,423
DICEY, I THINK.

10009
06:19:35,423 --> 06:19:37,725
THAT'S ACTUALLY ONE THING THAT

10010
06:19:37,725 --> 06:19:40,995
THE GENETICALLY OBESE ARE REALLY

10011
06:19:40,995 --> 06:19:43,497
GOOD FOR, IS PASSAGING FOR MASS

10012
06:19:43,497 --> 06:19:45,233
ADAPTATION BECAUSE TYPICALLY YOU

10013
06:19:45,233 --> 06:19:47,001
HAVE TO GO TEN OR MORE PASSAGES

10014
06:19:47,001 --> 06:19:54,008
TO GET A VIRUS MOUSE ADAPTED,

10015
06:19:54,008 --> 06:19:57,245
BACK AND FORTH, SPOSHLY GENETIC

10016
06:19:57,245 --> 06:20:00,214
SPLICE, YOU CAN DO TWO OR THREE

10017
06:20:00,214 --> 06:20:01,749
PASSAGES, BACK IN THE WILDTYPE

10018
06:20:01,749 --> 06:20:05,119
MICE IT IS  HOT.

10019
06:20:05,119 --> 06:20:08,055
>> IF YOU TAKE TEN MICE,
DO TEN

10020
06:20:08,055 --> 06:20:13,060
INDEPENDENT TRIALS, YOU GET TEN

10021
06:20:13,060 --> 06:20:14,295
DIFFERENT MOUSE ADAPTED VIRUSES.

10022
06:20:14,295 --> 06:20:16,597
WHICH HAS VIRTUE BECAUSE IT

10023
06:20:16,597 --> 06:20:17,732
GIVES -- SHOWS SHOWS POSSIBLE

10024
06:20:17,732 --> 06:20:19,367
ALTERNATIVES TO GETTING TO THE

10025
06:20:19,367 --> 06:20:25,239
SAME ENDPOINT. 

10026
06:20:25,239 --> 06:20:28,743
>> I'LL POINT OUT TOO IT'S
NOT

10027
06:20:28,743 --> 06:20:29,577
NECESSARILY JUST VIRUS STRAIN

10028
06:20:29,577 --> 06:20:34,215
SPECIFIC BUT MATCH BETWEEN VIRUS

10029
06:20:34,215 --> 06:20:36,550
AND HOST, DB AEROBICS MICE ARE

10030
06:20:36,550 --> 06:20:38,352
MORE SENSITIVE TO FLU THAT DON'T

10031
06:20:38,352 --> 06:20:43,724
MAKE A BLACK 6 OR BALD MOUSE SIX

10032
06:20:43,724 --> 06:20:54,101
THAT WILL KILL A DDA. 

10033
06:20:58,472 --> 06:20:59,240
>> OTHER QUESTIONS?

10034
06:20:59,240 --> 06:21:02,209
>> YEAH, FROM THE CHAT,
WORKING

10035
06:21:02,209 --> 06:21:07,682
WITH DIRTY MICE. 

10036
06:21:07,682 --> 06:21:11,218
I HAVE A QUESTION ABOUT DIRTY

10037
06:21:11,218 --> 06:21:12,987
MOUSE MODEL, IS THAT CONTROLLED

10038
06:21:12,987 --> 06:21:14,355
LEVEL, DO YOU SCREEN TO AVOID

10039
06:21:14,355 --> 06:21:17,658
RISK OF OUTBREAK IN THE MOUSE

10040
06:21:17,658 --> 06:21:18,759
FACILITY, HARD TO BALANCE RISK

10041
06:21:18,759 --> 06:21:20,728
FOR SAFETY AND FURTHER HOUSE FOR

10042
06:21:20,728 --> 06:21:22,697
GENERAL LABS ALTHOUGH IT'S AN

10043
06:21:22,697 --> 06:21:23,831
IMPORTANT MODEL FOR INFECTION

10044
06:21:23,831 --> 06:21:24,131
STUDY.

10045
06:21:24,131 --> 06:21:25,700
YOU MAY HAVE TOUCHED ON THIS AT

10046
06:21:25,700 --> 06:21:27,768
THE VERY END BUT MAYBE

10047
06:21:27,768 --> 06:21:29,503
CLARIFYING HOW YOU ACTUALLY DO

10048
06:21:29,503 --> 06:21:30,304
THIS WORK.

10049
06:21:30,304 --> 06:21:33,708
>> YEAH, WE DO DO THIS IN
A

10050
06:21:33,708 --> 06:21:34,709
MODIFIED BSL3 FACILITY.

10051
06:21:34,709 --> 06:21:36,644
I'VE BEEN DOING THIS NOW FOR

10052
06:21:36,644 --> 06:21:37,778
SEVEN YEARS.

10053
06:21:37,778 --> 06:21:40,181
WE SCREEN EVERY PET STORE

10054
06:21:40,181 --> 06:21:42,583
ANIMAL, EVERY CO-HOUSED ANIMAL,

10055
06:21:42,583 --> 06:21:44,652
EVERY SPF ANIMAL WE WORK WITH

10056
06:21:44,652 --> 06:21:46,487
FOR THESE EXPERIMENTS, WE'VE

10057
06:21:46,487 --> 06:21:47,922
NEVER SEEN CONTAMINATION OF SPF

10058
06:21:47,922 --> 06:21:48,255
ANIMALS.

10059
06:21:48,255 --> 06:21:51,092
I THINK THIS WORK CAN BE DONE IN

10060
06:21:51,092 --> 06:21:52,026
TERMS OF PROTECTING ANIMAL

10061
06:21:52,026 --> 06:21:55,196
FACILITIES ON CAMPUS.

10062
06:21:55,196 --> 06:21:56,364
WE HAVE IMMUNOCOMPROMISED MICE

10063
06:21:56,364 --> 06:21:57,264
IN OUR LABORATORY AND FACILITY

10064
06:21:57,264 --> 06:21:58,199
AND THEY ARE OKAY.

10065
06:21:58,199 --> 06:21:59,767
I THINK IT CAN BE DONE.

10066
06:21:59,767 --> 06:22:02,036
IT DOES REQUIRE EXTRA TIME,

10067
06:22:02,036 --> 06:22:04,271
MONEY, EFFORT, BUT PERSONALLY

10068
06:22:04,271 --> 06:22:06,073
IT'S WORTH IT BECAUSE I'M

10069
06:22:06,073 --> 06:22:06,874
WORRIED ABOUT HARMING THE ANIMAL

10070
06:22:06,874 --> 06:22:12,580
QUOLL 

10071
06:22:12,580 --> 06:22:13,447
COLONIES OF COLLEAGUES.

10072
06:22:13,447 --> 06:22:15,116
WE DON'T NEED TO SCREEN EVERY

10073
06:22:15,116 --> 06:22:18,386
TIME NOW WE KNOW PHENOTYPES ARE

10074
06:22:18,386 --> 06:22:19,920
STABLE FOR ALL THE VIRUSES BUT

10075
06:22:19,920 --> 06:22:21,655
WE DO IT ANYWAY BECAUSE WE'RE

10076
06:22:21,655 --> 06:22:23,090
INTERESTED IN UNDERSTANDING THAT

10077
06:22:23,090 --> 06:22:27,461
BIOLOGY, BUT THAT'S ANOTHER

10078
06:22:27,461 --> 06:22:30,431
COMPONENT THAT'S QUITE LABOR AND

10079
06:22:30,431 --> 06:22:39,540
COST EXPENSIVE. 

10080
06:22:39,540 --> 06:22:43,744
>> IF THERE ARE NO FURTHER

10081
06:22:43,744 --> 06:22:45,279
QUESTIONS, NO MORE FROM ZOOM

10082
06:22:45,279 --> 06:22:47,481
>> WE HAD ONE FROM MICHAEL
THAT

10083
06:22:47,481 --> 06:22:49,116
CAME AT THE END, DID NOT HAVE

10084
06:22:49,116 --> 06:22:55,122
TIME TO ANSWER BACK THEN. 

10085
06:22:55,122 --> 06:22:56,590
>> I HAVE A QUESTION.

10086
06:22:56,590 --> 06:22:58,759
OVER HERE.

10087
06:22:58,759 --> 06:23:00,828
WE'VE TALKED ABOUT DIFFERENT

10088
06:23:00,828 --> 06:23:03,264
ANIMAL MODELS, ARE THERE -- ARE

10089
06:23:03,264 --> 06:23:07,935
WE  HUNTING FOR NEW SMALL ANIMAL

10090
06:23:07,935 --> 06:23:12,106
MODELS, OTHER SPECIES, OR ARE WE

10091
06:23:12,106 --> 06:23:13,841
LOCKED INTO MICE, FERRET,

10092
06:23:13,841 --> 06:23:14,442
HAMSTERS, HUMANS?

10093
06:23:14,442 --> 06:23:15,843
ARE WE SEARCHING FOR NEW ANIMAL

10094
06:23:15,843 --> 06:23:19,914
MODELS?

10095
06:23:19,914 --> 06:23:21,348
>> I CAN QUICKLY MENTION,

10096
06:23:21,348 --> 06:23:23,217
SOMEONE IS HERE DEVELOPING

10097
06:23:23,217 --> 06:23:24,618
REALLY LESS TRADITIONAL ANIMAL

10098
06:23:24,618 --> 06:23:28,155
MODELS, MAYBE I'LL PHRASE IT.

10099
06:23:28,155 --> 06:23:30,658
>> YEAH, A LOT OF ANIMAL
MODELS,

10100
06:23:30,658 --> 06:23:33,094
TOMORROW I WILL PRESENT THEM.

10101
06:23:33,094 --> 06:23:33,828
>> WE HAVE OTHER MODELS.

10102
06:23:33,828 --> 06:23:36,030
I DON'T KNOW IF PETER IS GOING

10103
06:23:36,030 --> 06:23:38,399
TO TALK ABOUT THE ROBO HAMSTERS,

10104
06:23:38,399 --> 06:23:41,335
BUT IT'S A PERFECT EXAMPLE

10105
06:23:41,335 --> 06:23:42,870
BECAUSE IT'S A USEFUL ANIMAL

10106
06:23:42,870 --> 06:23:45,072
MODEL BUT THEY DON'T BREED VERY

10107
06:23:45,072 --> 06:23:45,272
MUCH.

10108
06:23:45,272 --> 06:23:46,841
MAKES IT A REAL CHALLENGE.

10109
06:23:46,841 --> 06:23:49,577
WE DO HAVE TO NOT ONLY HAVE A

10110
06:23:49,577 --> 06:23:51,345
SUSCEPTIBLE ANIMAL THAT GIVES

10111
06:23:51,345 --> 06:23:52,346
CERTAIN PROPERTIES, WE HAVE TO

10112
06:23:52,346 --> 06:23:54,281
MAKE SURE THEY ARE USABLE.

10113
06:23:54,281 --> 06:23:55,916
PETER'S LAB HAS BEEN ABLE TO USE

10114
06:23:55,916 --> 06:23:56,417
THEM.

10115
06:23:56,417 --> 06:23:57,618
I DON'T THINK TOO MANY LABS

10116
06:23:57,618 --> 06:24:03,023
WOULD WANT TO DO IT.

10117
06:24:03,023 --> 06:24:03,958
>> IT WILL ESPECIALLY BE

10118
06:24:03,958 --> 06:24:07,027
IMPORTANT WHEN YOU WANT TO GO TO

10119
06:24:07,027 --> 06:24:08,929
OTHER VIRUSES, BEYOND FLU AND

10120
06:24:08,929 --> 06:24:10,064
SARS-COV-2, BECAUSE NOT ALL THE

10121
06:24:10,064 --> 06:24:14,835
VIRUSES ARE AS GOOD IN MICE.

10122
06:24:14,835 --> 06:24:16,270
>> WE ACTUALLY HAVE A
BUNCH OF

10123
06:24:16,270 --> 06:24:19,240
ANIMAL MODELS THAT WE USE.

10124
06:24:19,240 --> 06:24:21,108
THIS ISN'T NECESSARILY WORK I

10125
06:24:21,108 --> 06:24:25,880
DO, THE MUNSTER LAB HAS A LOT.

10126
06:24:25,880 --> 06:24:28,315
WE WORKED WITH BATS, PRAIRIE

10127
06:24:28,315 --> 06:24:29,517
DOGS, FOR EXAMPLE, A FEW

10128
06:24:29,517 --> 06:24:30,050
INTERESTING ANIMAL MODELS.

10129
06:24:30,050 --> 06:24:31,719
I THINK THAT WORK IS REALLY

10130
06:24:31,719 --> 06:24:32,520
IMPORTANT, IT'S VERY INTERESTING

10131
06:24:32,520 --> 06:24:33,320
TO DO.

10132
06:24:33,320 --> 06:24:34,755
I THINK YOU RUN INTO THE SAME

10133
06:24:34,755 --> 06:24:37,491
PROBLEM AGAIN THAT THERE'S NOT

10134
06:24:37,491 --> 06:24:39,126
ENOUGH REAGENTS AND NOW OFTEN

10135
06:24:39,126 --> 06:24:40,794
SHIPPING IS REALLY EXPENSIVE TO

10136
06:24:40,794 --> 06:24:43,197
GET THEM TO YOUR FACILITY AND

10137
06:24:43,197 --> 06:24:47,568
THEN WITH DIFFERENT CAGES AND

10138
06:24:47,568 --> 06:24:48,235
DIFFERENT BRANCH LEADERS

10139
06:24:48,235 --> 06:24:50,171
LEARNING HOW TO DEAL WITH

10140
06:24:50,171 --> 06:24:52,706
ANIMALS, OTHER ANIMAL MODELS ARE

10141
06:24:52,706 --> 06:24:53,607
REALLY IMPORTANT, INVESTMENT YOU

10142
06:24:53,607 --> 06:24:56,110
NEED TO MAKE AS A LAB IS

10143
06:24:56,110 --> 06:24:56,911
SIGNIFICANT.

10144
06:24:56,911 --> 06:24:58,012
>> I ALSO THINK IT'S
IMPORTANT

10145
06:24:58,012 --> 06:25:00,514
TO KIND OF LOOK FOR OTHER ANIMAL

10146
06:25:00,514 --> 06:25:02,650
MODELS BECAUSE AT SOME POINT

10147
06:25:02,650 --> 06:25:03,984
WHEN NEW VIRUSES EMERGE, SO

10148
06:25:03,984 --> 06:25:05,819
THERE WILL BE SUGGESTIONS FROM

10149
06:25:05,819 --> 06:25:06,921
WHAT IS THE RESERVOIR, YOU MAY

10150
06:25:06,921 --> 06:25:10,324
WANT TO KIND OF BE READY TO HAVE

10151
06:25:10,324 --> 06:25:14,528
OTHER ANIMAL MODELS MAYBE

10152
06:25:14,528 --> 06:25:17,364
POTENTIAL RESERVOIR, ALREADY

10153
06:25:17,364 --> 06:25:18,432
BEEN GOING.

10154
06:25:18,432 --> 06:25:20,434
>> MAYBE FOR CORONAVIRUSES
AND

10155
06:25:20,434 --> 06:25:21,602
OTHER VIRUSES TOO PEOPLE ARE

10156
06:25:21,602 --> 06:25:23,237
INTERESTED IN THE BATS.

10157
06:25:23,237 --> 06:25:25,005
RECENTLY IN THE NEWS, DISCUSSION

10158
06:25:25,005 --> 06:25:32,646
OF THIS BUILDING A BAT FACILITY

10159
06:25:32,646 --> 06:25:36,116
AT COLORADO STATE, IT'S RUN

10160
06:25:36,116 --> 06:25:37,151
TOO -- NIMBY PROBLEMS OR

10161
06:25:37,151 --> 06:25:38,352
BIOSAFETY PROBLEMS, BUT IT'S

10162
06:25:38,352 --> 06:25:40,221
GOING TO BE BUILT, BUT THERE'S

10163
06:25:40,221 --> 06:25:42,189
SOME PROTESTS ABOUT IT.

10164
06:25:42,189 --> 06:25:46,727
IT'S A ALL NOT STRAIGHT FORWARD.

10165
06:25:46,727 --> 06:25:48,195
THERE'S SO MANY TYPES OF BATS.

10166
06:25:48,195 --> 06:25:50,764
A BAT IS NOT A BAT IS NOT A BAT.

10167
06:25:50,764 --> 06:25:57,204
WE HAVE A BAT COLONY, DIFFERENT

10168
06:25:57,204 --> 06:25:58,839
VIRUS, ENTIRELY DIFFERENT BATS

10169
06:25:58,839 --> 06:25:59,039
AGAIN.

10170
06:25:59,039 --> 06:26:00,975
IT GETS COMPLEX.

10171
06:26:00,975 --> 06:26:01,242
>> OKAY.

10172
06:26:01,242 --> 06:26:02,676
IF THERE'S NO MORE QUESTIONS I

10173
06:26:02,676 --> 06:26:04,378
THINK WE CAN THANK THE PANEL FOR

10174
06:26:04,378 --> 06:26:07,014
A GREAT DISCUSSION.

10175
06:26:07,014 --> 06:26:13,053
 

10176
06:26:13,053 --> 06:26:20,094
 

10177
06:26:20,094 --> 06:26:21,562
>> JUST BEFORE WE CLOSE
OUT THE

10178
06:26:21,562 --> 06:26:25,332
FIRST DAY OF OUR MEETING, I HAVE

10179
06:26:25,332 --> 06:26:27,901
COMPILED A FEW SLIDES OF THE

10180
06:26:27,901 --> 06:26:30,037
ANSWERS THAT WE'VE GOTTEN SO FAR

10181
06:26:30,037 --> 06:26:31,005
TO SOME QUESTIONS.

10182
06:26:31,005 --> 06:26:33,240
SO IF WE COULD BRING UP THAT

10183
06:26:33,240 --> 06:26:38,912
SLIDE SET THAT WOULD BE HELPFUL.

10184
06:26:38,912 --> 06:26:39,713
OKAY.

10185
06:26:39,713 --> 06:26:41,148
SO, YOU KNOW, DON'T GET EXCITED

10186
06:26:41,148 --> 06:26:42,683
IF YOUR ANSWER CAME IN LATE AND

10187
06:26:42,683 --> 06:26:43,784
IT'S NOT HERE.

10188
06:26:43,784 --> 06:26:45,953
WE'LL TALK ABOUT THIS TOMORROW,

10189
06:26:45,953 --> 06:26:46,387
RIGHT?

10190
06:26:46,387 --> 06:26:48,088
TO SORT OF CONTINUE TO THINK

10191
06:26:48,088 --> 06:26:51,558
ABOUT, YOU KNOW, SOME OF THE

10192
06:26:51,558 --> 06:26:52,726
REAGENTS NEEDED, SO ONES THAT

10193
06:26:52,726 --> 06:26:55,829
CAME IN FIRST ON THE TOP, AN

10194
06:26:55,829 --> 06:26:57,665
IMPORTANT POINT, WHICH IS THERE

10195
06:26:57,665 --> 06:27:00,534
MAYBE NEEDS TO BE A DATABASE OF

10196
06:27:00,534 --> 06:27:02,069
VALIDATED REAGENTS, FAR MORE

10197
06:27:02,069 --> 06:27:04,238
IMPORTANT THAN CREATING MORE AND

10198
06:27:04,238 --> 06:27:05,739
MORE UNVALIDATED ANTIBODIES,

10199
06:27:05,739 --> 06:27:06,540
RIGHT?

10200
06:27:06,540 --> 06:27:09,276
AND SO THIS IS SOMETHING THAT

10201
06:27:09,276 --> 06:27:10,944
WE'D LIKE TO ENTERTAIN, BUT ALSO

10202
06:27:10,944 --> 06:27:14,214
MAYBE SPEND SOME TIME DISCUSSING

10203
06:27:14,214 --> 06:27:16,850
TOMORROW BEST WAYS TO APPROACH

10204
06:27:16,850 --> 06:27:18,719
SUCH A DATABASE, RIGHT?

10205
06:27:18,719 --> 06:27:24,825
IT'S MORE THAN JUST JUST HAVING

10206
06:27:24,825 --> 06:27:27,528
A SPREADSHEET BUT GETTING

10207
06:27:27,528 --> 06:27:28,162
APPROPRIATE INPUT FROM ANYBODY

10208
06:27:28,162 --> 06:27:29,730
DOING RESEARCH IN THE AREAS.

10209
06:27:29,730 --> 06:27:32,499
THERE'S A COUPLE ADDITIONAL

10210
06:27:32,499 --> 06:27:35,002
SUGGESTIONS FOR VALIDATED HIGH

10211
06:27:35,002 --> 06:27:38,072
AFFINITY ANTIBODIES, T CELL

10212
06:27:38,072 --> 06:27:43,444
ANALYSIS, INTRACELLULAR CYTOKINE

10213
06:27:43,444 --> 06:27:45,546
STAINING, B CELLS BY FLOW ARE

10214
06:27:45,546 --> 06:27:46,847
HELPFUL, ANTIBODIES TO ASSESS

10215
06:27:46,847 --> 06:27:48,582
NUMBER AND FUNCTIONALITY OF

10216
06:27:48,582 --> 06:27:51,618
INNATE IMMUNE CELLS, SO WE'VE

10217
06:27:51,618 --> 06:27:52,986
HEARD THIS A FEW TIMES, THE

10218
06:27:52,986 --> 06:27:55,923
MEASUREMENTS OF IMMUNE CELLS

10219
06:27:55,923 --> 06:27:57,891
WILL BE REALLY IMPORTANT.

10220
06:27:57,891 --> 06:28:00,127
SO SECOND QUESTION THAT WHEE IS

10221
06:28:00,127 --> 06:28:03,130
NEED FOR USE OF CONSISTENT

10222
06:28:03,130 --> 06:28:06,133
VALIDATED CHALLENGE STRAINS OF

10223
06:28:06,133 --> 06:28:06,467
VIRUS.

10224
06:28:06,467 --> 06:28:07,835
SO SOMEBODY HAS SUGGESTED THAT

10225
06:28:07,835 --> 06:28:09,837
IT'S MORE IMPORTANT THAT VIRUS

10226
06:28:09,837 --> 06:28:11,472
STRAINS ARE DEEP SEQUENCED, THE

10227
06:28:11,472 --> 06:28:14,007
DATA IS AVAILABLE TO UNDERSTAND

10228
06:28:14,007 --> 06:28:15,676
THE EFFECTS ON PHENOTYPIC

10229
06:28:15,676 --> 06:28:17,911
OUTCOME, THERE COULD BE

10230
06:28:17,911 --> 06:28:20,981
QUASI-SPECIES WITHIN THE VIRAL

10231
06:28:20,981 --> 06:28:24,084
SAMPLES PEOPLE ARE USING.

10232
06:28:24,084 --> 06:28:31,825
PR 8 BASED  STRAINS OR MOUSE

10233
06:28:31,825 --> 06:28:33,894
ADAPTED STRAINS TO COMPARE IS

10234
06:28:33,894 --> 06:28:37,197
ONE IDEA THAT MERITS DISCUSSION.

10235
06:28:37,197 --> 06:28:38,832
EARLIER HAVING ANOTHER

10236
06:28:38,832 --> 06:28:42,436
DISCUSSION ABOUT USING REVERSE

10237
06:28:42,436 --> 06:28:43,771
GENETICS, YOU KNOW, BASED -- --

10238
06:28:43,771 --> 06:28:46,173
YOU KNOW, VIRUSES, RIGHT?

10239
06:28:46,173 --> 06:28:48,675
I THINK THAT ALSO IS A

10240
06:28:48,675 --> 06:28:52,413
MERITORIOUS IDEA THAT SHOULD BE

10241
06:28:52,413 --> 06:28:54,715
DISCUSSED AS WELL.

10242
06:28:54,715 --> 06:28:57,951
SO, THE LAST QUESTION IS A

10243
06:28:57,951 --> 06:28:59,420
LITTLE BIT MORE PHILOSOPHICAL IN

10244
06:28:59,420 --> 06:29:01,555
NATURE, WHEN WE'RE TALKING ABOUT

10245
06:29:01,555 --> 06:29:03,757
HOW TO COMPARE ANIMAL MODELS TO

10246
06:29:03,757 --> 06:29:04,958
THE HUMAN DATA THAT'S AVAILABLE

10247
06:29:04,958 --> 06:29:08,128
TO, YOU KNOW, CONTINUE TO ENSURE

10248
06:29:08,128 --> 06:29:10,898
SOME CLINICAL RELEVANCY, RIGHT?

10249
06:29:10,898 --> 06:29:11,999
INTERESTING SUGGESTION TO STUDY

10250
06:29:11,999 --> 06:29:14,067
FAILED CLINICAL TRIALS, WORK

10251
06:29:14,067 --> 06:29:15,803
BACKWARDS, TO UNDERSTAND WHY

10252
06:29:15,803 --> 06:29:17,104
ANIMAL MODELS WEREN'T

10253
06:29:17,104 --> 06:29:17,438
PREDICTIVE.

10254
06:29:17,438 --> 06:29:20,808
THAT'S A VERY BIG IDEA BUT ALSO

10255
06:29:20,808 --> 06:29:23,544
SOMETHING THAT IS A GOOD

10256
06:29:23,544 --> 06:29:23,777
THOUGHT.

10257
06:29:23,777 --> 06:29:25,612
AND OF COURSE IT DEPENDS ON THE

10258
06:29:25,612 --> 06:29:27,080
QUESTION THAT YOU'RE TRYING TO

10259
06:29:27,080 --> 06:29:28,282
ANSWER, RIGHT?

10260
06:29:28,282 --> 06:29:34,755
IF YOU'RE LOOKING AT

10261
06:29:34,755 --> 06:29:35,389
TRANSMISSIBILITY SOME MODELS ARE

10262
06:29:35,389 --> 06:29:39,460
BETTER THAN OTHERS. 

10263
06:29:39,460 --> 06:29:41,295
LOOKING AT PATHOGENESIS SOME

10264
06:29:41,295 --> 06:29:42,463
MODELS ARE BETTER THAN OTHERS.

10265
06:29:42,463 --> 06:29:43,530
WHAT I CHALLENGE YOU TO THINK

10266
06:29:43,530 --> 06:29:46,133
ABOUT IN YOUR SPECIFIC SITUATION

10267
06:29:46,133 --> 06:29:47,267
IF YOU'RE STUDYING TRANSMISSION,

10268
06:29:47,267 --> 06:29:52,906
RIGHT, YOU KNOW, HOW DO YOU SORT

10269
06:29:52,906 --> 06:29:56,243
OF ENTER THAT CLINICAL RELEVANCY

10270
06:29:56,243 --> 06:29:58,979
VERSUS STUDYING THE IMMUNE

10271
06:29:58,979 --> 06:29:59,913
RESPONSE, TRANSLATABILITY TO

10272
06:29:59,913 --> 06:30:01,048
HUMANS AS WELL.

10273
06:30:01,048 --> 06:30:05,085
WE'LL DISCUSS IN MORE DETAIL IN

10274
06:30:05,085 --> 06:30:06,119
SESSION 4 TOMORROW.

10275
06:30:06,119 --> 06:30:08,689
SO I'D LIKE TO THANK EVERYBODY

10276
06:30:08,689 --> 06:30:11,325
WHO GAVE WONDERFUL TALKS TODAY

10277
06:30:11,325 --> 06:30:14,061
AND FOR VERY ENGAGING PANEL

10278
06:30:14,061 --> 06:30:15,162
DISCUSSIONS, VERY MUCH

10279
06:30:15,162 --> 06:30:16,463
APPRECIATE EVERYBODY

10280
06:30:16,463 --> 06:30:26,463
PARTICIPATING.