1 00:02:00,971 --> 00:02:04,875 NEXTED SLIDE, PLEASE. SO THIS 2 00:02:04,875 --> 00:02:07,511 BRINGS US TO TODAY'S SEMINAR 3 00:02:07,511 --> 00:02:09,346 SPEAKER, DR. SUSAN WEISS. SUSAN 4 00:02:09,346 --> 00:02:11,615 RECEIVED HER BACHELOR'S DEGREE 5 00:02:11,615 --> 00:02:18,722 FROM ARE BRANDEIS, HER PHD WORK 6 00:02:18,722 --> 00:02:20,223 WITH MICHAEL BRIAN AT HARVARD 7 00:02:20,223 --> 00:02:25,629 AND BETWEEN 1976-1980 WAS A POST 8 00:02:25,629 --> 00:02:28,031 DOC WITH CAROL FARM AND MICHAEL 9 00:02:28,031 --> 00:02:32,769 BISHOP. IN 1980 RECEIPTED TO 10 00:02:32,769 --> 00:02:34,437 RECRUITED TO UNIVERSITY OF 11 00:02:34,437 --> 00:02:35,739 PENNSYLVANIA, WHICH SHE BECAME A 12 00:02:35,739 --> 00:02:38,175 FULLY TENURED PROFESSOR IN 1982 13 00:02:38,175 --> 00:02:46,816 IN THE SCHOOL OF MEDICINE. 2010 14 00:02:46,816 --> 00:02:47,884 AND 2019 WAS POST DOCTORATE IN 15 00:02:47,884 --> 00:02:49,152 TRAINING AND PROGRAMS IN THE 16 00:02:49,152 --> 00:02:52,055 SCHOOL OF MEDICINE AT UPENN. 17 00:02:52,055 --> 00:02:54,558 SINCE 2018, SHE SERVED AS VICE 18 00:02:54,558 --> 00:02:56,193 CHAIR OF THE DEPARTMENT OF 19 00:02:56,193 --> 00:02:58,595 MICROBIOLOGY AND SINCE 2020 20 00:02:58,595 --> 00:03:09,072 CO -DIRECTOR OF PEP 21 00:03:12,042 --> 00:03:12,842 CO -DIRECTOR OF PE -- PENN 22 00:03:12,842 --> 00:03:13,476 CENTER. IN 1994 ELECTED FELLOW 23 00:03:13,476 --> 00:03:15,879 OF AMERICAN ACADEMY OF 24 00:03:15,879 --> 00:03:17,981 MICROBIOLOGY, AND FELLOW OF AAAS 25 00:03:17,981 --> 00:03:19,149 AND LAST YEAR ELECTED MEMBER OF 26 00:03:19,149 --> 00:03:22,886 THE NATIONAL ACADEMY OF 27 00:03:22,886 --> 00:03:25,222 SCIENCES. NEXT, PLEASE. HER WORK 28 00:03:25,222 --> 00:03:30,794 FOCUSED ON PATHOGENGENESIS OF 29 00:03:30,794 --> 00:03:32,996 CORONAVIRUS AND ZIKA AND RNA 30 00:03:32,996 --> 00:03:38,034 INDUCED PATHWAYS AND ENDOGENOUS 31 00:03:38,034 --> 00:03:41,471 PATHOGENISIS. HER TALK IS 32 00:03:41,471 --> 00:03:43,873 ENTITLED CORONAVIRUS ACTIVATION, 33 00:03:43,873 --> 00:03:47,811 ANTAGONIST FROM MHV TO SARS-COV 34 00:03:47,811 --> 00:03:49,412 2. IF YOU CLICK ONE MORE WE WILL 35 00:03:49,412 --> 00:03:52,916 SEE THE CME CODE, 50127. SO WITH 36 00:03:52,916 --> 00:03:55,952 THAT LET'S PLEASE WELCOME SUSAN 37 00:03:55,952 --> 00:04:01,091 WEISS FOR THE 2024 KHOURY 38 00:04:01,091 --> 00:04:01,491 LECTURE. 39 00:04:01,491 --> 00:04:01,925 [ APPLAUSE ] 40 00:04:01,925 --> 00:04:03,026 >> SUSAN WEISS: THANK YOU, ERIC. 41 00:04:03,026 --> 00:04:04,828 I'M REALLY HONORED TO BE INVITED 42 00:04:04,828 --> 00:04:07,464 FOR THIS LECTURE. I DIDN'T 43 00:04:07,464 --> 00:04:08,298 PERSONALLY KNOW GEORGE R. BROWN 44 00:04:08,298 --> 00:04:18,642 BUT REMEMBER HIM. I HA-- NOT KNN 45 00:04:18,642 --> 00:04:19,943 GEORGE KHOURY BUT REMEMBER HIS 46 00:04:19,943 --> 00:04:21,478 WORK OVER THE YEARS. OKAY. THERE 47 00:04:21,478 --> 00:04:24,414 IS MY TITLE AGAIN. I BRIEF 48 00:04:24,414 --> 00:04:26,383 OVERVIEW OF MY TALK -- IS THIS 49 00:04:26,383 --> 00:04:28,551 OKAY? THE SOUND OKAY? I WILL 50 00:04:28,551 --> 00:04:31,588 GIVE A BRIEF INTRODUCTION TO 51 00:04:31,588 --> 00:04:33,256 CORONAVIRUS AND INTERFERON 52 00:04:33,256 --> 00:04:36,026 SIGNALLING PATHWAYS AND TALK 53 00:04:36,026 --> 00:04:39,162 ABOUT ROLL OF 2 PRIME 54 00:04:39,162 --> 00:04:40,730 PHOSPHODIESTERASE, OR PDE IN RNA 55 00:04:40,730 --> 00:04:42,832 CELL ANTAGONISTISM AND ENDURING 56 00:04:42,832 --> 00:04:46,870 CORONAVIRUS PATHOGENISIS, THE 57 00:04:46,870 --> 00:04:48,605 MODEL CORONAVIRUS MHV THEN TALK 58 00:04:48,605 --> 00:04:56,012 ABOUT VRS AND SARS ENCODED 59 00:04:56,012 --> 00:04:57,347 MULTI 60 00:04:57,347 --> 00:04:59,082 MULTIPLE ENABLED AND PROBABLY 61 00:04:59,082 --> 00:05:01,651 THE SECOND HALF IS INFECTION OF 62 00:05:01,651 --> 00:05:03,586 PRIMARY NASAL EPITHELIAL 63 00:05:03,586 --> 00:05:07,324 CULTURALS WE USE AS MODEL FOR 64 00:05:07,324 --> 00:05:10,293 THE EPITHELIAL WITH LETHAL AND 65 00:05:10,293 --> 00:05:11,795 INFECTIOUS CORONAVIRUS AND FOCUS 66 00:05:11,795 --> 00:05:13,530 ON ROLE OF SIGNALLING RESPONSES 67 00:05:13,530 --> 00:05:15,365 IN THIS MODEL SYSTEM. THEN THIS 68 00:05:15,365 --> 00:05:20,403 SORT OF BOTTOM LINE IS INTER FER 69 00:05:20,403 --> 00:05:22,539 RON DIFFERENTIATES AND IS 70 00:05:22,539 --> 00:05:27,444 CRITICAL FOR CONTROL OF HUMAN 71 00:05:27,444 --> 00:05:31,548 CORONAVIRUS VIRAL IN NASAL 72 00:05:31,548 --> 00:05:33,483 EPITHELIAL AREA. EVERYONE HAS 73 00:05:33,483 --> 00:05:35,585 SEEN THIS PICTURE. CORONAVIRUSES 74 00:05:35,585 --> 00:05:40,223 ARE A FAMILIAR WITHIN THE NIDAL 75 00:05:40,223 --> 00:05:42,592 VIRUS NAMED FOR MESSENGER RNAS 76 00:05:42,592 --> 00:05:44,728 GENERATING DURING INFECTION 77 00:05:44,728 --> 00:05:46,629 MEANING NESTED. THE PARTICLE HAS 78 00:05:46,629 --> 00:05:48,498 GOTTEN FAMOUS AS WELL. THE 79 00:05:48,498 --> 00:05:52,502 GENOME IS A VERY LONG 31-KILO 80 00:05:52,502 --> 00:05:57,607 B ASE, PROBABLY THE LARGEST 81 00:05:57,607 --> 00:05:59,676 RNA-VIRUS GENOME AND COMPLEX 82 00:05:59,676 --> 00:06:08,618 WITHIN PLATFORM TO FORM A 83 00:06:08,618 --> 00:06:10,920 HELICAL CAPSID, SURROUNDED BY A 84 00:06:10,920 --> 00:06:12,789 MEMBRANE DERIVED FROM HOST CELL, 85 00:06:12,789 --> 00:06:14,758 IN THE BLUE. IN THAT MEMBRANE 86 00:06:14,758 --> 00:06:18,161 THERE ARE THREE PROTEINS , THE 87 00:06:18,161 --> 00:06:19,295 SPIKE PROTEIN THAT HAS GOTTEN A 88 00:06:19,295 --> 00:06:21,598 LOT OF PUBLICITY. THIS IS THE 89 00:06:21,598 --> 00:06:26,202 PREE TEEN THAT MEDIATES -- 90 00:06:26,202 --> 00:06:28,471 PROTEIN THAT IMMEDIATES 91 00:06:28,471 --> 00:06:33,309 ATTACHMENT AND CELL-TO-CELL 92 00:06:33,309 --> 00:06:35,779 FUSION AND WITH SPREAD AND 93 00:06:35,779 --> 00:06:41,050 CONTAINS MAJOR EPITOPES FOR THE 94 00:06:41,050 --> 00:06:41,584 IMMUNE RESPONSE. 95 00:06:41,584 --> 00:06:47,624 THERE ARE TWO OTHER, THE M 96 00:06:47,624 --> 00:06:48,925 PROTEIN, MEMBRANE AND THEY ARE 97 00:06:48,925 --> 00:06:50,693 IMPORTANT FOR STRUCTURE OF THE 98 00:06:50,693 --> 00:06:54,197 VIRION AND OTHER STEPS DURING 99 00:06:54,197 --> 00:06:57,700 VIRAL REPLICATION. SOME 100 00:06:57,700 --> 00:07:00,603 CORONAVIRUSES ALSO IN HEMOGLUTEN 101 00:07:00,603 --> 00:07:06,576 AND ESTERASE. NOT FOR THIS BUT 102 00:07:06,576 --> 00:07:11,414 THIS IS NONESSENTIAL HOMOLOGUS 103 00:07:11,414 --> 00:07:12,916 TO THE ESSENTIAL PROTEIN. I WILL 104 00:07:12,916 --> 00:07:23,259 DO A BRIEF HISTORY OF 105 00:07:23,259 --> 00:07:24,594 CORONAVIRUSES. OKAY. CAN SEE. 106 00:07:24,594 --> 00:07:26,696 YEAH, CAN SEE THIS. OKAY. SO 107 00:07:26,696 --> 00:07:29,232 CORONAVIRUSES FIRST APPEAR IN 108 00:07:29,232 --> 00:07:31,100 LITERATURE IN THE 60S. AT THAT 109 00:07:31,100 --> 00:07:32,335 POINT THE ONLY HUMAN VIRUSES WE 110 00:07:32,335 --> 00:07:35,772 KNOW ABOUT WERE THE 43 AND 2290. 111 00:07:35,772 --> 00:07:37,674 THEY BOTH CAUSE THE COMMON COLD 112 00:07:37,674 --> 00:07:40,210 BUT VERY MANY ANIMAL 113 00:07:40,210 --> 00:07:41,444 CORONAVIRUSES KNOWN AT THAT 114 00:07:41,444 --> 00:07:45,448 TIME. INFECTIOUS BRONCHI SIS, 115 00:07:45,448 --> 00:07:47,684 BOVINE, GASTRO INTER IE TIS AND 116 00:07:47,684 --> 00:07:49,018 THESE WERE IMPORTANT FOR 117 00:07:49,018 --> 00:07:52,021 ANIMALS. FROM THE LATE 60s UNTIL 118 00:07:52,021 --> 00:07:54,491 THE FIRST SARS EPIDEMIC IN 2 # 119 00:07:54,491 --> 00:07:57,126 02 THERE IS A LOT OF BASIC 120 00:07:57,126 --> 00:07:59,028 BIOLOGY. NOBODY KNOWS A LOT BUT 121 00:07:59,028 --> 00:08:05,835 THERE WAS A SMALL GROUP OF CELLS 122 00:08:05,835 --> 00:08:08,505 AND HOW THEY COME OUT AND THE 123 00:08:08,505 --> 00:08:09,973 IMMUNE RESPONSE. THE CYCLES 124 00:08:09,973 --> 00:08:12,208 IDENTIFIED PROBABLY IN EARLY 80s 125 00:08:12,208 --> 00:08:18,114 IN THE SPIKE PROTEIN. SO WHEN 126 00:08:18,114 --> 00:08:24,220 SARS -- THE FIRST SARS -- THIS 127 00:08:24,220 --> 00:08:26,890 IS A LIST OF VIRUSES WE ARE 128 00:08:26,890 --> 00:08:28,591 WORKING ON. BASIC BIOLOGY WAS 129 00:08:28,591 --> 00:08:33,062 DONE ON ANIMAL VIRUS, LITTLE ON 130 00:08:33,062 --> 00:08:35,665 HUMAN. SO WHEN SARS, THE FIRST, 131 00:08:35,665 --> 00:08:37,267 EMERGED IN CHINA IN 2002 132 00:08:37,267 --> 00:08:38,601 EVERYBODY WAS SHOCKED. OUR FIELD 133 00:08:38,601 --> 00:08:40,537 WAS TOTALLY SURPRISED THIS COULD 134 00:08:40,537 --> 00:08:42,739 HAPPEN THAT, A HUMAN CORONA 135 00:08:42,739 --> 00:08:44,774 COULD CAUSE DISEASE LIKE THIS. 136 00:08:44,774 --> 00:08:46,576 IT SOON BECAME APPARENT -- I 137 00:08:46,576 --> 00:08:49,546 SHOULD MENTION THE FIRST 138 00:08:49,546 --> 00:08:50,813 INTERNATIONAL MEETING WAS HELD 139 00:08:50,813 --> 00:08:54,050 IN GERMANY IN 1980, ABOUT 60 AT 140 00:08:54,050 --> 00:08:55,051 THE MEETING, THE ENTIRE FIELD AT 141 00:08:55,051 --> 00:08:58,154 THE TIME. AFTER THE FIRST SARS 142 00:08:58,154 --> 00:08:59,322 EPIDEMIC HUNDREDS OF PEOPLE 143 00:08:59,322 --> 00:09:01,257 STARTED WORKING ON THESE 144 00:09:01,257 --> 00:09:02,792 VIRUSES. WE LEARNED SOON AFTER 145 00:09:02,792 --> 00:09:04,894 THAT THAT THEY HAD THEIR ORIGIN 146 00:09:04,894 --> 00:09:07,864 IN BATS AND HAD TRANSMITTED TO 147 00:09:07,864 --> 00:09:10,033 HUMANS THROUGH AN INTERMEDIATE 148 00:09:10,033 --> 00:09:11,868 SPECIES. THE OTHER THING THAT 149 00:09:11,868 --> 00:09:12,936 HAPPENED RIGHT AFTER THAT 150 00:09:12,936 --> 00:09:14,203 EPIDEMIC WAS THAT PEOPLE REALLY 151 00:09:14,203 --> 00:09:16,306 LOOK FOR MORE HUMAN CORONA 152 00:09:16,306 --> 00:09:23,279 VIRUSES. THESE TWO IDENTIFIED 153 00:09:23,279 --> 00:09:25,281 HKU1A, AND 163 AND TO CATEGORIZE 154 00:09:25,281 --> 00:09:27,283 HUMAN CORONA THOUGH THE 1 WAS 155 00:09:27,283 --> 00:09:29,652 ISOLATED WITH OLDER PERSON WITH 156 00:09:29,652 --> 00:09:33,856 PNEUMONIA AND 63 CAN CAUSE KROOP 157 00:09:33,856 --> 00:09:40,296 AND BRONCHI IE TIS. THINGS WERE 158 00:09:40,296 --> 00:09:42,732 QUIET UNTIL 2012 WHEN MERS 159 00:09:42,732 --> 00:09:44,567 RESPIRATORY SYNDROME VIRUS 160 00:09:44,567 --> 00:09:46,836 EMERGED IN SAUDI, CAUSING A 161 00:09:46,836 --> 00:09:49,272 SMALLER EPIDEMIC, WHICH STILL 162 00:09:49,272 --> 00:09:51,507 GOES ON. THERE ARE STILL PEOPLE 163 00:09:51,507 --> 00:09:53,443 INFECTED BY MERS CORONAVIRUS. IT 164 00:09:53,443 --> 00:10:01,951 WAS LESS TRANCE MMISSIBLE IN 165 00:10:01,951 --> 00:10:04,220 HUMANS BUT IS IN CAMELS AND 166 00:10:04,220 --> 00:10:06,856 TRANSMITTED TO HUMANS. THOUGH 167 00:10:06,856 --> 00:10:08,925 DIFFERENT FROM SARS. CAMELS ARE 168 00:10:08,925 --> 00:10:13,162 A LARGE RESERVOIR FOR MERS SO 169 00:10:13,162 --> 00:10:15,798 THEY ARE IN MIDDLE EAST AND 170 00:10:15,798 --> 00:10:17,500 AFRICA THAT HAVE HIGH LEVELS OF 171 00:10:17,500 --> 00:10:21,638 THE POSITIVITY TO MERS 172 00:10:21,638 --> 00:10:24,507 CORONAVIRUS. THINGS AGAIN WERE 173 00:10:24,507 --> 00:10:28,645 QUIET UNTIL 2019 WHEN AS WE ALL 174 00:10:28,645 --> 00:10:30,747 KNOW SARS-COV 2 EMERGED ON A 175 00:10:30,747 --> 00:10:33,182 DIFFERENT PART OF CHINA. MOSTLY 176 00:10:33,182 --> 00:10:34,951 LIKELY HAS BAD ORIGIN. THERE 177 00:10:34,951 --> 00:10:37,620 HAVE BEEN VIRUSES IDENTIFIED 178 00:10:37,620 --> 00:10:39,489 CLOSE TO THE-COV 2 BUT WE DON'T 179 00:10:39,489 --> 00:10:41,991 KNOW THE PRECURSOR YET. WE DON'T 180 00:10:41,991 --> 00:10:43,726 KNOW IF THERE WAS AN 181 00:10:43,726 --> 00:10:46,362 INTERMEDIATE SPECIES. THERE MAY 182 00:10:46,362 --> 00:10:48,231 BE, BUT THAT HASN'T REALLY BEEN 183 00:10:48,231 --> 00:10:50,033 PROVEN YET. OF COURSE WE KNOW 184 00:10:50,033 --> 00:10:55,371 THIS IS THE AGENT OF COVID-19. 185 00:10:55,371 --> 00:10:57,573 SO COMMON CORONAVIRUSES ARE Z 186 00:10:57,573 --> 00:11:01,878 ONOTIC AND SPREAD TO HUMANS. 187 00:11:01,878 --> 00:11:03,813 OC43 IS BELIEVED TO HAVE 188 00:11:03,813 --> 00:11:05,848 ORIGINATED IN CATTLE OR PIGS AND 189 00:11:05,848 --> 00:11:08,551 TRANSMITTED TO HUMANS IN LATE 190 00:11:08,551 --> 00:11:12,789 1890s. IT IS QUITE HOMOLOGOUS TO 191 00:11:12,789 --> 00:11:14,190 BOVINE AND MOUSE HEPATITIS VIRUS 192 00:11:14,190 --> 00:11:15,858 AND THOUGHT TO BE MUCH MORE 193 00:11:15,858 --> 00:11:19,629 SEVERE INFECTION AND SORT OF 194 00:11:19,629 --> 00:11:22,532 MORPHED INTO A COMMON COLD, VOL, 195 00:11:22,532 --> 00:11:25,234 SHOULD SAY. 2-2-90 IS BELIEVED 196 00:11:25,234 --> 00:11:27,970 TO HAVE ORIGIN IN TRANSMITTED TO 197 00:11:27,970 --> 00:11:30,273 CAMELS TO HUMANS IN LATE 18TH 198 00:11:30,273 --> 00:11:33,309 CENTURY. FINALLY NL63 ALSO IS 199 00:11:33,309 --> 00:11:38,614 BELIEVED TO HAVE ORIGIN IN BATS 200 00:11:38,614 --> 00:11:41,250 SO NOT SURPRISING THESE WERE 201 00:11:41,250 --> 00:11:44,287 TRANSMITTED TO HUMANS FROM 202 00:11:44,287 --> 00:11:46,155 ANIMALS. SO HUMAN CORONAVIRUSES 203 00:11:46,155 --> 00:11:49,025 BELONG TO DIFFERENT GENERA SO 204 00:11:49,025 --> 00:11:53,229 EITHER ALPHA OR BETA VIRUSES. 205 00:11:53,229 --> 00:11:58,067 2290 AND 63 ARE ALPHA. BETAS, 206 00:11:58,067 --> 00:12:06,809 HUMAN VIRUSES FALL INTO THREE 207 00:12:06,809 --> 00:12:08,745 SUBCATEGORIES. I WILL TALK ABOUT 208 00:12:08,745 --> 00:12:11,314 THESE. THE SARBEKA INCLUDE TWO 209 00:12:11,314 --> 00:12:21,858 SARS AND RUBEKO INCLUDE MRSA AND 210 00:12:23,860 --> 00:12:26,262 BAT VIRUSES. ALL THESE HAVE 211 00:12:26,262 --> 00:12:28,297 SIMILAR GENOME STRUCTURE AND 212 00:12:28,297 --> 00:12:30,566 ORGANIZATION WITH THIS VERY LONG 213 00:12:30,566 --> 00:12:32,468 OPEN FRAME 1A AND B AT FIVE 214 00:12:32,468 --> 00:12:35,238 PRIME END OF GENOME COMPRISING 215 00:12:35,238 --> 00:12:36,439 TWO-THIRDS OF GENOME. THESE 216 00:12:36,439 --> 00:12:38,708 PROTEINS ARE TRANSLATED 217 00:12:38,708 --> 00:12:41,744 EVENTUALLY INTO 16 ON STRUCTURE 218 00:12:41,744 --> 00:12:46,816 OF PROTEINS, WHICH I'M NOT GOING 219 00:12:46,816 --> 00:12:47,984 TO TALK ABOUT. DESPITE THIS THEY 220 00:12:47,984 --> 00:12:52,955 ARE ARRAYED IN SAME ORDER. WHAT 221 00:12:52,955 --> 00:12:53,556 DIFFERENTIATES AMONG THESE 222 00:12:53,556 --> 00:12:56,058 DIFFERENT GIVE NERA AND SURES 223 00:12:56,058 --> 00:12:57,927 ARE ACCESSORY GENES THAT ENCODE 224 00:12:57,927 --> 00:13:00,963 SMALL PROTEINS WITH NUMBER BY -- 225 00:13:00,963 --> 00:13:03,699 HERE LIKE 4A, 4B, ET CETERA. 226 00:13:03,699 --> 00:13:09,138 THESE ARE PROTEINS THAT INTERACT 227 00:13:09,138 --> 00:13:11,073 WITH SORT OF ANTAGONIZE THE 228 00:13:11,073 --> 00:13:12,975 HOSTS. SOME ARE WELL 229 00:13:12,975 --> 00:13:14,243 CHARACTERIZED. I WILL TALK ABOUT 230 00:13:14,243 --> 00:13:16,479 SOME. THAT IS WHAT -- SO YOU CAN 231 00:13:16,479 --> 00:13:18,281 SEE THE ALPHA CORONAVIRUS S HAVE 232 00:13:18,281 --> 00:13:21,050 MORE SIMPLE GENOME, JUST THIS 233 00:13:21,050 --> 00:13:23,452 WAS EVENTUALLY CAN BE ONE OR TWO 234 00:13:23,452 --> 00:13:26,989 OPEN READING FRAMES. WE SEE THAT 235 00:13:26,989 --> 00:13:28,758 THE BETA CORONAVIRUSES HAVE A 236 00:13:28,758 --> 00:13:31,661 LOT MORE PARTICULARLY SARS AND 237 00:13:31,661 --> 00:13:33,663 MERS HAVE QUITE A FEW ACCESSORY 238 00:13:33,663 --> 00:13:38,134 PROTEINS.LY 239 00:13:38,134 --> 00:13:38,768 PROTEINS.LY. AND I WILL TALK 240 00:13:38,768 --> 00:13:40,236 ABOUT THEM IN A BIT. I WILL TALK 241 00:13:40,236 --> 00:13:42,338 ABOUT OLD FINDING WHAT WE 242 00:13:42,338 --> 00:13:45,474 LEARNED FROM THE EMBEKO AND 243 00:13:45,474 --> 00:13:47,877 MOUSE. MHV COMES IN MANY 244 00:13:47,877 --> 00:13:49,779 STRAINS. SOME ARE SHOIN HERE. 245 00:13:49,779 --> 00:13:52,415 INFECT VERY DIFFERENT ORGANS, 246 00:13:52,415 --> 00:13:59,355 LIVER, BRAIN, LUNG, GF GI. THE 247 00:13:59,355 --> 00:14:04,227 ANIMALS ARE GITROPHIC. SOME CAN 248 00:14:04,227 --> 00:14:08,064 BE DUAL LIKE A-59 HERE. BECAUSE 249 00:14:08,064 --> 00:14:10,766 IT WAS FOUND EARLY ON AND 250 00:14:10,766 --> 00:14:12,501 IDENTIFIED THE RECEPTOR FOR MHV 251 00:14:12,501 --> 00:14:14,871 IN EARLY 90s, IF I REMEMBER 252 00:14:14,871 --> 00:14:16,606 CORRECTLY. IT WAS FOUND ALL THE 253 00:14:16,606 --> 00:14:19,942 STRAINS WAS SAME RECEPTOR, 254 00:14:19,942 --> 00:14:21,444 CCAM1. THAT SUGGESTS RECEPTOR IS 255 00:14:21,444 --> 00:14:25,748 NOT ONLY KEY TO PATHOGENISIS OR 256 00:14:25,748 --> 00:14:29,285 TROEKISM, SO WAY BACK IN 80s AND 257 00:14:29,285 --> 00:14:33,155 90s WE CONSTRUCTED CHIMERIC 258 00:14:33,155 --> 00:14:36,926 VIRUSES EXCHANGING BETWEEN 59 259 00:14:36,926 --> 00:14:40,696 AND JHM AND SOMETIMES J52 AND WE 260 00:14:40,696 --> 00:14:45,167 FOUND POST ENTRY EVENTS WERE 261 00:14:45,167 --> 00:14:51,140 LARGELY DETERMINE T V ROPHISM. 262 00:14:51,140 --> 00:14:53,042 SO IT WASN'T ALL ABOUT 263 00:14:53,042 --> 00:14:55,244 RECEPTORS. WE WANTED TO KNOW THE 264 00:14:55,244 --> 00:14:58,681 ROLE OF INTERFERON SIGNALLING IN 265 00:14:58,681 --> 00:15:01,083 DETERMINING PATHOGENISIS SO 266 00:15:01,083 --> 00:15:02,585 INFECTED INTERFERON KNOCK-OUT 267 00:15:02,585 --> 00:15:05,087 MICE WITH SOME OF THE STRAINS. 268 00:15:05,087 --> 00:15:07,290 BASICALLY WHAT WE FOUND IS THAT 269 00:15:07,290 --> 00:15:08,791 THE MICE DIED VERY QUICKLY, 270 00:15:08,791 --> 00:15:11,027 WITHIN TWO DAYS. THAT VIRUS 271 00:15:11,027 --> 00:15:14,130 INFECTED ORGANS THAT WERE NEVER 272 00:15:14,130 --> 00:15:16,198 INFECTED IN OTHER TYPE MICE. SO 273 00:15:16,198 --> 00:15:21,137 THIS JHM THAT IS HIGHLY 274 00:15:21,137 --> 00:15:23,005 NEUROTROPHIC COULD ONLY INFECT 275 00:15:23,005 --> 00:15:25,241 KIDNEY, LIVER, HEART OR ANY 276 00:15:25,241 --> 00:15:29,712 ORGAN. SO THAT INTERFERON WAS 277 00:15:29,712 --> 00:15:33,349 IMPORTANT IN SIGNALLING ORGAN 278 00:15:33,349 --> 00:15:37,453 TROEP PISTOL M. THEY HAVE 279 00:15:37,453 --> 00:15:38,854 GENERATED CON MREKSS AND THE 280 00:15:38,854 --> 00:15:40,523 DOUBLE-STRANDED RNA IS PART OF 281 00:15:40,523 --> 00:15:42,024 THE NATURAL REPLICATION CYCLE. 282 00:15:42,024 --> 00:15:44,393 THIS IS TRUE FOR ALL RNA 283 00:15:44,393 --> 00:15:48,264 VIRUSES. SOME DNA ALSO PRODUCE 284 00:15:48,264 --> 00:15:49,298 DOUBLE-STRANDED RNA. THIS IS 285 00:15:49,298 --> 00:15:51,667 WHEN SENSED BY HOST A SIGNAL TO 286 00:15:51,667 --> 00:15:53,536 INITIATE ANTI -VIRAL SIGNALLING 287 00:15:53,536 --> 00:15:57,139 OR INNATE RESPONSES. SO 288 00:15:57,139 --> 00:16:04,413 CORONAVIRUSES PRODUCE THESE 289 00:16:04,413 --> 00:16:10,419 DOUBLE-STRANDED RNAS AND THE 290 00:16:10,419 --> 00:16:14,323 ENDOPLASTIC. THIS IS HUMAN CALU 291 00:16:14,323 --> 00:16:16,525 CELLS. DESPITE THE FACT -- IT IS 292 00:16:16,525 --> 00:16:20,196 THOUGHT THE RS REPLICATES TO 293 00:16:20,196 --> 00:16:22,898 PROTECT DOUBLE-STRANDED RNA FROM 294 00:16:22,898 --> 00:16:25,735 BEING SENSED BY HOST AS DANGER 295 00:16:25,735 --> 00:16:29,138 SIGNAL TO INITIATE ANTI VIRAL 296 00:16:29,138 --> 00:16:31,807 PATHWAYS. DESPITE THAT THESE 297 00:16:31,807 --> 00:16:33,709 VIRUSES DO INDUCE ANTI -VIRAL 298 00:16:33,709 --> 00:16:35,411 SIGNALLING. SO I WANT TO TALK 299 00:16:35,411 --> 00:16:37,446 ABOUT THE DOUBLE-STRAND RNA AND 300 00:16:37,446 --> 00:16:39,782 ANTI -VIRAL PATHWAYS I'M TALKING 301 00:16:39,782 --> 00:16:42,418 ABOUT. CORONAVIRUSES PRODUCE 302 00:16:42,418 --> 00:16:43,419 DOUBLE-STRANDED RNA SHOWN HERE 303 00:16:43,419 --> 00:16:45,921 DURING THE REPLICATION AND 304 00:16:45,921 --> 00:16:47,256 TRANSCRIPTION. IN THAT SENSE BY 305 00:16:47,256 --> 00:16:50,926 THESE DIFFERENT SENSORS SO MDA5 306 00:16:50,926 --> 00:16:52,695 SENSES DOUBLE AS CORONAVIRUS 307 00:16:52,695 --> 00:16:56,999 RNA, RIDI DOES NOT. THE MDA 308 00:16:56,999 --> 00:16:59,702 SENSING SIGNALS TO PRODUCE 309 00:16:59,702 --> 00:17:04,240 INTERFERON WHICH THEN SIGNALS 310 00:17:04,240 --> 00:17:05,908 THROUGH STAT TRANSCRIPTION 311 00:17:05,908 --> 00:17:08,744 FACTORS TO INDUCE EXPRESSION OF 312 00:17:08,744 --> 00:17:17,686 ENDOCRINE GENES AS WELL AS SITE 313 00:17:17,686 --> 00:17:22,858 PSYTOCHINES. OASs AND SYNTHESIS, 314 00:17:22,858 --> 00:17:28,064 TWO IN HUMANS AND PRODUCE 2RA 315 00:17:28,064 --> 00:17:33,102 THAT ACTIVATES RYE BOW NUKE USE 316 00:17:33,102 --> 00:17:37,807 A AND LEAD TO APOPTOSIS AND 317 00:17:37,807 --> 00:17:39,341 INFLAMMATION. THE THIRD DOUBLE 318 00:17:39,341 --> 00:17:43,379 STRANDED RNA IS SENSED BY PKR, 319 00:17:43,379 --> 00:17:47,716 THAT AUTO PHOSPHOROLATES AND 320 00:17:47,716 --> 00:17:51,654 ALPHA, TRANSLATION INITIATION 321 00:17:51,654 --> 00:17:53,689 FACTOR AND ONCE DONE THE 322 00:17:53,689 --> 00:17:57,126 INITIATION IS SHUT DOWN LEAPING 323 00:17:57,126 --> 00:18:00,362 TO A POP TOE SIS AND 324 00:18:00,362 --> 00:18:02,264 INFLAMMATION. THESE ARE THREE 325 00:18:02,264 --> 00:18:04,266 INDEPENDENT PATHWAY, OAS AND PKR 326 00:18:04,266 --> 00:18:07,503 ARE STIMULATED SO SUPER-INDUCED 327 00:18:07,503 --> 00:18:12,975 AND ALSO INDUCED ONCE INTER 328 00:18:12,975 --> 00:18:14,176 INTERFERONS ARE PRODUCED. THIS 329 00:18:14,176 --> 00:18:15,644 IS SHOWN IMPORTANT IN TERMS OF 330 00:18:15,644 --> 00:18:18,614 COVID. THE GWA STUDIES EARLY 331 00:18:18,614 --> 00:18:20,416 DURING THE PANDEMIC SUGGESTED -- 332 00:18:20,416 --> 00:18:23,919 IDENTIFIED SUSCEPTIBILITY GENES. 333 00:18:23,919 --> 00:18:26,689 AMONG WERE TYPE 1 INTERCEPTOR 334 00:18:26,689 --> 00:18:33,796 AND THE OLOGOIC SYNTHETASIS. 335 00:18:33,796 --> 00:18:36,499 VIRUSES IN RESPONSE HAVE EVOLVED 336 00:18:36,499 --> 00:18:37,133 PROTEINS OR ACCESSORY PROTEINS 337 00:18:37,133 --> 00:18:41,737 TO COMBAT THESE PATHWAYS, 338 00:18:41,737 --> 00:18:43,706 RESPONSES. SO I WANT TO TALK 339 00:18:43,706 --> 00:18:47,710 ABOUT MHV ACCESSORY PROTEIN NS2, 340 00:18:47,710 --> 00:18:50,579 WHICH ANTAGONIZES THE RNA CELL 341 00:18:50,579 --> 00:18:52,214 ACTIVATION PATHWAY. THIS WORK 342 00:18:52,214 --> 00:18:53,616 WAS ALL DONE WITH BOB 343 00:18:53,616 --> 00:18:54,917 SILVERMAN , A CLOSE COLLABORATOR 344 00:18:54,917 --> 00:18:57,419 FOR MORE THAN TEN YEARS. HE 345 00:18:57,419 --> 00:18:59,421 RECENTLY RETIRED. SO TOGETHER 346 00:18:59,421 --> 00:19:01,657 WITH BOB WE STUDIED THIS 347 00:19:01,657 --> 00:19:04,126 PROTEIN. WE FOUND A VERY 348 00:19:04,126 --> 00:19:06,328 INTERESTING ACTIVITY FOR IT, I 349 00:19:06,328 --> 00:19:13,402 THINK. IT HAS TWO PRIME 350 00:19:13,402 --> 00:19:17,306 PHOSPHODIRESTERATES. ONS IS 2A5 351 00:19:17,306 --> 00:19:19,942 WHICH ACTIVATE RNA WHICH CLEAVE 352 00:19:19,942 --> 00:19:21,810 SINGLE STRANDED RNA, VIRUS AND 353 00:19:21,810 --> 00:19:23,746 HOST, LEADING TO REDUCTION OF 354 00:19:23,746 --> 00:19:26,949 REPLICATION AND ALSO BUT 355 00:19:26,949 --> 00:19:28,617 INCREASE IN INFLAMMATION AND 356 00:19:28,617 --> 00:19:31,654 CELL DATASET. IT IS AN ENZYME 357 00:19:31,654 --> 00:19:33,222 AND CLEAVES THIS CELL AND SHUTS 358 00:19:33,222 --> 00:19:35,224 DOWN THIS PATHWAY COMPLETELY. IN 359 00:19:35,224 --> 00:19:39,228 THE CASE OF MHV THIS IS A REALLY 360 00:19:39,228 --> 00:19:43,766 IMPORTANT ANTI VIRAL -- 361 00:19:43,766 --> 00:19:45,100 ANTI -HOST ANTAGONIST ACTIVITY. 362 00:19:45,100 --> 00:19:51,240 I WILL SEW Y SHOW YOU WHY. USIN 363 00:19:51,240 --> 00:19:53,209 THE A59 STRAIN AND MUTANT THAT 364 00:19:53,209 --> 00:19:59,782 WAS UNABLE -- HAS INACTIVE NS2 365 00:19:59,782 --> 00:20:06,155 EN SOO ENZYME WE COMPARED 366 00:20:06,155 --> 00:20:07,623 MACROPHAGES AND FOUND IT 367 00:20:07,623 --> 00:20:10,059 REPLICATES 10 TO THE 7 PER MIL, 368 00:20:10,059 --> 00:20:12,061 A LOG SCALE ON THE LEFT. WHEREAS 369 00:20:12,061 --> 00:20:13,662 THE MUTANT BARELY REP CANDIDATES 370 00:20:13,662 --> 00:20:18,033 AT ALL. THIS ACTIVITY WAS 371 00:20:18,033 --> 00:20:23,172 ESSENTIAL TO REPLICATE IN MACRO 372 00:20:23,172 --> 00:20:31,113 PHAGES FOR THIS RESPONSE, FIE 373 00:20:31,113 --> 00:20:32,581 FIBROBLASTS, NO NEED. AND WHEN 374 00:20:32,581 --> 00:20:34,283 WE DO THIS COMPARISON IN 375 00:20:34,283 --> 00:20:35,584 KNOCK-OUT MICE THE MUTANT 376 00:20:35,584 --> 00:20:37,386 RECOVERS REPLICATION. SO THIS 377 00:20:37,386 --> 00:20:40,723 ACTIVITY IS REALLY ESSENTIAL FOR 378 00:20:40,723 --> 00:20:43,359 REPLICATION FOR MHV. WE CAN SEE 379 00:20:43,359 --> 00:20:46,028 HERE THIS IS A BIOANALYZER ASSAY 380 00:20:46,028 --> 00:20:48,897 OF THE RNA FROM INFECTED 381 00:20:48,897 --> 00:20:55,771 WILD-TYPE BONE MARROW DERIVED M 382 00:20:55,771 --> 00:21:00,142 MA CEO PHAGES. WE SEE A TYPE OF 383 00:21:00,142 --> 00:21:02,278 RNA WHEREAS IN MUTANT INFECTED 384 00:21:02,278 --> 00:21:04,813 THERE IS ACTIVATION OF RNA CELL, 385 00:21:04,813 --> 00:21:08,684 EVIDENCED BY THIS DEGRADED OR 386 00:21:08,684 --> 00:21:10,619 CLEAVED MICROCELL RNA. BECAUSE 387 00:21:10,619 --> 00:21:13,222 THIS IS A HOUSE VIRUS WE CAN 388 00:21:13,222 --> 00:21:15,157 TRANSLATE TO NATURAL HOSTS AND 389 00:21:15,157 --> 00:21:16,825 LOOK AT WHAT HAPPENS IN THE 390 00:21:16,825 --> 00:21:20,596 MOUSE. TAKING THE SAME WILD TYPE 391 00:21:20,596 --> 00:21:22,965 AND MUTANT VIRUSES WE INFECT A 392 00:21:22,965 --> 00:21:29,772 MOUSE. CAN INFECT IT AS 393 00:21:29,772 --> 00:21:32,641 HEPATITIS OR INTERCRANIALLY, IN 394 00:21:32,641 --> 00:21:35,411 WHICH CASE WE GET ENCEPHALITIS 395 00:21:35,411 --> 00:21:39,748 OR HEPATITIS. WE INFECT THE 396 00:21:39,748 --> 00:21:41,517 MOUSE. WE SEE DRAMATICALLY THAT 397 00:21:41,517 --> 00:21:43,385 -- WE MEASURE VIRUS IN THE 398 00:21:43,385 --> 00:21:45,521 LIVERS FIVE DAYS AFTER 399 00:21:45,521 --> 00:21:47,289 INFECTION, THE PEAK OF 400 00:21:47,289 --> 00:21:48,891 REPLICATION. WE SEE THE WILD 401 00:21:48,891 --> 00:21:57,933 TYPE VIRUS PRODUCES AGAIN 10 TO 402 00:21:57,933 --> 00:22:01,770 THE AND THE MUTANT BARELY REP 403 00:22:01,770 --> 00:22:03,305 CANDIDATES. WE DO THIS IN 404 00:22:03,305 --> 00:22:07,142 KNOCK-OUT MICE THE MUTANT 405 00:22:07,142 --> 00:22:10,913 RECOVERS. EVEN INVIVO S2 IS 406 00:22:10,913 --> 00:22:13,115 VITAL. SAME THING, WE HAVE THE 407 00:22:13,115 --> 00:22:15,150 SUSTAINING OF H & E OF LIVER 408 00:22:15,150 --> 00:22:17,753 SECTIONS FROM THESE MICE. WE CAN 409 00:22:17,753 --> 00:22:22,358 SEE THE WILD SIDE VIRUS CAUSES 410 00:22:22,358 --> 00:22:24,393 INFLAMMATION IN WILD TYPE OR 411 00:22:24,393 --> 00:22:26,795 MUTANT. LIVERS WHEREAS MUTANT 412 00:22:26,795 --> 00:22:33,902 VIRUS SHOWS NO CITOPATH IK IC IN 413 00:22:33,902 --> 00:22:35,704 WILD BUT IS IN MUTANT. ONE OF 414 00:22:35,704 --> 00:22:37,473 THE INTERESTING THINGS IS WHEN 415 00:22:37,473 --> 00:22:38,941 WE LOOK AT SAME INFECTION BUT 416 00:22:38,941 --> 00:22:41,276 LOOK AT THE BRAIN WE SEE THAT 417 00:22:41,276 --> 00:22:43,679 THERE'S EQUAL REPLICATION IN 418 00:22:43,679 --> 00:22:46,815 MUTANT OR WILD TYPE MICE WITH 419 00:22:46,815 --> 00:22:50,686 EITHER VIRUS SO NS2 AND RNA 420 00:22:50,686 --> 00:22:51,653 ACTIVATION IS IRRELEVANT IN 421 00:22:51,653 --> 00:22:52,955 BRAIN. I WILL TELL YOU IN A 422 00:22:52,955 --> 00:22:56,125 MINUTE WHY THAT IS TRUE. THIS IS 423 00:22:56,125 --> 00:23:01,263 AN ORGAN-SPECIFIC ANTAGONIST IN 424 00:23:01,263 --> 00:23:03,265 MHV. JUST TO SUMMARIZE WE WORKED 425 00:23:03,265 --> 00:23:04,900 ON THIS PATHWAY A LONG TIME. 426 00:23:04,900 --> 00:23:06,735 LOTS OF ASPECTS. I'M GOING TO 427 00:23:06,735 --> 00:23:09,104 SUMMARIZE A FEW OF THE THINGS WE 428 00:23:09,104 --> 00:23:12,541 FOUND OUT. SO MHV INFECTION OF 429 00:23:12,541 --> 00:23:16,145 MICE, ANTAGONIST OF RNA IN TURNS 430 00:23:16,145 --> 00:23:18,580 OUT IN MYELOID IS REQUIRED FOR 431 00:23:18,580 --> 00:23:19,915 PATHOGENISIS IN LIVER, NOT IN 432 00:23:19,915 --> 00:23:22,718 THE BRAIN. THE REASON WE THINK 433 00:23:22,718 --> 00:23:25,587 THAT IS THE BRAIN HAS VERY LOW 434 00:23:25,587 --> 00:23:31,360 LEVELS OF OLIGOSYNTETASIS AND 435 00:23:31,360 --> 00:23:33,228 OTHER GENES AND TURNS OUT THIS 436 00:23:33,228 --> 00:23:35,764 IS TOTALLY DEPENDENT ON OAS 437 00:23:35,764 --> 00:23:39,568 GENES. RNA CELLS ARE 438 00:23:39,568 --> 00:23:41,470 CONSTITUENTIVEL EXPRESS 439 00:23:41,470 --> 00:23:43,739 SIMILARLY AND CON STITCH TIFLY 440 00:23:43,739 --> 00:23:46,875 IN ALL TYPES BUT VARIABLE AMONG 441 00:23:46,875 --> 00:23:49,378 CELL TYPES AND LOW IN BRAIN AND 442 00:23:49,378 --> 00:23:51,146 ALSO THAT RNA CELL COULD BE 443 00:23:51,146 --> 00:23:54,550 ACTIVATED INDEPENDENTLY OF MDA5 444 00:23:54,550 --> 00:23:55,451 AND MAD SIGNALLING IN HUMAN 445 00:23:55,451 --> 00:23:57,119 MOUSE AND BAT CELLS SO IS 446 00:23:57,119 --> 00:23:59,755 INDEPENDENT PATHWAY THAT CAN BE 447 00:23:59,755 --> 00:24:01,223 ACTIVATED EVEN WHEN INTERFERON 448 00:24:01,223 --> 00:24:03,659 CAN BE SHUT DOWN BY VIRUS 449 00:24:03,659 --> 00:24:08,964 VIRUSES. THE P THE 450 00:24:08,964 --> 00:24:11,967 PHOSPHODIESTERASES ARE ENCODED 451 00:24:11,967 --> 00:24:15,103 WITH MERS AND UNRELATED ROTO 452 00:24:15,103 --> 00:24:16,772 VIRUSES AND BELIEVED IT WAS 453 00:24:16,772 --> 00:24:20,242 PICKED UP FROM THE CELL AT SOME 454 00:24:20,242 --> 00:24:25,714 POINT. THE CELLULAR ACAP7 HAS A 455 00:24:25,714 --> 00:24:27,516 PHOSPHODIESTERASE STRAIN OF 456 00:24:27,516 --> 00:24:30,085 UNKNOWN FUNCTION IN HOST. 457 00:24:30,085 --> 00:24:31,520 FINALLY RNA CELL ACTIVATION FOR 458 00:24:31,520 --> 00:24:38,827 MANY VIRUSES IS DEPEN DONATE 459 00:24:38,827 --> 00:24:43,265 SYNTHESIS 3 NOT IN 1 OR 2. FOR A 460 00:24:43,265 --> 00:24:46,335 WHILE THERE WAS PUBLICATION 461 00:24:46,335 --> 00:24:48,737 SUGGESTING THAT OAS1 WAS 462 00:24:48,737 --> 00:24:51,340 IMPORTANT RESTRICTION FOR 463 00:24:51,340 --> 00:24:56,778 SARS-COV 2 AND I THINK IT IS NOT 464 00:24:56,778 --> 00:24:58,480 CLEAR WHAT IS THE OAS THAT IS 465 00:24:58,480 --> 00:24:59,848 IMPORTANT. SOMETHING WE ARE 466 00:24:59,848 --> 00:25:00,983 INTERESTED IN WORKING ON. 467 00:25:00,983 --> 00:25:04,620 CLEARLY FOR OTHER VIRUSES OAS3 468 00:25:04,620 --> 00:25:07,589 WAS THE ONLY ISOFORM THAT REALLY 469 00:25:07,589 --> 00:25:08,757 MATTERED. SO FROM HERE I'M GOING 470 00:25:08,757 --> 00:25:12,628 TO MOVE ON TO STUDYING MERS. WE 471 00:25:12,628 --> 00:25:16,231 INITIALLY GOT INTO THE INNATE 472 00:25:16,231 --> 00:25:19,434 IMMUNITY BECAUSE THERE IS HOM 473 00:25:19,434 --> 00:25:23,138 MOLL GOUS PE. BUT LOOKED AT THE 474 00:25:23,138 --> 00:25:25,541 BROAD ABILITY TO ANTAGONIZE HOST 475 00:25:25,541 --> 00:25:27,376 RESPONSES AND MOVED TO SARS 476 00:25:27,376 --> 00:25:30,145 DURING THE PANDEMIC. I WANT TO 477 00:25:30,145 --> 00:25:31,780 TALK A LITTLE ABOUT MERS AND 478 00:25:31,780 --> 00:25:34,216 SARS ENCODED ANTAGONIST OF 479 00:25:34,216 --> 00:25:36,184 DOUBLE-STRANDED INDUCED 480 00:25:36,184 --> 00:25:37,619 PATHWAYS. HERE IS THE MERS 481 00:25:37,619 --> 00:25:39,221 GENOME. AS I MENTIONED BEFORE 482 00:25:39,221 --> 00:25:42,558 THE MERS GENOME IS MORE COMPLEX 483 00:25:42,558 --> 00:25:45,027 THAN THE -- SOME OF THE OTHER 484 00:25:45,027 --> 00:25:46,862 VIRUSES AND HAS THESE SMALL OPEN 485 00:25:46,862 --> 00:25:49,231 READING FRAMES. MERS HAS AT 486 00:25:49,231 --> 00:25:59,041 LEAST THREE ANTAGONISTS AND THIS 487 00:25:59,041 --> 00:26:01,043 IS CONSERVATIVE FOR ALL 488 00:26:01,043 --> 00:26:02,878 CORONAVIRUS VIRUSES. THIS IS 489 00:26:02,878 --> 00:26:09,117 INTERESTING. ENDONUCLEASI THAT 490 00:26:09,117 --> 00:26:10,419 CLEAVES TO PREVENT ACCUMULATION 491 00:26:10,419 --> 00:26:12,621 OF DOUBLE-STRANDND RNA SO ALMOST 492 00:26:12,621 --> 00:26:13,789 SACRIFICES ITSELF BUT IMPORTANT 493 00:26:13,789 --> 00:26:17,526 TO FRE VENT ACCUMULATING 494 00:26:17,526 --> 00:26:18,527 DOUBLE-STRANDED RNA BECAUSE IT 495 00:26:18,527 --> 00:26:23,632 WILL INDUCE HOST RESPONSES. BUT 496 00:26:23,632 --> 00:26:26,134 THERE IS THE RNA BINDING PROTEIN 497 00:26:26,134 --> 00:26:28,003 THAT FURTHER SHIELDS FROM HOST 498 00:26:28,003 --> 00:26:31,540 DETECTION. NS4B IS HOM MOLL GOUS 499 00:26:31,540 --> 00:26:36,645 TO NS2 AND THE V SO A PRIME 500 00:26:36,645 --> 00:26:37,179 PHOSPHODIESTERASE WHICH 501 00:26:37,179 --> 00:26:40,582 ANTAGONIZING RNA CELL AND 502 00:26:40,582 --> 00:26:42,517 LOCALIZATION SIGNAL THAT 503 00:26:42,517 --> 00:26:47,456 PREVENTS NUCLEAR TRANSFER OF 504 00:26:47,456 --> 00:26:49,992 CAPAB AND INFLAMMATION DOWN 505 00:26:49,992 --> 00:26:52,494 STREAM. USING RECOMBINANT 506 00:26:52,494 --> 00:26:53,161 VIRUSES IN THESE DIFFERENT 507 00:26:53,161 --> 00:26:56,031 PROTEINS WE WERE ABLE TO SHOW 508 00:26:56,031 --> 00:26:58,433 THAT MERS PRETTY MUCH COMPLETELY 509 00:26:58,433 --> 00:27:00,335 SHUTS DOWN INNATE RESPONSES VIA 510 00:27:00,335 --> 00:27:04,373 THESE THREE PROTEINS. SARS IS A 511 00:27:04,373 --> 00:27:07,743 LITTLE DIFFERENT. HAS ENDOU AND 512 00:27:07,743 --> 00:27:14,249 15 LIKE MERS BUT DOESN'T HAVE A 513 00:27:14,249 --> 00:27:16,852 PHOSPHO OR DOUBLE-STRANDED 514 00:27:16,852 --> 00:27:18,186 BINDING PROTEIN AND LESS ABLE TO 515 00:27:18,186 --> 00:27:20,956 SHUT DOWN THE IMMUNITY. HAS OPEN 516 00:27:20,956 --> 00:27:22,991 READING FRAMES WHICH THE R6 517 00:27:22,991 --> 00:27:25,460 ENCODED PROTEIN IS BELIEVED TO 518 00:27:25,460 --> 00:27:28,163 PREVENT NUCLEAR TRANCE 519 00:27:28,163 --> 00:27:30,098 TRANSLOCATION OF STATS AND SHUT 520 00:27:30,098 --> 00:27:32,567 DOWN THE SIMULATED GENE 521 00:27:32,567 --> 00:27:33,702 EXPRESSION, ALTHOUGH COUPLE 522 00:27:33,702 --> 00:27:35,437 PUBLISHED STUDIES, AS WELL AS 523 00:27:35,437 --> 00:27:38,807 OUR OWN WORK DOESN'T SHOW THAT 524 00:27:38,807 --> 00:27:40,742 REALLY HAPPENS. SO BUT THERE'S 525 00:27:40,742 --> 00:27:43,378 LOTS TO LOOK AT IN THESE OTHER 526 00:27:43,378 --> 00:27:45,747 PROTEINS, AND IS STILL TO BE 527 00:27:45,747 --> 00:27:48,417 EXPLORED. SO JUST TO QUICKLY 528 00:27:48,417 --> 00:27:51,820 LOOK HOW MERS AND SARS INCREASED 529 00:27:51,820 --> 00:27:54,556 INTERFERON SIGNALLING WE USED 530 00:27:54,556 --> 00:27:59,461 LUNG DERIVED CALU AND HER IS 531 00:27:59,461 --> 00:28:01,229 LAMDA AND BETA AND STIMULATED 532 00:28:01,229 --> 00:28:04,232 GENE. THESE ARE QCPR LOOKING AT 533 00:28:04,232 --> 00:28:06,802 INDUCTION OVER MOCK-INFECTED 534 00:28:06,802 --> 00:28:08,770 CELLS AND CAN SEE THE SARS IN 535 00:28:08,770 --> 00:28:12,340 THE BLUE, WILD TYPE SARS INDUCES 536 00:28:12,340 --> 00:28:16,144 VERY LITTLE INTERFERON TYPE 3 OR 537 00:28:16,144 --> 00:28:18,246 TYPE 1. A SMALL AMOUNT OF THIS 538 00:28:18,246 --> 00:28:27,155 INTER FE IN/* F -- INTERFERON 539 00:28:27,155 --> 00:28:28,223 STRAIN WITHDRAWS THIS PRODUCES 540 00:28:28,223 --> 00:28:30,425 MORE IN THESE GENES. WHEN WE 541 00:28:30,425 --> 00:28:33,428 LOOK AT MERS, MERS INDUCES 542 00:28:33,428 --> 00:28:36,098 ALMOST UNDETECTABLE AMOUNTS OF 543 00:28:36,098 --> 00:28:39,634 INTERFERON BUT IF WE MUTATE 15 544 00:28:39,634 --> 00:28:43,805 OR 15-PLUS, NS4A WE CAN SEE A 545 00:28:43,805 --> 00:28:45,907 LOT MORE INDUCTION, UP TO 546 00:28:45,907 --> 00:28:47,375 9,000-FOLD OF INTERFERON DURING 547 00:28:47,375 --> 00:28:50,612 INFECTION OF THE CELL TYPE. 548 00:28:50,612 --> 00:28:52,080 SIMILARLY MERS DOESN'T INDUCE 549 00:28:52,080 --> 00:28:57,018 ANY OF THESE PKR OR RNA CELL BUT 550 00:28:57,018 --> 00:28:59,588 DOUBLE-MUTANTS DO. SO THESE 551 00:28:59,588 --> 00:29:01,389 ANTAGONIST PROTEINS ARE 552 00:29:01,389 --> 00:29:03,291 IMPORTANT TO MAINTAIN -- TO KEEP 553 00:29:03,291 --> 00:29:05,160 THE HOST RESPONSES DOWN. IF WE 554 00:29:05,160 --> 00:29:07,262 LOOK AT REPLICATION, WE CAN SEE 555 00:29:07,262 --> 00:29:10,232 IN THE CASE OF SARS A SMALL 556 00:29:10,232 --> 00:29:13,201 DEFECT IN THE NSP15 MUTANT AND 557 00:29:13,201 --> 00:29:14,970 LARGER IN MERS MUTANTS. I WILL 558 00:29:14,970 --> 00:29:17,506 GET BACK TO THIS LATER ON. SO 559 00:29:17,506 --> 00:29:21,209 THE POINT IS THAT BOTH THESE 560 00:29:21,209 --> 00:29:24,045 ADVISORS INDOUGS -- EXPRESS 561 00:29:24,045 --> 00:29:25,914 INTERFERON PROTAGONIST PROTEINS 562 00:29:25,914 --> 00:29:29,584 BUT MERS MUCH MORE THAN SARS. 563 00:29:29,584 --> 00:29:31,353 PERHAPS CORRELATING WITH IT 564 00:29:31,353 --> 00:29:34,089 BEING MORE PATHOGENIC. JUST TO 565 00:29:34,089 --> 00:29:38,026 SUMMARIZE THIS PART HERE, SO 566 00:29:38,026 --> 00:29:41,797 HERE IS SAME PATHWAYS. WE KNOW 567 00:29:41,797 --> 00:29:50,305 THE 15 OR ENDO %CONFLPREVENTS 568 00:29:50,305 --> 00:29:54,943 DOUBLE-CLEAVING AND THE NS4A 569 00:29:54,943 --> 00:29:58,146 DOUBLE-BINDING PROTEIN FROM MERS 570 00:29:58,146 --> 00:30:00,182 HERE. THEN THE MERS ENCODES THE 571 00:30:00,182 --> 00:30:01,683 PROTEIN TO SPECIFICALLY SHUT 572 00:30:01,683 --> 00:30:07,289 DOWN THIS PATHWAY, AS DOES MHV 573 00:30:07,289 --> 00:30:10,358 AND OC43 SO MERS TAKES CARE OF 574 00:30:10,358 --> 00:30:13,328 EVERYTHING. SARS IS DIFFERENT IN 575 00:30:13,328 --> 00:30:16,097 THAT IT DOES INTRODUCE 576 00:30:16,097 --> 00:30:17,032 SIGNALLING, NOT A LOT COMPARED 577 00:30:17,032 --> 00:30:19,434 TO OTHERS. I WILL SHOW YOU BUT 578 00:30:19,434 --> 00:30:23,171 DOES INDUCE THESE PATHWAYS. IT 579 00:30:23,171 --> 00:30:28,276 IS KIND OF AMAZING. KEEPS THE 580 00:30:28,276 --> 00:30:30,345 PHOS ALPHA THROUGHOUT 581 00:30:30,345 --> 00:30:31,646 REPLICATION BUT CONTINUES 582 00:30:31,646 --> 00:30:33,281 PROTEINS AND REPLICATES 583 00:30:33,281 --> 00:30:35,383 EFFICIENTLY WHEREAS OTHER 584 00:30:35,383 --> 00:30:36,785 VIRUSES -- I'M NOT GOING TO SHOW 585 00:30:36,785 --> 00:30:39,554 YOU, THEY NEED TO KEEP THIS 586 00:30:39,554 --> 00:30:43,959 ALPHA UNPHOSPHORELATED OR BAD 587 00:30:43,959 --> 00:30:47,629 FOR THEIR REPLICATION. WE DON'T 588 00:30:47,629 --> 00:30:52,667 UNDERSTAND HOW SARS WORKS 589 00:30:52,667 --> 00:30:55,237 DESPITE INDUCING THE PATHWAYS. 590 00:30:55,237 --> 00:30:58,273 IT SUGGESTS THAT IT SIMULATES 591 00:30:58,273 --> 00:30:59,975 THIS GENE EXPRESSION THOUGH WE 592 00:30:59,975 --> 00:31:02,210 HAVEN'T SEEN THAT 593 00:31:02,210 --> 00:31:03,612 EXPERIMENTALLY. THERE ARE OTHER 594 00:31:03,612 --> 00:31:07,949 PROTEINS WE ARE INTER TESINTERED 595 00:31:07,949 --> 00:31:10,585 AND WORKING ON THE RF6 ON THAT 596 00:31:10,585 --> 00:31:12,387 PROTEIN. AT THIS POINT I WANT TO 597 00:31:12,387 --> 00:31:16,157 SWITCH TO THE SORT OF -- TO TALK 598 00:31:16,157 --> 00:31:17,959 ABOUT OUR MOST RECENT STUDIES. 599 00:31:17,959 --> 00:31:21,429 ALL THEY STARTED DURING THE 600 00:31:21,429 --> 00:31:24,232 PANDE 601 00:31:24,232 --> 00:31:26,902 PANDEMIC. THE QUESTION IS HOW 602 00:31:26,902 --> 00:31:33,308 DOES IT INCREASE RESPONSE IN 603 00:31:33,308 --> 00:31:38,513 NASAL EPITHELIALIUM. WE USED 604 00:31:38,513 --> 00:31:39,981 DIFFERENT VIRUSES THAT AFFECTED 605 00:31:39,981 --> 00:31:41,483 THE RESPIRATORY TRACT AND CAUSES 606 00:31:41,483 --> 00:31:43,852 DIFFERENT DISEASES. MERZ CAUSES 607 00:31:43,852 --> 00:31:47,422 A LETHAL PNEUMONIA AND INFECTS 608 00:31:47,422 --> 00:31:50,191 MOSTLY LOWER RESPIRATORY, THE 609 00:31:50,191 --> 00:31:51,927 LUNGS. SARS-COV 2 CAUSES A REAL 610 00:31:51,927 --> 00:31:53,795 RANGE OF DISEASES FROM 611 00:31:53,795 --> 00:31:56,698 ASYSTEMATIC TO MILD UPPER 612 00:31:56,698 --> 00:31:59,000 RESPIRATORY DISEASE TO LOWER 613 00:31:59,000 --> 00:32:00,502 RESPIRATORY TO LETHAL DISEASE 614 00:32:00,502 --> 00:32:05,674 THIS THE LUNG AS WELL. THEN NL63 615 00:32:05,674 --> 00:32:07,709 AND 2290 THAT BOTH CAUSE 616 00:32:07,709 --> 00:32:08,643 PRIMARILY UPPER RESPIRATORY 617 00:32:08,643 --> 00:32:11,446 DISEASE. KIND OF CALL THEM THE 618 00:32:11,446 --> 00:32:13,181 COMMON COLD CORONA VIRUSES. WE 619 00:32:13,181 --> 00:32:14,983 ALSO USE FOR THESE EXPERIMENTS 620 00:32:14,983 --> 00:32:19,454 HUMAN RHINO VIRUS 16, A 621 00:32:19,454 --> 00:32:21,022 COMPLETELY DIFFERENT TYPE VIRUS. 622 00:32:21,022 --> 00:32:23,792 WE USE IT KIND OF AS CONTROL FOR 623 00:32:23,792 --> 00:32:27,362 HOW COMMON COLD VIRUS WILL 624 00:32:27,362 --> 00:32:30,932 BEHAVE. SO WHY DO WE THINK THE 625 00:32:30,932 --> 00:32:32,600 NASAL EPITHELIAL YUM IS 626 00:32:32,600 --> 00:32:35,770 IMPORTANT? IT IS THE FIRST LINE 627 00:32:35,770 --> 00:32:38,340 OF DEFENSE AGAINST RESPIRATORY 628 00:32:38,340 --> 00:32:40,675 PATHOGENS. INITIAL SIDE OF VIRAL 629 00:32:40,675 --> 00:32:43,011 REPLICATION. PRIMARILY COMPOSED 630 00:32:43,011 --> 00:32:46,815 OF SILLIATED AND GOBLET CELLS 631 00:32:46,815 --> 00:32:49,117 THAT PRODUCE MUSIC CUSS AND HAS 632 00:32:49,117 --> 00:32:51,586 THESE TIGHT JUNCTIONS AT THE 633 00:32:51,586 --> 00:32:54,856 APICAL SIDE OF THE CELLS SHOWN 634 00:32:54,856 --> 00:32:57,759 HERE THAT CONTRIBUTE TO 635 00:32:57,759 --> 00:33:07,402 EPITHELIAL BARRIER. THE MUCUS -- 636 00:33:07,402 --> 00:33:11,539 IS AN EARLY RESPONSE SO THE 637 00:33:11,539 --> 00:33:13,041 PSYLLIA PUSH MUCUS AROUND. WE 638 00:33:13,041 --> 00:33:15,577 BELIEVE THAT IS TO KEEP VIRUS 639 00:33:15,577 --> 00:33:17,879 FROM BEING ASPIRATED INTO THE 640 00:33:17,879 --> 00:33:19,914 LUNG. THERE IS A HIGH BASAL 641 00:33:19,914 --> 00:33:22,517 LEVEL OF EXPRESSION OF 642 00:33:22,517 --> 00:33:24,586 INTERFERON AND OTHER GENES IN 643 00:33:24,586 --> 00:33:27,155 THE NASAL EPITHELIAL YUM SO MAY 644 00:33:27,155 --> 00:33:29,491 BE PRIMED TO PREVENT AGAINST 645 00:33:29,491 --> 00:33:32,227 INVADING VIRUSES. THERE ARE 646 00:33:32,227 --> 00:33:34,129 CLINICALS PUBLISHED WHERE THEY 647 00:33:34,129 --> 00:33:37,766 LOOK BY RNA SIK BASAL LEVELS IN 648 00:33:37,766 --> 00:33:40,835 RESPONSE LEVELS IN NOSE AND 649 00:33:40,835 --> 00:33:43,271 FOUND HIGHER, BETTER LEVELS OF 650 00:33:43,271 --> 00:33:46,474 THESE GENES WAS ASSOCIATED WITH 651 00:33:46,474 --> 00:33:48,576 LESS SEVERE COVID 19. SO I THINK 652 00:33:48,576 --> 00:33:52,247 THE INTERFERON RESPONSE IN THE 653 00:33:52,247 --> 00:33:57,719 BRAIN IS QUITE IMPORTANT. WITH 654 00:33:57,719 --> 00:33:59,654 THE EPITHELIAL CELL MODEL 655 00:33:59,654 --> 00:34:03,224 CULTURES ON AIR LIQUID INTERFACE 656 00:34:03,224 --> 00:34:06,761 TO RECAPITULATE THE AIRWAY. ALL 657 00:34:06,761 --> 00:34:08,296 THIS WORK IS DONE IN 658 00:34:08,296 --> 00:34:10,698 COLLABORATION WITH NOEM CULLEN, 659 00:34:10,698 --> 00:34:16,471 AN EMT SURGEON AT PENN. HE HAS 660 00:34:16,471 --> 00:34:17,939 COLLECTION FROM HUNDREDS OF 661 00:34:17,939 --> 00:34:21,643 PATIENTS OF PRIMARY EPITHELIAL 662 00:34:21,643 --> 00:34:24,679 CELL IN A KIND OF BIOBANK SO WE 663 00:34:24,679 --> 00:34:26,848 HAVE AN UNENDING SUPPLY OF CELLS 664 00:34:26,848 --> 00:34:30,618 TO WORK WITH. WHEN WE USE THESE, 665 00:34:30,618 --> 00:34:32,787 WE PUT THEM ON TRANSWELLS, 666 00:34:32,787 --> 00:34:35,356 EXPAND IN LIQUID CULTURAL AND 667 00:34:35,356 --> 00:34:36,591 REMOVE THE LIQUID AND 668 00:34:36,591 --> 00:34:38,560 DIFFERENTIATE UNDER AIR LIQUID 669 00:34:38,560 --> 00:34:42,964 INTERFACE TO RECAPITULATE EN 670 00:34:42,964 --> 00:34:46,401 VIVO AIRWAY. HERE IS A PICTURE. 671 00:34:46,401 --> 00:34:50,205 THEY LOOK A LOT LIKE NASAL 672 00:34:50,205 --> 00:34:56,377 EPITHELIAL YUM. THIS IS THE 673 00:34:56,377 --> 00:34:58,246 CILIA HERE . YOU SHOULD BE ABLE 674 00:34:58,246 --> 00:35:00,348 TO SEE THE CILIA BEATING. THIS 675 00:35:00,348 --> 00:35:04,219 IS A CULTURE WHERE MUCUS HAS 676 00:35:04,219 --> 00:35:07,155 BEEN REMOVED SO YOU CAN SEE WHAT 677 00:35:07,155 --> 00:35:09,290 IS GOING ON WITH CILIA. THIS 678 00:35:09,290 --> 00:35:10,758 THIRD HAS NOT BEEN WASHED OFF. 679 00:35:10,758 --> 00:35:13,361 YOU CAN SEE THE CILIA KIND OF 680 00:35:13,361 --> 00:35:14,896 PUSHING AROUND THE MUCUS. SO 681 00:35:14,896 --> 00:35:19,300 AFTER SEVERAL WEEKS OF 682 00:35:19,300 --> 00:35:22,270 DIFFERENTIATION THEY ARE READY 683 00:35:22,270 --> 00:35:26,207 TO BE INFECTED. SO THIS IS THE 684 00:35:26,207 --> 00:35:27,275 KINETICS OF REPLICATION IN 685 00:35:27,275 --> 00:35:29,410 PRIMARY NASAL CULTURES. WE CAN 686 00:35:29,410 --> 00:35:32,247 SEE DIFFERENT PATTERNS. ALL 687 00:35:32,247 --> 00:35:35,917 THESE ARE DONE WITH -- WE NOW 688 00:35:35,917 --> 00:35:38,820 POOL YELLS FROM FOUR TO SIX 689 00:35:38,820 --> 00:35:40,155 DONORS AND REPEAT THAT ABOUT 690 00:35:40,155 --> 00:35:42,323 THREE TIMES. BY THE TIME WE ARE 691 00:35:42,323 --> 00:35:44,492 DONE WE HAVE LOOKED ABOUT 692 00:35:44,492 --> 00:35:47,061 SOMEWHERE BETWEEN 12 AND 18 693 00:35:47,061 --> 00:35:49,531 DONORS. THIS IS THE AVERAGE 694 00:35:49,531 --> 00:35:51,533 REPLICATION KINETICS. IF WE TAKE 695 00:35:51,533 --> 00:35:54,769 THAT AN PART WE CAN SEE THAT 696 00:35:54,769 --> 00:36:00,441 SARS AND MERS HAVE SIMILAR 697 00:36:00,441 --> 00:36:01,843 KINETICS. THESE ARE LONG 698 00:36:01,843 --> 00:36:05,547 CULTURE, GO UP FOR EIGHT DAYS, 699 00:36:05,547 --> 00:36:09,184 192 HOURS. IF WE LOOK AT THE 700 00:36:09,184 --> 00:36:10,985 COMMON COLD CORONAVIRUSES THEY 701 00:36:10,985 --> 00:36:13,922 REPLICATE EARLY AND CLEARED FROM 702 00:36:13,922 --> 00:36:18,059 CULTURES. THEN FINALLY IF WE ADD 703 00:36:18,059 --> 00:36:20,495 HUMAN RHINO VIRUS 16 IT BEHAVES 704 00:36:20,495 --> 00:36:22,363 PRETTY MUCH LIKE THE COMMON COLD 705 00:36:22,363 --> 00:36:25,233 VIRUSES SO HAVE SIMILAR 706 00:36:25,233 --> 00:36:31,139 REPLICATION PEAK THEN ARE CLE 707 00:36:31,139 --> 00:36:32,840 CLEARED. SO THERE ARE DIFFERENT 708 00:36:32,840 --> 00:36:34,142 TEMPERATURES IN THE UPPER AND 709 00:36:34,142 --> 00:36:36,044 LOWER TRACT. WITH NOSE HAVING 710 00:36:36,044 --> 00:36:37,712 TEMPERATURES IN RANGE OF THE -- 711 00:36:37,712 --> 00:36:42,717 OR THE NASAL CAVITY, LIKE 32, 33 712 00:36:42,717 --> 00:36:44,085 DEGREES. THE LUNGS WITH MORE 713 00:36:44,085 --> 00:36:46,154 LIKE A 37 DEGREES BODY 714 00:36:46,154 --> 00:36:48,022 TEMPERATURE. SO WE WANTED TO SEE 715 00:36:48,022 --> 00:36:49,724 HOW THESE VIRUSES REPLICATED AT 716 00:36:49,724 --> 00:36:51,059 THE DIFFERENT TEMPERATURES GIVEN 717 00:36:51,059 --> 00:36:54,495 THAT THEY REPLICATE IN DIFFERENT 718 00:36:54,495 --> 00:36:57,465 PARTS OF THE RESPIRATORY TRACT. 719 00:36:57,465 --> 00:37:02,070 WHAT WE FOUND IS COLD VIRUSES, 720 00:37:02,070 --> 00:37:04,606 98, 63 AND HRV16 ALL SORT HAVE 721 00:37:04,606 --> 00:37:06,040 SIMILAR PATTERN, THEY REPLICATED 722 00:37:06,040 --> 00:37:09,877 MUCH BETTER AT LOWER TEMPERATURE 723 00:37:09,877 --> 00:37:12,046 SHOWN HERE, 33 DEGREES THAN AT 724 00:37:12,046 --> 00:37:13,381 37 DEGREES. IT WAS PRETTY 725 00:37:13,381 --> 00:37:19,854 DRAMATIC FOR NL63, FOR EXAMPLE. 726 00:37:19,854 --> 00:37:22,090 SO THIS IS MORE THE NASAL 727 00:37:22,090 --> 00:37:23,658 AIRWAY, NOT THE LUNG. WHEN WE 728 00:37:23,658 --> 00:37:27,195 LOOKED AT THE SAME DIFFERENCE IN 729 00:37:27,195 --> 00:37:30,298 TEMPERATURE FOR SARS AND MERS WE 730 00:37:30,298 --> 00:37:33,234 SAW FOR SARS UP UNTIL 144 HOUR, 731 00:37:33,234 --> 00:37:34,936 NO PREFERENCE FOR EITHER 732 00:37:34,936 --> 00:37:38,306 TEMPERATURE BUT CRASHES AT 37. 733 00:37:38,306 --> 00:37:39,607 REALLY NEEDS 33 DEGREES TO 734 00:37:39,607 --> 00:37:41,876 CONTINUE TO REPLICATE. I WILL 735 00:37:41,876 --> 00:37:44,612 GET BACK TO THIS LATER. MERS 736 00:37:44,612 --> 00:37:46,514 REALLY HAS NO PREFERENCE FOR 737 00:37:46,514 --> 00:37:50,018 TEMPERATURE. IT CAN REPLICATE 738 00:37:50,018 --> 00:37:58,159 EQUALLY AT 33 OR 37. SO THE 16 739 00:37:58,159 --> 00:37:59,694 PEAKS AT EARLY TIMES, FOLLOWED 740 00:37:59,694 --> 00:38:03,064 BY CLEARANCE. THE REPLICATION OF 741 00:38:03,064 --> 00:38:05,900 SARS AND MERS PLATEAUS WITHOUT 742 00:38:05,900 --> 00:38:07,835 EVIDENCE OF CLEARANCE. SIMPLY 743 00:38:07,835 --> 00:38:09,037 COMMON COLD VIRUSES REPLICATE 744 00:38:09,037 --> 00:38:12,940 MORE EFFICIENTLY AT 33, COMPARED 745 00:38:12,940 --> 00:38:15,510 TO 37. SARS ALSO REPLICATES 746 00:38:15,510 --> 00:38:19,213 OPTIMALLY AT 33. ONLY AT LATE 747 00:38:19,213 --> 00:38:20,982 TIME POINTS AND MERS IS NOT 748 00:38:20,982 --> 00:38:22,183 IMPACTED BY TEMPERATURE AT ALL. 749 00:38:22,183 --> 00:38:25,753 SO WE WANTED TO KNOW WAS HOW DO 750 00:38:25,753 --> 00:38:26,888 INTERFERENCE SIGNALLING 751 00:38:26,888 --> 00:38:29,257 RESPONSES VARY AMONG INFECTION 752 00:38:29,257 --> 00:38:33,328 WITH VIRUS VIRUSES, RESPIRATORY 753 00:38:33,328 --> 00:38:38,733 VIRUSES. SO WE DID AN RNA SIK 754 00:38:38,733 --> 00:38:40,601 EXPERIMENT TO INFECTED CULTURALS 755 00:38:40,601 --> 00:38:42,437 WITH ALL THESE AND EXTRACTED RNA 756 00:38:42,437 --> 00:38:46,007 AND SUBJECTED IT TO RNA SEEK. 757 00:38:46,007 --> 00:38:48,443 THESE ARE VOLCANO PLOTS -- I 758 00:38:48,443 --> 00:38:51,546 WILL PUT THEM ALL UP FIRST. 759 00:38:51,546 --> 00:38:53,514 WHERE REGULATION OF GENES IS TO 760 00:38:53,514 --> 00:38:55,550 THE RIGHT AND DOWN REGULATION TO 761 00:38:55,550 --> 00:38:58,152 THE LEFT. THE INTERFERON SIGNALS 762 00:38:58,152 --> 00:38:59,921 ARE HIGHLIGHTED IN GREEN. WE CAN 763 00:38:59,921 --> 00:39:02,523 SEE IF WE LOOK AT MERS, THERE'S 764 00:39:02,523 --> 00:39:05,693 VERY LITTLE INDUCTION OF 765 00:39:05,693 --> 00:39:07,862 INTERFERON SIGNALLING GENES. A 766 00:39:07,862 --> 00:39:09,364 FEW THAT ARE DOWN REGULATED. 767 00:39:09,364 --> 00:39:11,599 SARS A BIT MORE, AS WE SAW IN 768 00:39:11,599 --> 00:39:15,036 THE CALU CELLS. IF YOU LOOK AT 769 00:39:15,036 --> 00:39:17,739 COLD VIRUSES, JUST WAY, WAY MORE 770 00:39:17,739 --> 00:39:19,841 GENES INDUCED IN THE SIGNALLING 771 00:39:19,841 --> 00:39:22,643 GENES INDUCED AND HIGHER LEVELS 772 00:39:22,643 --> 00:39:25,380 AS WELL. WHEN WE QUANTIFIED THE 773 00:39:25,380 --> 00:39:27,682 NUMBER OF INTERFERON RESPONSE 774 00:39:27,682 --> 00:39:34,956 GENES INDUCED REGULATED NICHE IK 775 00:39:34,956 --> 00:39:35,656 FEBRUAR 776 00:39:35,656 --> 00:39:36,657 INFECTION, MERS LOW AND SARS 777 00:39:36,657 --> 00:39:37,892 MINIMAL AND OTHER THREE HIGHER. 778 00:39:37,892 --> 00:39:40,962 ONE OF THE TRADEMARKS OF COLD IS 779 00:39:40,962 --> 00:39:45,299 INTRODUCE A LOT OF INTER FOR RON 780 00:39:45,299 --> 00:39:46,334 SIGNALLING. THE IS A KEY PIECE 781 00:39:46,334 --> 00:39:49,437 OF VALIDATION. I TRUST PCR 782 00:39:49,437 --> 00:39:50,872 BETTER, IT IS QUANTITATIVE SO WE 783 00:39:50,872 --> 00:39:53,708 DO THIS TO MAKE SURE THE RNA 784 00:39:53,708 --> 00:39:56,244 SEEK ACTUALLY MAKES SENSE OR 785 00:39:56,244 --> 00:39:58,713 CORRESPONDS WITH IT. WE CAN SEE 786 00:39:58,713 --> 00:40:00,748 AGAIN VERY LITTLE SARS -- 787 00:40:00,748 --> 00:40:02,483 INDUCED BY SARS, ALMOST NOTHING 788 00:40:02,483 --> 00:40:04,519 DETECTABLE BY MERS AND OTHER 789 00:40:04,519 --> 00:40:07,021 VIRUSES TO DIFFERENT EXTENTS ARE 790 00:40:07,021 --> 00:40:11,526 INDUCING MORE INTER INTERFERON 791 00:40:11,526 --> 00:40:13,127 AND STIMULATED GENES. THE OTHER 792 00:40:13,127 --> 00:40:15,363 WAY WE LOOK, WE LIKE THIS, IS 793 00:40:15,363 --> 00:40:19,066 LOOKING AT THE INTERFERON 794 00:40:19,066 --> 00:40:20,802 PROTEIN EXPRESSION BY WESTERN 795 00:40:20,802 --> 00:40:24,238 BLOT. WE CAN SEE IF WE LOOK AT 796 00:40:24,238 --> 00:40:28,242 -- THIS IS THE FIRST SUSTAINING 797 00:40:28,242 --> 00:40:36,250 FOR PHOS STAT TYPES FOR GENES. 798 00:40:36,250 --> 00:40:37,885 MERS REALLY INDUCES NO RESPONSE 799 00:40:37,885 --> 00:40:40,121 AT ALL. EVEN IF WE LOOK AT ANY 800 00:40:40,121 --> 00:40:42,323 TIME POINT, WE DON'T SEE IT. 801 00:40:42,323 --> 00:40:44,125 SARS WE SEE LATE TIME POINTS, 802 00:40:44,125 --> 00:40:47,395 SOME 92 HOURS. EIGHT DAY 803 00:40:47,395 --> 00:40:48,596 POST-INFECTION, NOTHING UNTIL 804 00:40:48,596 --> 00:40:50,898 THEN. WHEREAS OTHER VIRUSES BY 805 00:40:50,898 --> 00:40:56,270 48 TO 96 HOURS ARE INDUCING STAT 806 00:40:56,270 --> 00:40:57,672 PHORELATION. WHEN WE LOOK AT A 807 00:40:57,672 --> 00:41:01,008 BUNCH OF STIMULATED GENES WE SEE 808 00:41:01,008 --> 00:41:03,578 SAME. NOTHING FOR MERS. SARS 809 00:41:03,578 --> 00:41:07,014 LATE. OTHER VIRUSES MUCH 810 00:41:07,014 --> 00:41:09,050 EARLIER. THEN WE ALSO LOOK AT 811 00:41:09,050 --> 00:41:13,054 PKR ACTIVATION JUST TO REMIND 812 00:41:13,054 --> 00:41:17,658 YOU, WE MEASURE THIS BY PHOSPR 813 00:41:17,658 --> 00:41:19,794 AND ALPHA. WE SEE THE SAME 814 00:41:19,794 --> 00:41:21,696 PATTERN. NOTHING FOR MERS, SARS 815 00:41:21,696 --> 00:41:23,931 LATE, OTHER VIRUSES AT EARLIER 816 00:41:23,931 --> 00:41:32,540 TIME POINTS ARE INDUCING 817 00:41:32,540 --> 00:41:34,375 PHOSPHORELATION OF THE PATHWAY. 818 00:41:34,375 --> 00:41:36,844 THIS IS BLOTTING BOARD THAT CAPS 819 00:41:36,844 --> 00:41:39,113 AND PROTEINS OF EACH VIRUS TO 820 00:41:39,113 --> 00:41:43,084 SHOW THEY ARE REPLICATING TO 821 00:41:43,084 --> 00:41:44,952 REASONABLE EXTENT. SO FROM THIS 822 00:41:44,952 --> 00:41:46,821 WE CONCLUDE THERE ARE THREE 823 00:41:46,821 --> 00:41:48,589 DIFFERENT KINDS OF PATTERNS THAT 824 00:41:48,589 --> 00:41:55,763 FOR MERS REALLY NO SPONRESPONSER 825 00:41:55,763 --> 00:41:59,066 SARS 2 DELAYED AND 6290 AND 826 00:41:59,066 --> 00:42:00,568 RHINO, EARLY AND ROBUST 827 00:42:00,568 --> 00:42:01,869 RESPONSES. THE NEXT THING WE 828 00:42:01,869 --> 00:42:03,704 WANT TO KNOW WHAT HAPPENS IF WE 829 00:42:03,704 --> 00:42:06,040 TAKE AWAY INTERFERON SIGNALLING 830 00:42:06,040 --> 00:42:07,875 RESPONSE, WHAT WILL HAPPEN TO 831 00:42:07,875 --> 00:42:10,311 REPLICATION OF THESE VIRUSES? SO 832 00:42:10,311 --> 00:42:14,949 WE USED A DRUG CALLED 833 00:42:14,949 --> 00:42:19,453 RUXALITANEM, IMPAIRING 834 00:42:19,453 --> 00:42:21,822 INTERFERON SIGNALLING AND REACTS 835 00:42:21,822 --> 00:42:23,925 WITH INTERCEPTOR CAUSING 836 00:42:23,925 --> 00:42:33,467 ACTIVATION OF CHIN 837 00:42:33,467 --> 00:42:35,002 CHINASEPHOSPHOROLATES. AND RUX 838 00:42:35,002 --> 00:42:37,705 INHIBITS JACK ACTIVITY, 839 00:42:37,705 --> 00:42:40,675 PREVENTING PHOS OF STAT AND 840 00:42:40,675 --> 00:42:44,078 GREATLY REDUCING 841 00:42:44,078 --> 00:42:46,547 INTERFERON-SIMULATED GENE 842 00:42:46,547 --> 00:42:48,883 TRANSCRIPTION. WHEN WE TREAT 843 00:42:48,883 --> 00:42:51,152 CELLS WITH RUX AND THEN INFECT 844 00:42:51,152 --> 00:42:54,388 THEM WE SEE THIS PATTERN FOR THE 845 00:42:54,388 --> 00:42:56,123 THREE COLD VIRUSES THAT WERE 846 00:42:56,123 --> 00:42:57,992 CLEARED FROM INFECTION, NO 847 00:42:57,992 --> 00:43:01,395 LONGER CLEARED. THEY PLATEAU, 848 00:43:01,395 --> 00:43:04,999 SORT OF RESEMBLE MORE KINETICS 849 00:43:04,999 --> 00:43:07,702 OF VIRULENT VIRUSES OF MERS AND 850 00:43:07,702 --> 00:43:09,604 SARS. WHEN WE DO SAME TREATMENT 851 00:43:09,604 --> 00:43:13,174 TO THESE WE SEE LITTLE EFFECT ON 852 00:43:13,174 --> 00:43:14,275 SARS-LATENT INFEBRUARYING SHN 853 00:43:14,275 --> 00:43:22,650 AND NO EFFECT ON MERS. SO THIS 854 00:43:22,650 --> 00:43:23,818 SUBSTANTIATES THAT THE RESPONSE 855 00:43:23,818 --> 00:43:27,021 IS WHAT IS LIMITING COLD VIRUSES 856 00:43:27,021 --> 00:43:33,828 IN NOSE. WHEREAS TWO VIRTUAL 857 00:43:33,828 --> 00:43:36,030 LENT DON'T INDUCE MUCH RESPONSE. 858 00:43:36,030 --> 00:43:39,634 TO SUMMARIZE HERO HUMAN 859 00:43:39,634 --> 00:43:43,371 CORONAVIRUSES INDUCE A WIDE 860 00:43:43,371 --> 00:43:46,440 RANGE OF DIFFERENT SIGNALLING 861 00:43:46,440 --> 00:43:48,309 RESPONSES AND SARS SIGNIFICANTLY 862 00:43:48,309 --> 00:43:51,712 DELAYS INTERFERON RESPONSES. THE 863 00:43:51,712 --> 00:43:55,549 INHIBITION OF INTERFERON WITH 864 00:43:55,549 --> 00:43:57,418 RUX IMPAIRS CLEARANCE OF COMMON 865 00:43:57,418 --> 00:43:59,654 COLD BUT MINIMAL EFFECT ON 866 00:43:59,654 --> 00:44:02,223 REPLICATION OF LETHAL VIRUSES. 867 00:44:02,223 --> 00:44:03,658 SO WE SUGGEST FROM ALL THIS THAT 868 00:44:03,658 --> 00:44:06,827 THE EXTENT OF INTERFERON 869 00:44:06,827 --> 00:44:07,862 SIGNALLING IN NOSE MAY IN PART 870 00:44:07,862 --> 00:44:10,364 DETERMINE IF INFECTION CAN 871 00:44:10,364 --> 00:44:11,932 PROGRESS. SO THE VIRUS ISN'T 872 00:44:11,932 --> 00:44:14,502 CLEARED FROM THE NOSE AND CAN BE 873 00:44:14,502 --> 00:44:16,704 MORE EASILY ASPIRATED FROM LUNG. 874 00:44:16,704 --> 00:44:18,973 SO WE WANTED TO KNOW THE ROLE OF 875 00:44:18,973 --> 00:44:21,575 VIRUS ENCODED ANNING THE KNISS I 876 00:44:21,575 --> 00:44:23,210 TALKED ABOUT IN REGULATING 877 00:44:23,210 --> 00:44:24,545 REPLICATION AND CLEARANCE IN THE 878 00:44:24,545 --> 00:44:25,980 NASAL CELL MODEL. SO THESE ARE 879 00:44:25,980 --> 00:44:29,650 THE SAME VIRUSES I SHOWED YOU 880 00:44:29,650 --> 00:44:32,286 BEFORE, THE MERS MUTANTS. THEY 881 00:44:32,286 --> 00:44:35,389 ARE EVEN MORE AT TEN YOU WAITED 882 00:44:35,389 --> 00:44:38,192 IN THE MODEL. SAME FOR SARS 883 00:44:38,192 --> 00:44:40,494 WHICH DIDN'T SHOW MUCH DEFECT 884 00:44:40,494 --> 00:44:45,800 AND CELL LINE IS LOOKING AT 885 00:44:45,800 --> 00:44:47,301 ATTENUATED. WE CAN LOOK AT THIS 886 00:44:47,301 --> 00:44:51,072 AGAIN BY WESTERN BLOT AND WE SEE 887 00:44:51,072 --> 00:44:58,312 THAT SARS MUTANT INDUCES MORE 888 00:44:58,312 --> 00:45:00,414 PSTAT THAN WILD BUT BOTH DO 889 00:45:00,414 --> 00:45:03,184 INDUCE WHEREAS MERS, THERE IS 890 00:45:03,184 --> 00:45:05,720 NOTHING, NO INDIRECTION BY MERS. 891 00:45:05,720 --> 00:45:08,589 THEY INDUCE EARLY AND ROBUST 892 00:45:08,589 --> 00:45:11,325 COMPARED TO WILD TYPE. SAME 893 00:45:11,325 --> 00:45:13,994 THING AGAIN FOR INTERFERON 894 00:45:13,994 --> 00:45:15,896 STIMULATED. THE MUTANT INDUCES 895 00:45:15,896 --> 00:45:19,800 QUITE WELL. THE MUTANT SARS MAY 896 00:45:19,800 --> 00:45:21,535 INDUCE EARLIER BUT STILL THIS 897 00:45:21,535 --> 00:45:23,304 DELAYED INDUCTION, WHEREAS MERS 898 00:45:23,304 --> 00:45:25,372 IS NOT DELAYED AT ALL. IF WE 899 00:45:25,372 --> 00:45:29,176 LOOK AT PKR WE SEE SAME PATTERN 900 00:45:29,176 --> 00:45:31,245 THAT MUTANT VIRUSES INDUCE MORE 901 00:45:31,245 --> 00:45:34,548 PKR, NOT SURPRISINGLY, THAN WILD 902 00:45:34,548 --> 00:45:36,383 TYPE. AGAIN, JUST THIS IS JUST 903 00:45:36,383 --> 00:45:39,887 TO SHOW THAT ALL THE VIRUSES ARE 904 00:45:39,887 --> 00:45:42,089 REPLICATING. OKAY. SO WE THEN 905 00:45:42,089 --> 00:45:44,859 TREATED -- WE TREATED CELLS WITH 906 00:45:44,859 --> 00:45:47,094 RUX AND INFECTED WITH WILD TYPE 907 00:45:47,094 --> 00:45:50,097 AND MUTANT VIRUSES AND SEE 908 00:45:50,097 --> 00:45:51,899 INTERESTINGLY HERE IS THE SOLID 909 00:45:51,899 --> 00:45:54,468 LINES ARE UNTREATED AND DOTTED 910 00:45:54,468 --> 00:45:58,372 LINES ARE TREATED WITH RUX AND 911 00:45:58,372 --> 00:46:01,041 WE CAN SEE THAT THE MUTANT VIRUS 912 00:46:01,041 --> 00:46:03,244 THAT WAS -- DIDN'T REPLICATION 913 00:46:03,244 --> 00:46:04,678 VERY WELL IN PRESENCE AND 914 00:46:04,678 --> 00:46:06,914 WITHOUT THE DRUG NOW IS RESCUED 915 00:46:06,914 --> 00:46:08,082 FOR REPLICATION. IN OTHER WORDS, 916 00:46:08,082 --> 00:46:10,684 THE SAME THING IS TRUE WITH THE 917 00:46:10,684 --> 00:46:12,887 MERS MUTANTS. SO TREATING OR 918 00:46:12,887 --> 00:46:15,456 INHIBITING THE INTERFERON SIGNAL 919 00:46:15,456 --> 00:46:17,158 ALLOWS MUTANT VIRUSS TO BEHAVE 920 00:46:17,158 --> 00:46:20,227 AS WILD TYPE SO JUST SHOWS AGAIN 921 00:46:20,227 --> 00:46:24,765 THAT THESE ANTAGONISTS PREVENT 922 00:46:24,765 --> 00:46:27,668 THE EFFECTS OF INTERFERON 923 00:46:27,668 --> 00:46:29,270 SIGNALLING AND ONCE GONE, THERE 924 00:46:29,270 --> 00:46:32,273 ARE WILD TYPE VIRUSES. SO OKAY. 925 00:46:32,273 --> 00:46:34,375 SO IN ADDITION TO INDUCING 926 00:46:34,375 --> 00:46:35,676 DIFFERENT PATTERNS OF 927 00:46:35,676 --> 00:46:37,645 SIGNALLING, AS I SHOWED YOU, 928 00:46:37,645 --> 00:46:39,380 THERE'S DIFFERENT PATTERNS OF 929 00:46:39,380 --> 00:46:40,881 TEMPERATURE DEPENDENCE FOR 930 00:46:40,881 --> 00:46:43,250 REPLICATION. WE WONDERED WHETHER 931 00:46:43,250 --> 00:46:44,985 DOES INTERFERON SIGNALLING 932 00:46:44,985 --> 00:46:45,719 RESPONSE CONTRIBUTE TO 933 00:46:45,719 --> 00:46:47,388 TEMPERATURE DEPENDENCE. WE SAW 934 00:46:47,388 --> 00:46:50,324 THESE THREE PATTERNS BOTH FOR 935 00:46:50,324 --> 00:46:51,625 INTERFERON SIGNALLING AND 936 00:46:51,625 --> 00:46:53,060 TEMPERATURE DEPENDENCE THAT SORT 937 00:46:53,060 --> 00:46:57,698 OF ALONG THE SAME LINES. SO 938 00:46:57,698 --> 00:46:59,934 STARTING WITH SARS WE ASKED 939 00:46:59,934 --> 00:47:02,102 WHETHER INTERFERON SIGNALLING TO 940 00:47:02,102 --> 00:47:04,538 SARS WAS MORE ROBUST AT 37 941 00:47:04,538 --> 00:47:05,906 VERSUS 33 AND WE FOUND IT WAS. 942 00:47:05,906 --> 00:47:09,543 IF WE LOOK HERE WE CAN SEE AT 943 00:47:09,543 --> 00:47:12,146 EACH TEMPERATURE THERE IS MORE 944 00:47:12,146 --> 00:47:14,014 PSTAT AND STIMULATED GENES AND 945 00:47:14,014 --> 00:47:16,483 MORE PPKR WHEN THE EXPERIMENT IS 946 00:47:16,483 --> 00:47:22,423 DONE AT 37 DEGREES COMPARED TO 947 00:47:22,423 --> 00:47:24,225 33. HOWEVER WHEN WE TREAT THE -- 948 00:47:24,225 --> 00:47:28,829 THESE CELLS WITH RUX, WE CAN SEE 949 00:47:28,829 --> 00:47:31,165 THAT THE 37-DEGREE REPLICATION 950 00:47:31,165 --> 00:47:33,100 IS NOW RESCUED, SO THE VIRUS NO 951 00:47:33,100 --> 00:47:36,403 LONGER IS TEMPERATURE-SENSITIVE 952 00:47:36,403 --> 00:47:42,943 WHEN WE GET RID OF INTERFERON 953 00:47:42,943 --> 00:47:45,679 SIGNALLING. THESE TWO ARE VERY 954 00:47:45,679 --> 00:47:49,250 ENTER TWINED. AND THIS IS TRUE 955 00:47:49,250 --> 00:47:53,320 WITH NL63. SO NL63 IS HIGHLY 956 00:47:53,320 --> 00:47:55,189 TEMPERATURE DEPENDENT, LOWER 957 00:47:55,189 --> 00:47:58,092 TEMPERATURE DEPENDENT FOR 958 00:47:58,092 --> 00:47:59,994 REPLICATION. IF WE LOOK AT -- 959 00:47:59,994 --> 00:48:02,096 AGAIN, AT THE INTERFERON 960 00:48:02,096 --> 00:48:03,297 SIGNALLING RESPONSE WE SEE EARLY 961 00:48:03,297 --> 00:48:06,700 IN INFECTION IT IS MUCH MORE 962 00:48:06,700 --> 00:48:08,936 ROBUST AT 37. AT 24 AND 48 963 00:48:08,936 --> 00:48:10,638 HOURS. WHEN WE GO TO THE LATER 964 00:48:10,638 --> 00:48:12,973 TIMES IT BECOMES MORE ROBUST AT 965 00:48:12,973 --> 00:48:14,541 33 BECAUSE THE VIRUS CLEARLY 966 00:48:14,541 --> 00:48:17,511 DOESN'T REPLICATE OUT HERE AT 967 00:48:17,511 --> 00:48:18,946 37. REPLICATES SO POORLY. AGAIN, 968 00:48:18,946 --> 00:48:23,217 IF WE TREAT THE CELLS WITH RUX, 969 00:48:23,217 --> 00:48:25,986 IT CAN NOW REPLICATE AT 37 970 00:48:25,986 --> 00:48:27,855 DEGREES, SHOWN HERE. JUST LIKE 971 00:48:27,855 --> 00:48:29,623 THE WILD TYPE VIRUS. JUST LIKE 972 00:48:29,623 --> 00:48:35,829 THE 33-DEGREE REPLICATION. SO 973 00:48:35,829 --> 00:48:37,731 INHIBITION OF THE SIGNALLING 974 00:48:37,731 --> 00:48:39,633 RESCUES REPLICATION AT 37. SO 975 00:48:39,633 --> 00:48:42,536 JUST TO SUMMARIZE, SO THE LETHAL 976 00:48:42,536 --> 00:48:44,538 CORONAVIRUS ENCODE ANTAGONISTS 977 00:48:44,538 --> 00:48:49,310 THAT PREVENT INDUCTION OF 978 00:48:49,310 --> 00:48:50,377 INTERFERON SIGNALLING AND 979 00:48:50,377 --> 00:48:52,246 CLEARANCE AND CELLS AND 980 00:48:52,246 --> 00:48:54,048 ACTIVATION OF THE ANTAGONIST 981 00:48:54,048 --> 00:48:55,582 RESULTS IN FINE TYPES THAT 982 00:48:55,582 --> 00:49:01,255 MIRROR COMMON COLD VIRUSES SO WE 983 00:49:01,255 --> 00:49:02,289 CAN FLIP FROM VIRAL LENT TO 984 00:49:02,289 --> 00:49:04,458 COMMON COLD WITH GETTING RID OF 985 00:49:04,458 --> 00:49:06,026 THESE OR ACTIVATING THE 986 00:49:06,026 --> 00:49:07,728 ANTAGONIST. THE OPTIMAL 987 00:49:07,728 --> 00:49:08,796 REPLICATION OF COMMON COLD 988 00:49:08,796 --> 00:49:10,998 CORONAVIRUSES AT 33 IS AT LEAST 989 00:49:10,998 --> 00:49:12,866 PART DUE TO 990 00:49:12,866 --> 00:49:14,335 TEMPERATURE-DEPENDENT INTERFERON 991 00:49:14,335 --> 00:49:16,437 RESPONSES. THIS WAS ALSO SHOWN 992 00:49:16,437 --> 00:49:19,206 EARLIER BY FAIL AND FOXMAN FOR 993 00:49:19,206 --> 00:49:22,176 RHINO VIRUS, SIMILAR KIND OF 994 00:49:22,176 --> 00:49:23,944 FINDING. SO THIS IS ONE MORE -- 995 00:49:23,944 --> 00:49:25,446 THIS IS THE LAST VIGNETTE I'M 996 00:49:25,446 --> 00:49:27,881 GOING TO TALK ABOUT. THAT IS THE 997 00:49:27,881 --> 00:49:29,249 QUESTION OF HAVE SARS 998 00:49:29,249 --> 00:49:30,851 CORONAVIRUS MUTANTS EVOLVED TO 999 00:49:30,851 --> 00:49:33,320 BE MORE SIMILAR TO A COMMON COLD 1000 00:49:33,320 --> 00:49:35,322 VIRUS. SO IT SEEMS, FROM THE 1001 00:49:35,322 --> 00:49:37,558 LITERATURE, FROM OBSERVATIONS, 1002 00:49:37,558 --> 00:49:39,360 THAT THE LATER VARIANTS ARE MORE 1003 00:49:39,360 --> 00:49:41,362 UPPER RESPIRATORY AND MAYBE LESS 1004 00:49:41,362 --> 00:49:43,697 VIRAL LENT SO WE WANTED TO KNOW 1005 00:49:43,697 --> 00:49:45,399 WHETHER THEY ACTUALLY HAD THE 1006 00:49:45,399 --> 00:49:46,200 CHARACTERISTICS WE HAVE 1007 00:49:46,200 --> 00:49:47,401 IDENTIFIED OF THE COMMON COLD 1008 00:49:47,401 --> 00:49:49,036 VIRUSES. SO REPLICATING MORE 1009 00:49:49,036 --> 00:49:50,971 EFFICIENTLY AT LOWER 1010 00:49:50,971 --> 00:49:53,574 TEMPERATURE, INDUCING A ROBUST 1011 00:49:53,574 --> 00:49:54,375 INTERFERON RESPONSE AND 1012 00:49:54,375 --> 00:49:56,543 CLEARANCE FROM THE NASAL 1013 00:49:56,543 --> 00:49:58,379 EPITHELIAL CELLS. SO WE 1014 00:49:58,379 --> 00:50:02,049 INITIALLY INFECTED THESE 1015 00:50:02,049 --> 00:50:05,219 CULTURES WITH WILD-TYPE 1016 00:50:05,219 --> 00:50:07,788 WASHINGTON STRAIN OF SARS COVID 1017 00:50:07,788 --> 00:50:13,394 2, ALPHA, BETA, DELTA AND EARLY 1018 00:50:13,394 --> 00:50:15,029 OMNICHRON VARIANT. ALL VARIANTS 1019 00:50:15,029 --> 00:50:16,597 REPLICATED BETTER THAN WILD TYPE 1020 00:50:16,597 --> 00:50:19,366 TO SOME EXTENT, THOUGH ALL 1021 00:50:19,366 --> 00:50:21,568 REPLICATE QUITE WELL. WE DIDN'T 1022 00:50:21,568 --> 00:50:29,676 GO FAR OUT, BUT OMNICHRON WINS 1023 00:50:29,676 --> 00:50:31,612 THE REPLICATION FOR KINETICS. WE 1024 00:50:31,612 --> 00:50:34,114 WANTED TO KNOW WHAT KIND OF 1025 00:50:34,114 --> 00:50:35,983 INTERFERON RESPONSE DID IT 1026 00:50:35,983 --> 00:50:39,186 INDUCE. WE USE THE RNA SEEK AND 1027 00:50:39,186 --> 00:50:41,321 VOLCANO PLOTS. HERE IS WILD TYPE 1028 00:50:41,321 --> 00:50:43,390 SARS, USED DELTA AS COMPARISON 1029 00:50:43,390 --> 00:50:49,063 AND HERE IS OMNICHRON. I BOXED 1030 00:50:49,063 --> 00:50:53,300 IN THE AREAS. SARS INDUCES A 1031 00:50:53,300 --> 00:50:58,739 SMALL RESPONSE. WILD TYPE SARS, 1032 00:50:58,739 --> 00:51:03,777 DELTA MAYBE SIMILAR BUT OMNICRON 1033 00:51:03,777 --> 00:51:10,384 INDUCES MORE. SO DID SEEM LIKE 1034 00:51:10,384 --> 00:51:12,486 A COMMON COLD VIRUS, THOUGH NOT 1035 00:51:12,486 --> 00:51:14,054 QUITE TO THE EXTENT. WE WANTED 1036 00:51:14,054 --> 00:51:15,689 TO LOOK AT REPLICATION. WE 1037 00:51:15,689 --> 00:51:18,058 THOUGHT IT WOULD PROBABLY HAVE 1038 00:51:18,058 --> 00:51:20,928 REQUIREMENT FOR LOW TEMPERATURE 1039 00:51:20,928 --> 00:51:22,262 REPLICATION BUT WE WERE 1040 00:51:22,262 --> 00:51:24,431 COMPLETELY WRONG. HERE IS 1041 00:51:24,431 --> 00:51:26,867 KINETICS OF WILD TYPE SARS AND 1042 00:51:26,867 --> 00:51:30,337 KINETICS OF BA1. SEEMS TO BE 1043 00:51:30,337 --> 00:51:32,272 INSENSITIVE TO HIGH TEMPERATURES 1044 00:51:32,272 --> 00:51:35,209 SO WE DON'T UNDERSTAND HOW IT 1045 00:51:35,209 --> 00:51:39,012 DOES THAT. THAT SEEMED SORT OF 1046 00:51:39,012 --> 00:51:42,116 QUIZZICAL BECAUSE HOW COULD IT 1047 00:51:42,116 --> 00:51:48,689 SURVIVE AND SPREAD SO WELL. BUT 1048 00:51:48,689 --> 00:51:50,858 THEN WE FOUND IT IS LESS 1049 00:51:50,858 --> 00:51:52,426 SENSITIVE TO TYPE 1 AND 3 1050 00:51:52,426 --> 00:51:53,827 INTERFERON TREATMENT. THAT IS 1051 00:51:53,827 --> 00:51:56,530 SHOWN HERE. HERE IS TYPE 1 1052 00:51:56,530 --> 00:51:58,565 INTERFERON TREATMENT THAT WILD 1053 00:51:58,565 --> 00:52:03,003 TYPE VIRUS IS QUITE SENSITIVE 1054 00:52:03,003 --> 00:52:06,039 WHEREAS OMNICRON IS NOT. FOUND 1055 00:52:06,039 --> 00:52:08,408 BE PRETREATING CELLS. SAME FOR 1056 00:52:08,408 --> 00:52:16,183 LAMBDA AND TYPE 3 INTERFERON, 1057 00:52:16,183 --> 00:52:17,351 MUCH LESS SENSITIVE SO SOMETHING 1058 00:52:17,351 --> 00:52:18,619 WE CAN'T UNDERSTAND. SO IN 1059 00:52:18,619 --> 00:52:21,555 SUMMARY OF THE WHOLE THING, 1060 00:52:21,555 --> 00:52:23,357 CORONAVIRUS ENCODE NONSTRUCTURAL 1061 00:52:23,357 --> 00:52:25,359 PROTEINS AND SUB-GENEROUS 1062 00:52:25,359 --> 00:52:26,860 ACCESSORY PROTEINS THAT 1063 00:52:26,860 --> 00:52:28,462 ANTAGONIZE NATIVE IMMUNE 1064 00:52:28,462 --> 00:52:29,863 RESPONSES. IN FACT, THERE ARE 1065 00:52:29,863 --> 00:52:33,700 LOT MORE ACTIVITIES WITHIN THE 1066 00:52:33,700 --> 00:52:38,639 REPLICASE. LOCIS ON THIS. HAVE 1067 00:52:38,639 --> 00:52:42,809 BUNCH OF CAPPING AND 1068 00:52:42,809 --> 00:52:46,713 METHYL IZATION ENZYMES. COMMON 1069 00:52:46,713 --> 00:52:50,517 COLD LIKE RHINO 16 PREFER LOWER 1070 00:52:50,517 --> 00:52:52,386 AND INDUCE SIGNALLING WHICH 1071 00:52:52,386 --> 00:52:57,791 LEADS TO CLEARANCE. LETHAL VIRUS 1072 00:52:57,791 --> 00:52:59,126 AND MARIE INDUCE AND PERSIST IN 1073 00:52:59,126 --> 00:53:06,934 AIR LIQUID INTERFACE AND ARES AR 1074 00:53:06,934 --> 00:53:08,669 RATED INTO THE LUNG WE BELIEVE 1075 00:53:08,669 --> 00:53:10,704 AND THIS CONTRIBUTES TO 33 1076 00:53:10,704 --> 00:53:13,607 DEGREE FOR COMMON COLD VIRUSES 1077 00:53:13,607 --> 00:53:18,946 AND FOR SARS LATENT INFECTION. 1078 00:53:18,946 --> 00:53:23,584 OMNICRON HAS EVOLVED UNIQUE FINE 1079 00:53:23,584 --> 00:53:24,585 PHENOTYPES AND WE ARE TRYING TO 1080 00:53:24,585 --> 00:53:27,020 LOOK AT THOSE TO SEE HOW THEY 1081 00:53:27,020 --> 00:53:29,289 BEHAVE WITH RESPECT TO 1082 00:53:29,289 --> 00:53:30,591 INTERFERON INDUCTION AND 1083 00:53:30,591 --> 00:53:33,260 TEMPERATURE REQUIREMENTS. THEN 1084 00:53:33,260 --> 00:53:35,329 SO FINALLY INDUCTION OF 1085 00:53:35,329 --> 00:53:36,797 INTERFERON SIGNALLING IN 1086 00:53:36,797 --> 00:53:39,199 EPITHELIAL YUM CAN CONVERT 1087 00:53:39,199 --> 00:53:40,434 LETHAL VIRUS INTO COMMON COLD 1088 00:53:40,434 --> 00:53:45,806 VIRUS. WE ARE WONDERING IF 1089 00:53:45,806 --> 00:53:46,907 INTERFERON IS A POSSIBLE 1090 00:53:46,907 --> 00:53:48,575 THERAPEUTIC APPROACH FOR THESE 1091 00:53:48,575 --> 00:53:51,578 VIRUSES TO SORT OF CONVERT -- 1092 00:53:51,578 --> 00:53:54,214 CONVERT THEM BACK AND FORTH WITH 1093 00:53:54,214 --> 00:53:56,049 INTERFERON TREATMENT. SO JUST 1094 00:53:56,049 --> 00:53:57,584 ACKNOWLEDGE THE PEOPLE IN MY 1095 00:53:57,584 --> 00:53:59,286 LAB. THIS IS MY CURRENT GROUP OF 1096 00:53:59,286 --> 00:54:01,888 PEOPLE. SOME OF THESE -- CLAYTON 1097 00:54:01,888 --> 00:54:04,124 OTTER DID ALMOST ALL THE WORK I 1098 00:54:04,124 --> 00:54:05,792 DESCRIBED IN THE SECOND HALF OF 1099 00:54:05,792 --> 00:54:09,363 THE SEMINAR. HE IS AMAZING. MD 1100 00:54:09,363 --> 00:54:10,464 PHD STUDENT WHO JUST WENT BACK 1101 00:54:10,464 --> 00:54:12,799 TO MEDICAL SCHOOL. THESE ARE MY 1102 00:54:12,799 --> 00:54:15,902 -- NOEM'S BEEN A CLOSE 1103 00:54:15,902 --> 00:54:17,537 COLLABORATOR. HE IS RIGHT HERE. 1104 00:54:17,537 --> 00:54:19,373 BOB SILVERMAN FOR MANY, MANY 1105 00:54:19,373 --> 00:54:22,109 YEARS AND THESE ARE MORE RECENT 1106 00:54:22,109 --> 00:54:25,145 COLLABORATORS, ALL OF THEM GREAT 1107 00:54:25,145 --> 00:54:27,147 COLLABORATORS AND FUNDING IS 1108 00:54:27,147 --> 00:54:31,251 FROM NIH. I WILL STOP THERE. 1109 00:54:31,251 --> 00:54:35,756 [ APPLAUSE ] 1110 00:54:35,756 --> 00:54:35,922 1111 00:54:35,922 --> 00:54:40,794 >> IF ANYONE HAS QUESTIONS, USE 1112 00:54:40,794 --> 00:54:42,496 THE MICS. YEAH, QUESTIONS. MAYBE 1113 00:54:42,496 --> 00:54:44,598 I WILL GET STARTED. SO YOU 1114 00:54:44,598 --> 00:54:45,832 MENTIONED IN THE INTRODUCTION 1115 00:54:45,832 --> 00:54:49,169 THAT ONE OF THE EARLY SEASONAL 1116 00:54:49,169 --> 00:54:52,205 CORONAVIRUSES THAT EMERGED IN 1117 00:54:52,205 --> 00:54:58,912 THE 1890s, OC43 WAS HIGHLY 1118 00:54:58,912 --> 00:55:00,814 PATHOGENIC, OR THOUGHT TO BE. IS 1119 00:55:00,814 --> 00:55:01,615 THERE ANYTHING KNOWN ABOUT 1120 00:55:01,615 --> 00:55:04,017 WHETHER THE VIRUS CHANGED 1121 00:55:04,017 --> 00:55:05,218 SUBSEQUENT TO THAT INITIAL -- OR 1122 00:55:05,218 --> 00:55:08,221 WHETHER IT WITH WAS THE 1123 00:55:08,221 --> 00:55:09,356 POST-POPULATION ISSUE OR DRIFT 1124 00:55:09,356 --> 00:55:14,828 OR IS THERE ANY REMNANTS OF ANY 1125 00:55:14,828 --> 00:55:16,129 ISOLATES AVAILABLE FROM THOSE -- 1126 00:55:16,129 --> 00:55:18,598 >> I DON'T KNOW. IT IS SORT OF 1127 00:55:18,598 --> 00:55:22,202 LIKE WONDERING WHETHER OMNICRON 1128 00:55:22,202 --> 00:55:23,403 BECOMING LESS UPPER RESPIRATORY 1129 00:55:23,403 --> 00:55:25,238 HAS TO DO WITH VACCINE OR 1130 00:55:25,238 --> 00:55:26,840 CHANGES IN THE VIRUS. I DO THINK 1131 00:55:26,840 --> 00:55:30,477 FOR EXAMPLE 229A, THEY HAVE TWO 1132 00:55:30,477 --> 00:55:32,045 SMALL OPEN READING FRAMES THAT 1133 00:55:32,045 --> 00:55:38,819 USED TO -- IN THE MORE CLINICAL 1134 00:55:38,819 --> 00:55:40,587 ISOLATES WERE ONE AND ANTAGONIST 1135 00:55:40,587 --> 00:55:42,289 SO IT IS POSSIBLE THEY HAVE LOST 1136 00:55:42,289 --> 00:55:48,695 SOME OF THOSE ANTAGONIST -- 1137 00:55:48,695 --> 00:55:50,464 >> INOCULATING THE HOST? 1138 00:55:50,464 --> 00:55:53,400 >> THAT IS WHY OMNICROM 1139 00:55:53,400 --> 00:55:55,669 SURVIVES, IT DOESN'T KILL THE 1140 00:55:55,669 --> 00:55:59,539 HOST. I MEAN, SIMPLISTICALLY. 1141 00:55:59,539 --> 00:56:00,474 >> YES. 1142 00:56:00,474 --> 00:56:02,642 >> THANK YOU. VERY CLEAN AND 1143 00:56:02,642 --> 00:56:05,579 CLEAR LECTURE. I WAS WONDERING A 1144 00:56:05,579 --> 00:56:08,448 COUPLE THINGS. SO ONE, THE 1145 00:56:08,448 --> 00:56:10,350 INTERFERON ISSUE CANNOT BE THE 1146 00:56:10,350 --> 00:56:12,285 SOLE DRIVER FOR TEMPERATURE 1147 00:56:12,285 --> 00:56:13,420 DIFFERENTIAL, RIGHT, BECAUSE 1148 00:56:13,420 --> 00:56:15,322 ISN'T WORKING IN CASE OF THE 1149 00:56:15,322 --> 00:56:16,390 LAST VARIANT -- 1150 00:56:16,390 --> 00:56:18,191 >> SAY THAT AGAIN? 1151 00:56:18,191 --> 00:56:20,227 >> THE INTERFERON RESPONSES 1152 00:56:20,227 --> 00:56:21,995 CANNOT BE THE ONLY DRIVER OF 1153 00:56:21,995 --> 00:56:22,996 TEMPERATURE DIFFERENTIAL. I WAS 1154 00:56:22,996 --> 00:56:24,931 WONDERING IF THERE ARE OTHER 1155 00:56:24,931 --> 00:56:26,466 HYPOTHESIS YOU ARE WORKING ON. 1156 00:56:26,466 --> 00:56:28,602 >> OKAY, SO -- WELL, COULD BE A 1157 00:56:28,602 --> 00:56:30,437 MAJOR DRIVER OF IT, I THINK. WE 1158 00:56:30,437 --> 00:56:32,873 DID -- WE HAVE LOOKED AT LIKE 1159 00:56:32,873 --> 00:56:34,741 THE THERMAL STABILITY OF THE 1160 00:56:34,741 --> 00:56:35,942 ACTUALLY VIRUS PARTICLES, FOR 1161 00:56:35,942 --> 00:56:37,043 ALL THESE. THEY ARE REALLY ALL 1162 00:56:37,043 --> 00:56:39,980 THE SAME. SO IT IS NOT INHERENT 1163 00:56:39,980 --> 00:56:42,516 IN THE VIRION. IF THAT IS 1164 00:56:42,516 --> 00:56:44,951 UNTABLE -- ORIGINALLY I THOUGHT 1165 00:56:44,951 --> 00:56:50,023 IT WOULD BE EN ENZYMES BUT THE 1166 00:56:50,023 --> 00:56:51,892 FACT WE TREAT WITH RUX AND GET 1167 00:56:51,892 --> 00:56:54,961 RID OF INTERFERON SIGNALLING, 1168 00:56:54,961 --> 00:56:56,897 LOSES THAT SENSITIVITY, TELLS ME 1169 00:56:56,897 --> 00:57:00,700 IT IS PROBABLY A MAJOR 1170 00:57:00,700 --> 00:57:01,034 EXPLANATION. 1171 00:57:01,034 --> 00:57:03,637 >> THAT DOESN'T WORK FOR THE 1172 00:57:03,637 --> 00:57:05,372 OMNI CRON THOUGH? 1173 00:57:05,372 --> 00:57:09,543 >> I DON'T UNDERSTAND OMNICRONS 1174 00:57:09,543 --> 00:57:10,010 SO -- 1175 00:57:10,010 --> 00:57:11,511 >> MUST BE OTHER ISSUE. 1176 00:57:11,511 --> 00:57:12,846 >> THEY ARE NOT TEMPERATURE 1177 00:57:12,846 --> 00:57:14,748 SENSITIVE. I DON'T KNOW. I HAVE 1178 00:57:14,748 --> 00:57:16,883 NO IDEA WHAT GENES OR WHAT 1179 00:57:16,883 --> 00:57:19,453 PROTEINS IN OMNICRON ARE GIVING 1180 00:57:19,453 --> 00:57:20,954 THAT. I COULDN'T BELIEVE THAT 1181 00:57:20,954 --> 00:57:22,122 RESULT. SEEMED VERY STRANGE. 1182 00:57:22,122 --> 00:57:27,127 >> THE OTHER QUESTION I HAD, THE 1183 00:57:27,127 --> 00:57:30,297 CULTURE DATA CLEARLY DEMONSTRATE 1184 00:57:30,297 --> 00:57:34,968 THAT WHEN THE INFECTION IS UPPER 1185 00:57:34,968 --> 00:57:38,538 RESPIRATORY CONFINED, IS 1186 00:57:38,538 --> 00:57:39,439 SELF-LIMITING, WITH CONTRIBUTION 1187 00:57:39,439 --> 00:57:45,479 WITH INTERFERON RESPONSE. IN 1188 00:57:45,479 --> 00:57:47,581 TERMS OF THE ADAPTIVE IMMUNE 1189 00:57:47,581 --> 00:57:49,049 RESPONSE, WHAT IS THE DEAL? 1190 00:57:49,049 --> 00:57:51,084 >> SO WE ARE -- THAT IS ONE OF 1191 00:57:51,084 --> 00:57:53,620 THE THINGS WE HAVE BEEN TRYING 1192 00:57:53,620 --> 00:57:58,058 TO DO. PUT MACROPHAGES OR OTHERS 1193 00:57:58,058 --> 00:58:00,894 INTO THE CELL CULTURES. NOT 1194 00:58:00,894 --> 00:58:01,895 EASY. THIS CAN ONLY TELL US 1195 00:58:01,895 --> 00:58:04,130 ABOUT EARLY STEPS BEFORE THERE 1196 00:58:04,130 --> 00:58:05,866 IS ADAPTIVE IMMUNITY. A 1197 00:58:05,866 --> 00:58:07,267 LIMITATION, FOR SURE. 1198 00:58:07,267 --> 00:58:08,568 >> YOU MENTIONED YOU USE NUMBER 1199 00:58:08,568 --> 00:58:10,837 OF DIFFERENT DONORS IN THESE 1200 00:58:10,837 --> 00:58:13,039 PRIMARY NASAL EPITHELIAL 1201 00:58:13,039 --> 00:58:14,341 CULTURES. IF YOU LOOK AT 1202 00:58:14,341 --> 00:58:17,344 INDIVIDUAL DONOR, DO YOU SEE 1203 00:58:17,344 --> 00:58:19,045 EVIDENCE OF STRONG DONOR 1204 00:58:19,045 --> 00:58:20,914 DEPENDENCE? IS THERE ANY WAY 1205 00:58:20,914 --> 00:58:24,918 POTENTIALLY TO LINK THAT BACK TO 1206 00:58:24,918 --> 00:58:26,820 PATHOGENISIS AND THE 1207 00:58:26,820 --> 00:58:28,722 INDIVIDUAL'S HOME CELLS DRIVE. 1208 00:58:28,722 --> 00:58:30,156 >> I'M REALLY GLAD YOU ASKED 1209 00:58:30,156 --> 00:58:33,026 THAT QUESTION. THE MOST STRIKING 1210 00:58:33,026 --> 00:58:35,295 THING WE FOUND -- IN BEGINNING 1211 00:58:35,295 --> 00:58:37,130 WE DID INDIVIDUAL DONORS. TURNS 1212 00:58:37,130 --> 00:58:38,798 OUT WHEN YOU AVERAGE IT IS THE 1213 00:58:38,798 --> 00:58:40,200 SAME. THE MOST STRIKING THING IS 1214 00:58:40,200 --> 00:58:42,536 THERE ARE A LOT OF DONORS THAT 1215 00:58:42,536 --> 00:58:46,072 SEEM ALMOST RESISTANT TO MERS 1216 00:58:46,072 --> 00:58:47,107 INFECTION COMPLETELY. THAT IS 1217 00:58:47,107 --> 00:58:48,408 SOMETHING WE ARE REALLY TRYING 1218 00:58:48,408 --> 00:58:50,610 TO UNDERSTAND NOW. WE ARE ALSO 1219 00:58:50,610 --> 00:58:53,747 LOOKING AT BRONCHIAL CULTURES 1220 00:58:53,747 --> 00:58:55,882 FROM SAME PERSON, NASAL AND 1221 00:58:55,882 --> 00:58:58,018 BRONCHIAL AND HOW THEY MAY 1222 00:58:58,018 --> 00:59:00,754 DIFFER. BUT THE MERS -- IN THE 1223 00:59:00,754 --> 00:59:03,223 PATIENTS OR DONORS THAT ARE SO 1224 00:59:03,223 --> 00:59:05,358 INSENSITIVE TO MERS SEEM MORE 1225 00:59:05,358 --> 00:59:07,460 SUSCEPTIBLE TO SARS. THE OTHER 1226 00:59:07,460 --> 00:59:10,463 THING WE DID FIND IS IF WE TREAT 1227 00:59:10,463 --> 00:59:13,867 THESE WITH IL13, A SORT OF 1228 00:59:13,867 --> 00:59:16,169 ASTHMA MIMIC -- MIMICS ASTHMA, 1229 00:59:16,169 --> 00:59:18,772 WE GET A TILTING TOWARD GOBLET 1230 00:59:18,772 --> 00:59:21,074 CELLS. I DIDN'T MENTION THIS BUT 1231 00:59:21,074 --> 00:59:26,279 MERS INFECTS GOBLET, SARS 1232 00:59:26,279 --> 00:59:30,450 AFFECTS CILIA CELLS. SO MAY BE 1233 00:59:30,450 --> 00:59:32,085 PEOPLE WITH MORE GOBLET CELLS, 1234 00:59:32,085 --> 00:59:34,588 THAT MAY BE A DIFFERENCE -- ALSO 1235 00:59:34,588 --> 00:59:37,891 LOOKING AT PEOPLE WITH SORT OF 1236 00:59:37,891 --> 00:59:40,794 CHRONIC RHINO SINUSITIS SO THERE 1237 00:59:40,794 --> 00:59:46,299 IS DIFFERENCES AMONG THE 1238 00:59:46,299 --> 00:59:46,900 INDIVIDUALS. 1239 00:59:46,900 --> 00:59:49,336 >> I'M SURE YOU KNOW TOGETHER 1240 00:59:49,336 --> 00:59:52,505 TRIALS SHOWED THAT LAMBDA 1 WAS 1241 00:59:52,505 --> 00:59:54,708 PRETTY EFFECTIVE OF GIVEN EARLY. 1242 00:59:54,708 --> 00:59:58,545 WONDERING YOUR THOUGHTS ON THAT. 1243 00:59:58,545 --> 01:00:01,915 WHETHER YOU THINK INTRA NASAL, 1244 01:00:01,915 --> 01:00:03,216 LAMBDAL OR OTHER INTERFERENCE 1245 01:00:03,216 --> 01:00:04,784 WOULD BE SUPERIOR. 1246 01:00:04,784 --> 01:00:06,820 >> I DON'T REALLY -- FROM MY OWN 1247 01:00:06,820 --> 01:00:09,823 EXPERIENCE I DON'T KNOW. SOUNDS 1248 01:00:09,823 --> 01:00:11,925 LIKE SOMETHING THAT COULD BE 1249 01:00:11,925 --> 01:00:14,494 TRIED. I MEAN, IT DOES SEEM TO 1250 01:00:14,494 --> 01:00:15,061 WORK. 1251 01:00:15,061 --> 01:00:15,195 1252 01:00:15,195 --> 01:00:18,431 >> WE HAVE A COUPLE QUESTIONS 1253 01:00:18,431 --> 01:00:20,066 ONLINE. HOWARD YOUNG IN 1254 01:00:20,066 --> 01:00:21,568 FREDERICK. LOW DOSE ORAL 1255 01:00:21,568 --> 01:00:24,571 INTERFERON IS REPORTED TO HAVE 1256 01:00:24,571 --> 01:00:25,872 ANTI VIRAL ACTIVITY. 1257 01:00:25,872 --> 01:00:27,874 >> WHAT KIND? 1258 01:00:27,874 --> 01:00:29,576 >> LOW DOSE ORAL INTERFERON. 1259 01:00:29,576 --> 01:00:31,578 >> WE HAVEN'T DONE THAT. I THINK 1260 01:00:31,578 --> 01:00:36,316 IT SOUNDS LIKE IT MAKES SENSE. 1261 01:00:36,316 --> 01:00:38,818 >> ADAM K, PERHAPS I MISSED BUT 1262 01:00:38,818 --> 01:00:41,321 IN NASAL EPITHELIAL YUM BEHAVING 1263 01:00:41,321 --> 01:00:42,656 IN UNIQUE WAYS WITH CORONAVIRUS 1264 01:00:42,656 --> 01:00:44,858 COMPARED TO OTHERS OR IS IT JUST 1265 01:00:44,858 --> 01:00:45,592 DOING ITS REGULAR DUTY? 1266 01:00:45,592 --> 01:00:47,394 >> I THINK IT IS DOING ITS 1267 01:00:47,394 --> 01:00:49,396 REGULAR DUTY? THE REASON WE USED 1268 01:00:49,396 --> 01:00:51,197 THE RHINO WAS TO KIND OF HAVE A 1269 01:00:51,197 --> 01:00:53,867 CONTROL THAT WOULD BE AN 1270 01:00:53,867 --> 01:00:55,435 ORDINARY COMMON COLD VIRUS, 1271 01:00:55,435 --> 01:00:57,470 COMPLETELY DIFFERENT TYPE OF 1272 01:00:57,470 --> 01:01:00,707 VIRUS. ONE'S MEMBRANE, ONE IS 1273 01:01:00,707 --> 01:01:02,075 NON-MEMBRANE, REALLY DIFFERENT. 1274 01:01:02,075 --> 01:01:03,943 TO THAT EXTENT I WOULD THINK IT 1275 01:01:03,943 --> 01:01:07,180 IS DOING ITS NORMAL JOB. 1276 01:01:07,180 --> 01:01:09,883 >> ANYBODY ELSE? ALL RIGHT. 1277 01:01:09,883 --> 01:01:11,918 LET'S THANK SUSAN FOR A 1278 01:01:11,918 --> 01:01:14,421 BEAUTIFUL SEMINAR. 1279 01:01:14,421 --> 01:01:14,754 [ APPLAUSE ] 1280 01:01:14,754 --> 01:01:14,888 1281 01:01:14,888 --> 01:01:19,325 >> THERE WILL BE A RECEPTION 1282 01:01:19,325 --> 01:01:20,527 OUTSIDE. THANK YOU. 1283 01:01:20,527 --> 01:01:21,327 HOPEFULLY IT IS THERE.