1 00:00:08,908 --> 00:00:11,611 >> SO IT GIVES ME GREAT PLEASURE 2 00:00:11,678 --> 00:00:14,881 TO INTRODUCE TO YOU A 3 00:00:14,948 --> 00:00:16,416 LONG-STANDING COLLEAGUE AND 4 00:00:16,483 --> 00:00:17,951 FRIEND, SUBASH BABU, WHO'S GOING 5 00:00:18,017 --> 00:00:20,787 TO GIVE TODAY'S IIG SEMINAR. 6 00:00:20,854 --> 00:00:24,391 A LITTLE BIT ABOUT SUBASH, HE 7 00:00:24,457 --> 00:00:28,762 RECEIVED HIS -- FROM INDIA AND 8 00:00:28,828 --> 00:00:32,832 EARNED A PH.D. IN IMMUNOLOGY AT 9 00:00:32,899 --> 00:00:35,769 THE UNIVERSITY OF CONNECTICUT. 10 00:00:35,835 --> 00:00:37,303 DURING HIS TIME AS A GRADUATE 11 00:00:37,370 --> 00:00:39,939 STUDENT, HE MADE THESE 12 00:00:40,006 --> 00:00:43,109 INCREDIBLE SEMINOLE 13 00:00:43,176 --> 00:00:43,977 CONTRIBUTIONS TO THE 14 00:00:44,043 --> 00:00:45,078 UNDERSTANDING OF FILARIAL 15 00:00:45,145 --> 00:00:46,045 INFECTIONS, SOMETHING THAT'S 16 00:00:46,112 --> 00:00:47,814 NEAR AND DEAR TO MY HEART, USING 17 00:00:47,881 --> 00:00:49,749 MOUSE MODELS. 18 00:00:49,816 --> 00:00:54,053 AND THESE REALLY LED TO A GREAT 19 00:00:54,120 --> 00:00:56,222 LEAP FORWARD GENERALLY IN THE 20 00:00:56,289 --> 00:00:56,556 FIELD. 21 00:00:56,623 --> 00:00:58,625 THEN WE WERE REALLY LUCKY TO 22 00:00:58,691 --> 00:01:01,694 RECRUIT HIM AFTER HIS PH.D. AT 23 00:01:01,761 --> 00:01:03,329 THE HELMINTH IMMUNOLOGY SECTION 24 00:01:03,396 --> 00:01:06,166 IN THE NIAID, WHERE HE WAS A 25 00:01:06,232 --> 00:01:07,901 VISITING FELLOW FOR ABOUT FIVE 26 00:01:07,967 --> 00:01:11,304 YEARS AND HE CONDUCTED RESEARCH 27 00:01:11,371 --> 00:01:14,274 ON HUMAN RESPONSES TO FILARIAL 28 00:01:14,340 --> 00:01:14,808 INFECTIONS. 29 00:01:14,874 --> 00:01:18,311 AND THEN AFTER AN INCREDIBLY 30 00:01:18,378 --> 00:01:19,446 PRODUCTIVE FIVE YEARS, HE BECAME 31 00:01:19,512 --> 00:01:22,749 A STAFF SCIENTIST HERE, BUT SOON 32 00:01:22,816 --> 00:01:28,755 THEREAFTER, MOVED TO AND HELPED 33 00:01:28,822 --> 00:01:36,629 ESTABLISH WHAT WAS THE LPD ICMR 34 00:01:36,696 --> 00:01:38,264 CHENNAI ICER, THESE ARE 35 00:01:38,331 --> 00:01:39,132 INTERNATIONAL CENTERS FOR 36 00:01:39,199 --> 00:01:39,899 EXCELLENCE IN RESEARCH. 37 00:01:39,966 --> 00:01:42,869 AND HE'S ACTUALLY BEEN THERE ON 38 00:01:42,936 --> 00:01:47,006 THE GROUND SINCE THEN, AND IS 39 00:01:47,073 --> 00:01:49,742 CURRENTLCURRENTLY ITS SCIENTIFIC 40 00:01:49,809 --> 00:01:50,510 DIRECTOR. 41 00:01:50,577 --> 00:01:53,346 OVER THESE LAST 20 YEARS, 42 00:01:53,413 --> 00:01:55,014 ALMOST, HE AND HIS COLLEAGUES IN 43 00:01:55,081 --> 00:01:58,051 INDIA HAVE MADE INCREDIBLE 44 00:01:58,117 --> 00:02:01,454 CONTRIBUTIONS TO THE IMMUNOLOGY 45 00:02:01,521 --> 00:02:04,090 OF HUMAN HELMINTH INFECTIONS AS 46 00:02:04,157 --> 00:02:10,763 WELL AS IMMUNOLOGY OF TB IN 47 00:02:10,830 --> 00:02:13,466 HUMANS. 48 00:02:13,533 --> 00:02:18,605 HE HAD THREE SORT OF BROAD AREAS 49 00:02:18,671 --> 00:02:20,039 OF RESEARCH, ONE SORT OF 50 00:02:20,106 --> 00:02:21,674 MECHANISM UNDERLYING 51 00:02:21,741 --> 00:02:23,643 PATHOGENESIS OF FILARIAL 52 00:02:23,710 --> 00:02:25,311 INFECTIONS, A SECOND ABOUT THE 53 00:02:25,378 --> 00:02:28,581 INFLUENCE OF SOIL TRANSMITTED 54 00:02:28,648 --> 00:02:30,416 HELMINTHS ON THE OUTCOMES OF 55 00:02:30,483 --> 00:02:33,052 METABOLIC DISORDERS AND OTHER 56 00:02:33,119 --> 00:02:34,721 INFECTIOUS NON-PARASITIC 57 00:02:34,787 --> 00:02:36,122 INFECTIOUS DISORDERS, AND THEN 58 00:02:36,189 --> 00:02:40,393 THE INTERFACE BETWEEN TB AND 59 00:02:40,460 --> 00:02:43,997 HELMINTH INFECTIONS AS WELL AS 60 00:02:44,063 --> 00:02:44,564 DIABETES. 61 00:02:44,631 --> 00:02:45,632 SO THROUGHOUT THE 20 YEARS THAT 62 00:02:45,698 --> 00:02:47,267 I'VE KNOWN HIM, HE'S COMMITTED 63 00:02:47,333 --> 00:02:48,935 HIMSELF TO KIND OF APPLYING BOTH 64 00:02:49,002 --> 00:02:52,305 BASIC AND TRANSLATIONAL RESEARCH 65 00:02:52,372 --> 00:02:55,041 TO IMPORTANT PUBLIC HEALTH 66 00:02:55,108 --> 00:02:56,242 IMPLICATIONS, AND AS A 67 00:02:56,309 --> 00:02:58,878 CONSEQUENCE OR WHILE DOING THIS, 68 00:02:58,945 --> 00:03:01,180 HE'S MENTORED AN EXTRAORDINARY 69 00:03:01,247 --> 00:03:04,017 NUMBER OF GRADUATE STUDENTS AND 70 00:03:04,083 --> 00:03:05,752 MASTERS STUDENTS AND 71 00:03:05,818 --> 00:03:07,620 UNDERGRADUATES IN INDIA, AND AS 72 00:03:07,687 --> 00:03:08,855 A CONSEQUENCE, HAS RECEIVED 73 00:03:08,922 --> 00:03:11,457 MULTIPLE AWARDS FOR HIS WORK. 74 00:03:11,524 --> 00:03:16,062 SO HE'S BACK HERE, AND SO IT 75 00:03:16,129 --> 00:03:18,231 GIVES ME REALLY GREAT PLEASURE 76 00:03:18,298 --> 00:03:20,867 TO HAVE HIM GIVE TODAY'S IIG 77 00:03:20,934 --> 00:03:21,301 LECTURE. 78 00:03:21,367 --> 00:03:23,403 SO THANKS. 79 00:03:23,469 --> 00:03:33,446 [APPLAUSE] 80 00:03:33,513 --> 00:03:34,881 >> GOOD AFTERNOON, EVERYONE. 81 00:03:34,948 --> 00:03:35,515 THANK YOU FOR COMING. 82 00:03:35,582 --> 00:03:37,817 THANK YOU SO MUCH, TOM, FOR THE 83 00:03:37,884 --> 00:03:39,652 KIND INTRODUCTION, AND THANKS TO 84 00:03:39,719 --> 00:03:41,087 JULIE FOR HELPING ME OUT WITH 85 00:03:41,154 --> 00:03:42,055 ALL THE ARRANGEMENTS FOR THIS 86 00:03:42,121 --> 00:03:44,157 TALK TODAY. 87 00:03:44,223 --> 00:03:45,792 SO AS TOM MENTIONED, I'M GOING 88 00:03:45,858 --> 00:03:49,929 TO BE TALKING ABOUT IMMUNE 89 00:03:49,996 --> 00:03:52,031 RESPONSES, HUMAN IMMUNE 90 00:03:52,098 --> 00:03:57,070 RESPONSES, SPECIFICALLY 91 00:03:57,136 --> 00:03:58,104 PARASITIC INFECTION FOR 92 00:03:58,171 --> 00:03:59,138 STRONGYLOIDES STERCORALIS AND 93 00:03:59,205 --> 00:04:01,441 IMPLICATIONS FOR THE IMMUNE 94 00:04:01,507 --> 00:04:03,409 RESPONSE BY HELMINTH ON BOTH THE 95 00:04:03,476 --> 00:04:04,577 CLINICAL PICTURE AS WELL AS 96 00:04:04,644 --> 00:04:07,447 IMMUNE RESPONSES, TWO VERY 97 00:04:07,513 --> 00:04:09,983 DIVERSE DISEASE PROCESSES, 98 00:04:10,049 --> 00:04:11,284 TUBERCULOSIS AND TYPE 99 00:04:11,351 --> 00:04:12,752 2 DIABETES. 100 00:04:12,819 --> 00:04:14,787 SO BEFORE I GO ON, I JUST WANTED 101 00:04:14,854 --> 00:04:16,756 TO GIVE A BRIEF INTRODUCTION OF 102 00:04:16,823 --> 00:04:18,625 OUR PROGRAM. 103 00:04:18,691 --> 00:04:23,296 SO THE INTERNATIONAL CENTER FOR 104 00:04:23,363 --> 00:04:30,303 EXCELLENCE IN RESEARCH IN INDIA 105 00:04:30,370 --> 00:04:31,738 WERE ESTABLISHED IN THE 2000s, 106 00:04:31,804 --> 00:04:35,008 WE ARE BASICALLY LOCATED IN 107 00:04:35,074 --> 00:04:36,409 CHENNAI, A CITY IN SOUTH INDIA 108 00:04:36,476 --> 00:04:38,611 WITH THE POPULATION OF ABOUT 109 00:04:38,678 --> 00:04:39,045 12 MILLION PEOPLE. 110 00:04:39,112 --> 00:04:42,448 OUR RESEARCH MISSION IS TO BE A 111 00:04:42,515 --> 00:04:45,318 SECTOR FOR RESEARCH ON PARASITIC 112 00:04:45,385 --> 00:04:46,285 INFECTIONS, TUBERCULOSIS, HIV 113 00:04:46,352 --> 00:04:48,788 AND OTHER DISEASES, WITH A MAJOR 114 00:04:48,855 --> 00:04:51,524 FOCUS ON DISEASE INTERACTIONS. 115 00:04:51,591 --> 00:04:54,060 AND THIS CENTER IS BASICALLY A 116 00:04:54,127 --> 00:04:56,863 COLLABORATION BETWEEN NIAID AND 117 00:04:56,929 --> 00:04:58,731 THE INDIAN COUNCIL OF MEDICAL 118 00:04:58,798 --> 00:05:00,600 RESEARCH, WHICH IS THE -- PRETTY 119 00:05:00,667 --> 00:05:05,304 MUCH THE NIH EQUAL OF INDIA. 120 00:05:05,371 --> 00:05:08,808 AS TOM MENTIONED, WE WORK ON A 121 00:05:08,875 --> 00:05:12,745 VARIETY OF RESEARCH AREAS. 122 00:05:12,812 --> 00:05:14,614 OUR RESEARCH PORTFOLIO MAINLY 123 00:05:14,681 --> 00:05:16,149 FOCUSED ON HELMINTHS, STARTING 124 00:05:16,215 --> 00:05:22,388 OFF WITH LYMPHATIC FILARIASIS. 125 00:05:22,455 --> 00:05:24,657 WE ALSO DO A LOT OF WORK ON 126 00:05:24,724 --> 00:05:26,626 TUBERCULOSIS, MAINLY LOOKING AT 127 00:05:26,693 --> 00:05:29,362 IMMUNOLOGY AS WELL AS BIOMARKER 128 00:05:29,429 --> 00:05:31,564 DISCOVERY IN PULMONARY AND EXTRA 129 00:05:31,631 --> 00:05:32,765 PULMONARY FORMS OF TB. 130 00:05:32,832 --> 00:05:35,068 WE WORK ON VIROLOGY AS WELL, 131 00:05:35,134 --> 00:05:37,904 VIRAL INFECTIONS INCLUDING 132 00:05:37,970 --> 00:05:40,206 COVID-19, HIV, AND A VARIETY OF 133 00:05:40,273 --> 00:05:42,041 VIRAL COINFECTIONS, AND AS WELL 134 00:05:42,108 --> 00:05:44,577 AS MISCELLANEOUS -- MULTISYSTEM 135 00:05:44,644 --> 00:05:45,344 INFLAMMATORY SYNDROME IN 136 00:05:45,411 --> 00:05:47,980 CHILDREN. 137 00:05:48,047 --> 00:05:49,615 OUR NICHE AREA IS LOOKING AT 138 00:05:49,682 --> 00:05:51,684 COINFECTIONS AND COMORBIDITIES, 139 00:05:51,751 --> 00:05:55,421 WHEREIN WE DON'T LACK AT -- IN 140 00:05:55,488 --> 00:05:56,823 SILO BUT RATHER DISEASE 141 00:05:56,889 --> 00:05:58,224 INTERACTIONS BETWEEN INFECTIONS 142 00:05:58,291 --> 00:06:00,226 AND OTHER MORBIDITIES. 143 00:06:00,293 --> 00:06:05,298 A FEW EXAMPLES OF THAT ARE DM 144 00:06:05,364 --> 00:06:08,634 AND TB, UNDERNUTRITION AND TB, 145 00:06:08,701 --> 00:06:15,842 HEL MIHELMINTHS AND TB, HELMINTD 146 00:06:15,908 --> 00:06:20,780 DM AND SI VIRUSES AND TB. 147 00:06:20,847 --> 00:06:22,215 THE TWO MAJOR VACCINES THAT WE 148 00:06:22,281 --> 00:06:27,120 WORK ON, ONE IS BCG, THE VACCINE 149 00:06:27,186 --> 00:06:28,321 AGAINST TUBERCULOSIS, AND THE 150 00:06:28,387 --> 00:06:30,823 OTHER, THE TWO MAJOR COVID-19 151 00:06:30,890 --> 00:06:32,925 VACCINES THAT ARE ADMINISTERED 152 00:06:32,992 --> 00:06:36,963 IN INDIA, COVAXIN AND 153 00:06:37,029 --> 00:06:37,263 COVISHIELD. 154 00:06:37,330 --> 00:06:38,731 SO WITH THAT BACKGROUND, MY TALK 155 00:06:38,798 --> 00:06:40,466 IS GOING TO BE FOCUSED ON FOUR 156 00:06:40,533 --> 00:06:44,070 MAJOR RESEARCH AREAS. 157 00:06:44,137 --> 00:06:45,171 SO INITIALLY I'M GOING TO WALK 158 00:06:45,238 --> 00:06:47,540 YOU THROUGH A BACKGROUND ON 159 00:06:47,607 --> 00:06:48,174 STRONGYLOIDES STERCORALIS 160 00:06:48,241 --> 00:06:48,875 INFECTION BECAUSE THIS IS NOT 161 00:06:48,941 --> 00:06:51,944 SOMETHING THAT IS COMMONLY 162 00:06:52,011 --> 00:06:52,712 UNDERSTOOD. 163 00:06:52,779 --> 00:06:55,248 I'M GOING TO TALK A GREAT DEAL 164 00:06:55,314 --> 00:06:58,351 WITH THE HUMAN RESPONSE TO 165 00:06:58,417 --> 00:06:59,185 STRONGYLOIDES STERCORALIS 166 00:06:59,252 --> 00:06:59,886 INFECTION AND THEN TALK TO YOU A 167 00:06:59,952 --> 00:07:05,091 LITTLE BIT ABOUT THE BYSTANDER 168 00:07:05,158 --> 00:07:07,059 EFFECT ON TUBERCULOSIS AND TYPE 169 00:07:07,126 --> 00:07:07,493 2 DIABETES. 170 00:07:07,560 --> 00:07:09,028 SO AS MOST OF YOU MIGHT ALREADY 171 00:07:09,095 --> 00:07:13,166 KNOW, HELMINTH INFECTIONS ARE A 172 00:07:13,232 --> 00:07:17,537 MAJOR AFFLICTION IN TERMS OF THE 173 00:07:17,603 --> 00:07:18,871 INFECTIONS AFFECTING THE GLOBAL 174 00:07:18,938 --> 00:07:21,507 HEALTH MAJORITY, SO HELMINTH 175 00:07:21,574 --> 00:07:24,110 INFECTIONS AFFECT ABOUT 176 00:07:24,177 --> 00:07:25,545 2 BILLION PEOPLE WORLDWIDE AND 177 00:07:25,611 --> 00:07:28,581 ARE BROADLY CLASSIFIED INTO 178 00:07:28,648 --> 00:07:36,355 THREE TYPES, INCLUDING EC HMENT 179 00:07:36,422 --> 00:07:42,261 INOCOCCUS TAENIA, AND WHAT I AM 180 00:07:42,328 --> 00:07:45,565 PARTICULARLY INTERESTED IN, THE 181 00:07:45,631 --> 00:07:49,535 HOOK WORMS, FILARIAL WORMS, ALL 182 00:07:49,602 --> 00:07:51,337 OF WHICH AFFECT ANYWHERE FROM 183 00:07:51,404 --> 00:07:52,371 500 MILLION PEOPLE TO 184 00:07:52,438 --> 00:07:54,507 800 MILLION PEOPLE, SO IT'S A 185 00:07:54,574 --> 00:07:58,144 HUGE PROBLEM GLOBALLY. 186 00:07:58,211 --> 00:08:00,079 AND HELMINTH INFECTIONS ARE ALSO 187 00:08:00,146 --> 00:08:01,747 INTERESTING TO IMMUNOLOGISTS 188 00:08:01,814 --> 00:08:05,017 MAINLY BECAUSE OF THE 189 00:08:05,084 --> 00:08:08,087 STEREOTYPICAL RESPONSES TO THE 190 00:08:08,154 --> 00:08:09,722 USUALLY -- THE HOST. 191 00:08:09,789 --> 00:08:11,324 SO THE INTERACTION BETWEEN THE 192 00:08:11,390 --> 00:08:13,793 EARLY STAGE LARVAE OR EGGS OF 193 00:08:13,860 --> 00:08:18,130 THE PARASITE WITH THE HOST 194 00:08:18,197 --> 00:08:19,899 IMMUNE SYSTEM TYPICALLY INDUCES 195 00:08:19,966 --> 00:08:22,735 A CLASSICAL ALARMED RESPONSE 196 00:08:22,802 --> 00:08:25,905 WITH THE PRODUCTION OF THE THREE 197 00:08:25,972 --> 00:08:28,541 CYTOKINES, DSLP, IL25 AND IL-33, 198 00:08:28,608 --> 00:08:29,842 WHICH THEN, IN FACT, WITH A 199 00:08:29,909 --> 00:08:31,611 VARIETY OF CELL TYPES IN THE 200 00:08:31,677 --> 00:08:34,413 HOST INCLUDING DENDRITIC CELLS, 201 00:08:34,480 --> 00:08:35,748 MACROPHAGES, EOSINOPHILS, 202 00:08:35,815 --> 00:08:37,984 BASOPHILS AND INNATE LYMPHOID 203 00:08:38,050 --> 00:08:39,018 CELLS SETTING IN MOTION A 204 00:08:39,085 --> 00:08:40,786 CASCADE OF CYTOKINE PRODUCTION 205 00:08:40,853 --> 00:08:42,955 THAT THEN DRIVES T-CELL AND B 206 00:08:43,022 --> 00:08:43,723 CELL DIFFERENTIATION. 207 00:08:43,789 --> 00:08:47,460 SO T-CELL DIFFERENTIATION, CLASS 208 00:08:47,526 --> 00:08:50,296 CLICK ASSOCIATED WITH THE 209 00:08:50,363 --> 00:08:52,598 TH2 PHENOTYPE AND THIS IS 210 00:08:52,665 --> 00:08:56,569 IMPORTANT IN -- MASTOCYTOSIS AS 211 00:08:56,636 --> 00:08:59,171 WELL AS IMMUNE MODULATION AND 212 00:08:59,238 --> 00:09:00,573 REGULATING NETWORKS WHICH 213 00:09:00,640 --> 00:09:04,176 INCLUDE IL10, TGF BETA, T 214 00:09:04,243 --> 00:09:06,712 REGULATORY CELLS, AND SO ON. 215 00:09:06,779 --> 00:09:09,749 AND FINALLY, B CELL PRODUCTION 216 00:09:09,815 --> 00:09:15,121 OF THE ANTIBODY -- PREDOMINANTLY 217 00:09:15,187 --> 00:09:18,724 IGG 4 AND IGE IN HUMANS. 218 00:09:18,791 --> 00:09:22,128 SO WHY ARE WE INTERESTED IN 219 00:09:22,194 --> 00:09:22,561 STRONGYLOIDES? 220 00:09:22,628 --> 00:09:23,829 IT ACTUALLY CONSIDERED ONE OF 221 00:09:23,896 --> 00:09:26,165 THE MOST NEGLECTED AMONG THE 222 00:09:26,232 --> 00:09:27,066 TROPICAL DISEASES BECAUSE VERY 223 00:09:27,133 --> 00:09:34,273 LITTLE IS KNOWN IN TERMS OF 224 00:09:34,340 --> 00:09:36,876 VIRULENCE AND THE PATHOGEN 225 00:09:36,943 --> 00:09:37,643 ASSISTED -- ABOUT A COUPLE OF 226 00:09:37,710 --> 00:09:41,113 YEARS AGO, IF YOU HAD LOOKED AT 227 00:09:41,180 --> 00:09:44,116 THE PREVALENCE, MOST LITERATURE 228 00:09:44,183 --> 00:09:46,552 WOULD HAVE SAID THAT IT INFECTS 229 00:09:46,619 --> 00:09:48,254 AROUND 30 TO 100 MILLION PEOPLE 230 00:09:48,321 --> 00:09:48,587 WORLDWIDE. 231 00:09:48,654 --> 00:09:52,091 NOW THEY HAVE COMPLETELY REVISED 232 00:09:52,158 --> 00:09:56,729 THE ESTIMATES TO AS MANY AS 233 00:09:56,796 --> 00:09:57,763 600 MILLION PEOPLE WORLDWIDE SO 234 00:09:57,830 --> 00:09:59,966 THERE'S THIS HUGE JUMP IN WHAT 235 00:10:00,032 --> 00:10:01,267 WAS THOUGHT TO BE AND THAT 236 00:10:01,334 --> 00:10:05,671 CLEARLY SHOWS HOW NEGLECTED THE 237 00:10:05,738 --> 00:10:08,074 INFECTION IS AROUND THE WORLD. 238 00:10:08,140 --> 00:10:09,475 THE REASON WHY IS BECAUSE IT 239 00:10:09,542 --> 00:10:11,344 USUALLY OCCURS ONLY IN LOW AND 240 00:10:11,410 --> 00:10:13,312 MIDDLE INCOME COUNTRIES SUCH AS 241 00:10:13,379 --> 00:10:15,281 ASIA, AFRICA, LATIN AMERICA, AND 242 00:10:15,348 --> 00:10:17,016 ALSO BECAUSE FOR THE MOST PART, 243 00:10:17,083 --> 00:10:18,317 IT IS ASYMPTOMATIC. 244 00:10:18,384 --> 00:10:22,555 S IS ONLY DURING 245 00:10:22,621 --> 00:10:23,789 IMMUNOCOMPROMISE THAT IT 246 00:10:23,856 --> 00:10:25,458 ACTUALLY MANIFESTS AS A 247 00:10:25,524 --> 00:10:27,426 POTENTIALLY FATAL CONDITION. 248 00:10:27,493 --> 00:10:28,494 DIAGNOSIS OFTEN INVOLVES 249 00:10:28,561 --> 00:10:30,363 SEROLOGY AND STOOL EXAMINATION, 250 00:10:30,429 --> 00:10:32,331 AND TREATMENT TYPICALLY 251 00:10:32,398 --> 00:10:33,766 COMPRISES OF THE DRUG 252 00:10:33,833 --> 00:10:34,533 IVERMECTIN. 253 00:10:34,600 --> 00:10:37,737 AND AS I ALREADY MENTIONED, 254 00:10:37,803 --> 00:10:38,471 IMMUNOSUPPRESSION, WHETHER DUE 255 00:10:38,537 --> 00:10:40,539 TO MEDICATION LIKE 256 00:10:40,606 --> 00:10:41,540 CORTICOSTEROIDS OR INFECTIONS 257 00:10:41,607 --> 00:10:45,678 SUCH AS HTLV OR HIV 258 00:10:45,745 --> 00:10:47,646 SIGNIFICANTLY INCREASES THE RISK 259 00:10:47,713 --> 00:10:50,483 OF HYPERINFECTION SYNDROME AND 260 00:10:50,549 --> 00:11:01,193 DISSEMINATED STRONG LOW DIASIS. 261 00:11:01,260 --> 00:11:02,661 I WANT YOU TO FOCUS ON THE RED 262 00:11:02,728 --> 00:11:03,863 AREAS ON THIS GLOBAL MAP. 263 00:11:03,929 --> 00:11:09,468 WHAT YOU CAN CLEARLY SEE IS IT'S 264 00:11:09,535 --> 00:11:17,743 PREDOMINANTLY PREVALENT -- SO 265 00:11:17,810 --> 00:11:20,713 THE LIFECYCLE OF STRONGY IS VERY 266 00:11:20,780 --> 00:11:21,747 COMPLEX, I'M NOT GOING TO GO 267 00:11:21,814 --> 00:11:22,882 INTO THE TEE TAILS OF THIS 268 00:11:22,948 --> 00:11:23,983 EXCEPT TO TELL YOU THAT THERE 269 00:11:24,050 --> 00:11:25,618 ARE TWO STAGES, TWO DIFFERENT 270 00:11:25,684 --> 00:11:27,153 CYCLES WUFNLT IS A FREE-LIVING 271 00:11:27,219 --> 00:11:31,090 CYCLE AND PARASITIC CYCLE, AND 272 00:11:31,157 --> 00:11:31,957 STRONGY INFECTION USUALLY BEGINS 273 00:11:32,024 --> 00:11:33,492 WITH THE INFECTIOUS LARVAE 274 00:11:33,559 --> 00:11:34,927 PENETRATING THE SKIN, GETTING TO 275 00:11:34,994 --> 00:11:38,531 THE CIRCULATION, AND THEN GOING 276 00:11:38,597 --> 00:11:40,299 INTO THE -- TREE WHERE IT ENDS 277 00:11:40,366 --> 00:11:42,701 UP IN THE LUNGS DUE TO MIGRATION 278 00:11:42,768 --> 00:11:46,405 INTO THE LUNG PARENCHYMA. 279 00:11:46,472 --> 00:11:48,140 STRONGY -- GET COUGHED UP, 280 00:11:48,207 --> 00:11:51,010 ASPIRATED AND THEN BASICALLY 281 00:11:51,077 --> 00:11:54,947 REGURGITATED OR INTO THE 282 00:11:55,014 --> 00:11:56,682 GASTROINTESTINAL TRACT, WHERE 283 00:11:56,749 --> 00:11:59,085 THE ADULT FEMALE WORMS SETTLE 284 00:11:59,151 --> 00:12:00,419 AND USUALLY CONTINUE THE 285 00:12:00,486 --> 00:12:00,719 LIFECYCLE. 286 00:12:00,786 --> 00:12:02,922 SO THE LIFECYCLE CAN ACTUALLY 287 00:12:02,988 --> 00:12:04,323 TAKE AS I SAID TWO FORMS. 288 00:12:04,390 --> 00:12:07,626 YOU CAN HAVE LARVAE WHICH ARE 289 00:12:07,693 --> 00:12:10,262 PRODUCED DIRECTLY FROM THE 290 00:12:10,329 --> 00:12:12,765 PATHOGENIC FEMALE AND THESE 291 00:12:12,832 --> 00:12:15,234 LARVAE -- OF THE CAPACITY TO 292 00:12:15,301 --> 00:12:17,136 CAUSE AUTO INFECTION, AND THIS 293 00:12:17,203 --> 00:12:20,539 IS ONE OF THE REALLY UNIQUE 294 00:12:20,606 --> 00:12:23,142 MECHANISMS BY WHICH STRONGY IS 295 00:12:23,209 --> 00:12:25,010 ABLE TO ESTABLISH LONG-STANDING 296 00:12:25,077 --> 00:12:30,616 CHRONIC INFECTIONS IN THE HOST. 297 00:12:30,683 --> 00:12:34,220 DIAGNOSIS IS MAINLY THROUGH -- 298 00:12:34,286 --> 00:12:37,056 THE PATHOLOGY FROM STRONGY 299 00:12:37,123 --> 00:12:38,390 USUALLY IS A REFLECTION OF THE 300 00:12:38,457 --> 00:12:39,024 MIGRATION STAGES. 301 00:12:39,091 --> 00:12:41,060 SO THE SKIN PHASE IS BECAUSE OF 302 00:12:41,127 --> 00:12:46,465 THE INVASION OF THE LARVAE, THE 303 00:12:46,532 --> 00:12:49,201 RESPIRATORY PHASE BECAUSE OF THE 304 00:12:49,268 --> 00:12:51,737 MIGRATION OF THE LARVAE AND 305 00:12:51,804 --> 00:12:55,007 TISSUE DESTRUCTION. 306 00:12:55,074 --> 00:12:57,176 THE CLINICAL MANIFESTATIONS OF 307 00:12:57,243 --> 00:12:59,712 STRONGY CAN BE SUBDIVIDED INTO 308 00:12:59,778 --> 00:13:02,114 ACUTE AND CHRONIC STRONGYLOIDES 309 00:13:02,181 --> 00:13:05,918 AND BASICALLY PREDOMINANTLY SKIN 310 00:13:05,985 --> 00:13:07,887 MANIFESTATIONS, ABDOMINAL 311 00:13:07,953 --> 00:13:10,856 MANIFESTATION AND PULMONARY 312 00:13:10,923 --> 00:13:12,491 MANIFESTATIONS BASED ON THE 313 00:13:12,558 --> 00:13:16,228 MIGRATION STAGE OF THE PARASITE. 314 00:13:16,295 --> 00:13:17,863 SO WITH THAT BACKGROUND I WOULD 315 00:13:17,930 --> 00:13:19,498 NOW LIKE TO FOCUS OUR ATTENTION 316 00:13:19,565 --> 00:13:21,367 ON OUR WORK ON HUMAN IMMUNE 317 00:13:21,433 --> 00:13:22,801 RESPONSES. 318 00:13:22,868 --> 00:13:26,505 AND I'D LIKE TO BASICALLY TELL 319 00:13:26,572 --> 00:13:30,376 YOU HERE THAT WE HAVE BEEN STU 320 00:13:30,442 --> 00:13:31,644 STUDYING STRONGY FOR OVER A 321 00:13:31,710 --> 00:13:33,279 DECADE NOW, WE'VE HAD THREE 322 00:13:33,345 --> 00:13:35,481 LARGE PROTOCOLS IN WHICH WE'VE 323 00:13:35,548 --> 00:13:37,650 DONE SCREENING ACROSS THE SOUTH 324 00:13:37,716 --> 00:13:39,285 INDIAN POPULATION AND THE SAMPLE 325 00:13:39,351 --> 00:13:40,386 SIZES OF THE DIFFERENT STUDIES 326 00:13:40,452 --> 00:13:41,720 ARE SHOWN HERE. 327 00:13:41,787 --> 00:13:47,059 SO BASED ON THIS, WE USUALLY 328 00:13:47,126 --> 00:13:49,595 UTILIZE THE SEROLOGY TEST FOR 329 00:13:49,662 --> 00:13:51,764 DIAGNOSING STRONGY, AND WHAT WE 330 00:13:51,830 --> 00:13:54,833 FOUND IS THAT WHEN WE SCREENED 331 00:13:54,900 --> 00:14:00,839 ABOUT 4,700 THUS FAR, THE ZERO 332 00:14:00,906 --> 00:14:02,708 POSITIVITY IN THIS POPULATION IS 333 00:14:02,775 --> 00:14:03,008 AROUND 29%. 334 00:14:03,075 --> 00:14:05,578 THIS IS THE AGE AND GENDER 335 00:14:05,644 --> 00:14:08,480 DISTRIBUTION OF STRONGY. 336 00:14:08,547 --> 00:14:11,550 SO WITH THESE COHORTS THAT WE 337 00:14:11,617 --> 00:14:14,620 HAVE, WE HAVE WANTED TO GO AHEAD 338 00:14:14,687 --> 00:14:18,457 AND EXAMINE CERTAIN OBJECTIVES 339 00:14:18,524 --> 00:14:19,558 LOOK AT CERTAIN OBJECTIVES. 340 00:14:19,625 --> 00:14:22,828 ONE WAS TO CHARACTERIZE THE 341 00:14:22,895 --> 00:14:26,131 BASELINE HEMATOLOGICAL AND 342 00:14:26,198 --> 00:14:27,433 BIOCHEMICAL PARAMETERS IN THESE 343 00:14:27,499 --> 00:14:28,834 INDIVIDUALS, TO CHARACTERIZE THE 344 00:14:28,901 --> 00:14:34,006 REGULATION OF CD4 SUBSETS IN 345 00:14:34,073 --> 00:14:37,042 THESE INFECTIONS, AND TO 346 00:14:37,109 --> 00:14:39,144 CHARACTERIZE THE SYSTEMIC 347 00:14:39,211 --> 00:14:39,845 CYTOKINE RESPONSES IN 348 00:14:39,912 --> 00:14:40,446 STRONGYLOIDES STERCORALIS 349 00:14:40,512 --> 00:14:42,948 INFECTION AND DELINEATE THE 350 00:14:43,015 --> 00:14:44,049 CHANGES THAT HAPPENED AFTER 351 00:14:44,116 --> 00:14:45,784 TREATING THE STRONGY PATIENT. 352 00:14:45,851 --> 00:14:51,724 SO IF YOU LOOK AT HEMATOLOGY IN 353 00:14:51,790 --> 00:14:56,462 STRONGY INFECTION -- TYPICALLY 354 00:14:56,528 --> 00:14:57,396 ASSOCIATED -- AND INDEED IF YOU 355 00:14:57,463 --> 00:14:58,931 LOOK AT EITHER ABSOLUTE NUMBERS 356 00:14:58,998 --> 00:15:01,100 SHOWN ON THE UPPER PANEL OR 357 00:15:01,166 --> 00:15:03,135 FREQUENCIES SHOWN IN THE LOWER 358 00:15:03,202 --> 00:15:05,037 PANEL, YOU'LL SEE THAT STRONGY 359 00:15:05,104 --> 00:15:06,038 INFECTED INDIVIDUALS INDEED DO 360 00:15:06,105 --> 00:15:09,208 HAVE A SIGNIFICANTLY HIGHER 361 00:15:09,275 --> 00:15:10,776 NUMBER OF EOSINOPHILS COMPARED 362 00:15:10,843 --> 00:15:12,378 TO THE UNINFECTED INDIVIDUALS. 363 00:15:12,444 --> 00:15:14,146 BUT ALSO INTERESTINGLY, WE ALSO 364 00:15:14,213 --> 00:15:15,814 FOUND THAT THERE IS AN INCREASE 365 00:15:15,881 --> 00:15:18,183 IN THE NUMBERS OF MONOCYTES AS 366 00:15:18,250 --> 00:15:21,687 WELL AS BASOPHILS IN THE STRONGY 367 00:15:21,754 --> 00:15:25,824 INFECTED IN OUR COHORT, THIS IS 368 00:15:25,891 --> 00:15:27,993 ACCOMPANIED BY A CO CONCOMITANT 369 00:15:28,060 --> 00:15:30,095 DECREASE IN THE NUMBER OF 370 00:15:30,162 --> 00:15:34,133 LYMPHOCYTES. 371 00:15:34,199 --> 00:15:38,837 WHEN WE LOOK AT -- HERE AGAIN WE 372 00:15:38,904 --> 00:15:40,939 ARE LOOKING AT THE LIVER 373 00:15:41,006 --> 00:15:43,642 FUNCTION TESTS, RENAL FUNCTION 374 00:15:43,709 --> 00:15:46,278 TESTS AS WELL AS BLOOD GLUCOSE 375 00:15:46,345 --> 00:15:49,448 INDICES, WHAT BA BASICALLY STOOD 376 00:15:49,515 --> 00:15:54,053 OUT WAS THAT STRONGY POSITIVE 377 00:15:54,119 --> 00:15:55,054 EOSIN FILLS WERE SIGNIFICANTLY 378 00:15:55,120 --> 00:15:56,789 ASSOCIATED WITH A DECREASE IN 379 00:15:56,855 --> 00:15:58,223 THE RANDOM BLOOD GLUCOSE LEVEL 380 00:15:58,290 --> 00:16:00,726 AS WELL AS THE HEMOGLOBIN A1C 381 00:16:00,793 --> 00:16:03,462 LEVELS, BOTH OF WHICH ARE 382 00:16:03,529 --> 00:16:05,230 INDICATORS OF CONTROL OF 383 00:16:05,297 --> 00:16:06,365 DIABETES OR THE OCCURRENCE OF 384 00:16:06,432 --> 00:16:07,833 DIABETES. 385 00:16:07,900 --> 00:16:10,869 AND SO I'M GOING TO COME BACK TO 386 00:16:10,936 --> 00:16:12,538 THIS PARTICULAR FINDING IN THE 387 00:16:12,604 --> 00:16:16,375 LATER PART OF MY TALK. 388 00:16:16,442 --> 00:16:25,317 SO IN TERMS OF THE IMMUNOLOGY OF 389 00:16:25,384 --> 00:16:26,952 CD4 T CELLS AND THEIR RESPONSES, 390 00:16:27,019 --> 00:16:28,921 WE BASICALLY USE WHOLE BLOOD 391 00:16:28,987 --> 00:16:30,255 CULTURES FROM STRONGY INFECTED 392 00:16:30,322 --> 00:16:37,029 OR CONTROL INFECTED PEOPLE AN 393 00:16:37,096 --> 00:16:40,532 AND -- NIE OR CONTROL ANDROGENS 394 00:16:40,599 --> 00:16:41,734 PPD AND -- AND ASKED THE 395 00:16:41,800 --> 00:16:44,470 QUESTION WHAT SORT OF T-CELL 396 00:16:44,536 --> 00:16:45,437 SUBSET DIFFERENTIATION RESPONSE 397 00:16:45,504 --> 00:16:48,607 DO YOU FIND IN THESE HUMANS WITH 398 00:16:48,674 --> 00:16:54,213 STRONGY INFECTION. 399 00:16:54,279 --> 00:16:55,647 THIS IS SHOWING THE EXPRESSION 400 00:16:55,714 --> 00:16:58,884 OF TH1 CYTOKINES, EITHER AT 401 00:16:58,951 --> 00:17:01,086 BASELINE SHOWN IN THE UPPER 402 00:17:01,153 --> 00:17:02,187 PANEL ANTIGEN STIMULATION IN THE 403 00:17:02,254 --> 00:17:06,325 MIDDLE OR IN THE -- OR 404 00:17:06,392 --> 00:17:08,193 FOLLOWING -- AND LOOKING AT THE 405 00:17:08,260 --> 00:17:12,030 EXPRESSION OF INTERFERON GAMMA, 406 00:17:12,097 --> 00:17:13,899 TNF ALPHA AND IL2. 407 00:17:13,966 --> 00:17:16,201 WHEN WE DO THIS, WHAT WE FIND IS 408 00:17:16,268 --> 00:17:17,836 INTERESTINGLY EVEN AT BASELINE 409 00:17:17,903 --> 00:17:19,371 IN STRONGY INFECTED INDIVIDUALS, 410 00:17:19,438 --> 00:17:22,741 THE FREQUENCY OF BOTH MONO 411 00:17:22,808 --> 00:17:24,276 FUNCTIONAL AS WELL AS DUAL 412 00:17:24,343 --> 00:17:26,478 FUNCTIONAL TH1 CELLS IS 413 00:17:26,545 --> 00:17:29,548 SIGNIFICANTLY LOWER IN STRONGY 414 00:17:29,615 --> 00:17:30,516 INFECTED INDIVIDUALS COMPARED TO 415 00:17:30,582 --> 00:17:31,550 THE UNINFECTED INDIVIDUALS, AND 416 00:17:31,617 --> 00:17:34,253 THIS ACTUALLY GETS SIGNIFICANTLY 417 00:17:34,319 --> 00:17:35,988 AUGMENTED WHEN WE LOOK AT 418 00:17:36,054 --> 00:17:37,089 ANTIGEN STIMULATION, SO EITHER 419 00:17:37,156 --> 00:17:38,624 LOOKING AT SOMATIC ANTIGEN ON 420 00:17:38,690 --> 00:17:41,126 THE TOP OR THE RECOMBINANT 421 00:17:41,193 --> 00:17:47,699 ANTIGEN IN THE BOTTOM, WE FIND 422 00:17:47,766 --> 00:17:48,767 TH1 MONO FUNCTIONAL, DUAL 423 00:17:48,834 --> 00:17:49,668 FUNCTIONAL -- OF CELLS, THE 424 00:17:49,735 --> 00:17:51,069 FREQUENCY OF THESE CELLS ARE 425 00:17:51,136 --> 00:17:52,838 SIGNIFICANTLY LOWER IN STRONGY 426 00:17:52,905 --> 00:17:54,473 INFECTED INDIVIDUALS COMPARED TO 427 00:17:54,540 --> 00:17:58,410 UNINFECTED INDIVIDUALS. 428 00:17:58,477 --> 00:17:59,478 INTERESTINGLY, IF YOU LOOK AT 429 00:17:59,545 --> 00:18:02,114 CONTROL ANTIGEN STIMULATION 430 00:18:02,181 --> 00:18:03,882 OR -- THIS DIFFERENTIAL RESPONSE 431 00:18:03,949 --> 00:18:07,219 DOES NOT HOLD SO THAT THIS 432 00:18:07,286 --> 00:18:08,687 RESPONSE APPEARS TO BE ONLY AT 433 00:18:08,754 --> 00:18:14,493 BASELINE OR AFTER PARASITE 434 00:18:14,560 --> 00:18:15,160 ANTIGEN INFECTION. 435 00:18:15,227 --> 00:18:24,870 BUT WHAT ABOUT ABO ABOUT TH2 A, 436 00:18:24,937 --> 00:18:27,706 LOOKING FOR IL4, IL5 AND IL13 437 00:18:27,773 --> 00:18:28,173 PRODUCTION. 438 00:18:28,240 --> 00:18:31,009 SO WHEN WE LOOK AT MONO 439 00:18:31,076 --> 00:18:33,512 FUNCTIONAL OR DUAL FUNCTIONAL 440 00:18:33,579 --> 00:18:34,947 TH2 CELLS, AGAIN WE SEE THIS 441 00:18:35,013 --> 00:18:36,348 VERY DIFFERENT TREND OF WHAT WE 442 00:18:36,415 --> 00:18:38,317 SAW WITH TH1 CELLS BUT WHAT YOU 443 00:18:38,383 --> 00:18:42,054 WOULD EXPECT BASED ON WHAT 444 00:18:42,120 --> 00:18:43,021 HELMINTH INFECTION -- IN THAT 445 00:18:43,088 --> 00:18:44,356 THERE IS A SIGNIFICANTLY 446 00:18:44,423 --> 00:18:45,958 INCREASED FREQUENCY EVEN AT 447 00:18:46,024 --> 00:18:49,361 BASELINE WITHOUT ANY STIMULATION 448 00:18:49,428 --> 00:18:51,463 OF MONO FUNCTIONAL AND DUAL 449 00:18:51,530 --> 00:18:53,332 FUNCTIONAL TH2 CELLS, AND THIS 450 00:18:53,398 --> 00:18:56,802 IS AGAIN SIGNIFICANTLY AUGMENTED 451 00:18:56,869 --> 00:18:58,036 OR ENHANCED UPON ANTIGEN 452 00:18:58,103 --> 00:18:59,338 STIMULATION, SO YOU SEE 453 00:18:59,404 --> 00:19:01,974 SIGNIFICANTLY HIGHER FREQUENCIES 454 00:19:02,040 --> 00:19:05,010 OF BOTH MONO AND DUAL FUNCTIONAL 455 00:19:05,077 --> 00:19:07,079 TH2 CELLS IN RESPONSE TO -- OR 456 00:19:07,145 --> 00:19:10,148 IN RESPONSE TO -- AND WHAT WE 457 00:19:10,215 --> 00:19:12,117 SAW WITH TH1 CELLS, NO 458 00:19:12,184 --> 00:19:13,886 SIGNIFICANT DIFFERENCE UPON -- 459 00:19:13,952 --> 00:19:16,488 STIMULATION OR IF YOU STIMULATED 460 00:19:16,555 --> 00:19:21,627 WITH CONTROL --. 461 00:19:21,693 --> 00:19:25,030 SO THE NEXT THING WE WANTED 462 00:19:25,097 --> 00:19:26,999 TO -- NEXT T-CELL SUBSET WE 463 00:19:27,065 --> 00:19:29,101 WANTED TO LOOK AT WAS TH9 CELLS. 464 00:19:29,167 --> 00:19:30,836 SO THERE HAS NOT BEEN A LOT OF 465 00:19:30,903 --> 00:19:33,005 LITERATURE DESCRIBING THE 466 00:19:33,071 --> 00:19:34,973 EXPRESSION PATTERNS OF TH9 CELLS 467 00:19:35,040 --> 00:19:36,842 IN HUMAN HELMINTH INFECTIONS, SO 468 00:19:36,909 --> 00:19:38,877 WHEN WE DID THIS, WHAT WE FIND 469 00:19:38,944 --> 00:19:40,579 IS THAT -- SO THIS IS BASICALLY 470 00:19:40,646 --> 00:19:42,080 A CONTOUR PLOT LOOKING AT 471 00:19:42,147 --> 00:19:44,650 EXPRESSION OF IL4, IL9 AND IL10 472 00:19:44,716 --> 00:19:46,818 AND WE BASICALLY DEFINE 473 00:19:46,885 --> 00:19:50,622 TH9 CELLS IN THIS CASE AS 474 00:19:50,689 --> 00:19:53,258 IL9 POSITIVE, IL10 POSITIVE OR 475 00:19:53,325 --> 00:19:55,460 NEGATIVE BUT IL4 NEGATIVE. 476 00:19:55,527 --> 00:19:57,095 SO IN ORDER TO DIFFERENTIATE 477 00:19:57,162 --> 00:19:59,364 THEM FROM CLASSICAL TH2 CELLS. 478 00:19:59,431 --> 00:20:01,233 WHEN WE DO THIS, WE FIND THAT 479 00:20:01,300 --> 00:20:05,837 EITHER THE SINGLE -- CELLS OR 480 00:20:05,904 --> 00:20:08,140 THE IL11 DOUBLE -- CELLS ARE 481 00:20:08,206 --> 00:20:09,007 SIGNIFICANTLY INCREASED IN 482 00:20:09,074 --> 00:20:10,375 FREQUENCY IN STRONGY INFECTION 483 00:20:10,442 --> 00:20:12,010 AT BASELINE, AND THIS IS 484 00:20:12,077 --> 00:20:14,580 ACTUALLY TRUE WHEN WE LOOK AT 485 00:20:14,646 --> 00:20:15,747 ANTIGEN STIMULATION AS WELL, SO 486 00:20:15,814 --> 00:20:23,889 IF YOU LOOK AT IL9 -- -- YOU SEE 487 00:20:23,956 --> 00:20:26,291 A SIGNIFICANT ENHANCEMENT IN THE 488 00:20:26,358 --> 00:20:27,492 EXPANSION AND FREQUENCY OF THESE 489 00:20:27,559 --> 00:20:30,128 SUBSETS. 490 00:20:30,195 --> 00:20:31,430 AGAIN YOU DON'T SEE ANY 491 00:20:31,496 --> 00:20:35,367 DIFFERENCE IN RESPONSE TO --. 492 00:20:35,434 --> 00:20:38,003 FINALLY, WHEN WE LOOK AT TH17 493 00:20:38,070 --> 00:20:41,573 CELLS, IN RESPONSE TO EITHER 494 00:20:41,640 --> 00:20:48,614 TRON GEE INFSTRONGY INFECTED IN. 495 00:20:48,680 --> 00:20:52,417 WE FIND A BASELINE INCREASE IN 496 00:20:52,484 --> 00:20:54,186 TH17 CELLS, BUT SURPRISINGLY THE 497 00:20:54,252 --> 00:20:56,355 BABASELINE INCREASE IS ACTUALLY 498 00:20:56,421 --> 00:20:57,889 NOT REFLECTED WHEN WE LOOK AT 499 00:20:57,956 --> 00:20:59,157 ANTIGEN STIMULATION, SO WHEN WE 500 00:20:59,224 --> 00:21:00,525 LOOK AT ANTIGEN STIMULATED 501 00:21:00,592 --> 00:21:01,827 CELLS, WE ACTUALLY START 502 00:21:01,893 --> 00:21:04,129 SEEING -- WE SEE A SIGNIFICANT 503 00:21:04,196 --> 00:21:06,098 CONTRACTION IN THE FREQUENCY OF 504 00:21:06,164 --> 00:21:08,166 THESE TH17 CELLS IN RESPONSE TO 505 00:21:08,233 --> 00:21:11,136 STRONGY INFECTION. 506 00:21:11,203 --> 00:21:13,205 -- DUAL FUNCTIONAL TH17 CELLS. 507 00:21:13,271 --> 00:21:17,909 AND AGAIN, SAME RESPONSE IN -- 508 00:21:17,976 --> 00:21:21,613 WITH RESPECT TO CONTROL ANTIGEN. 509 00:21:21,680 --> 00:21:22,514 FINALLY, ONE OTHER INTERESTING 510 00:21:22,581 --> 00:21:25,150 FEATURE THAT WE NOTICED IN 511 00:21:25,217 --> 00:21:27,419 STRONGY INFECTION IS THAT 512 00:21:27,486 --> 00:21:28,754 STRONGY INFECTION IS ONE OF THE 513 00:21:28,820 --> 00:21:32,357 FEW HUMAN HEALTH -- HELMINTH 514 00:21:32,424 --> 00:21:33,892 INFECTIONS IN WHICH WE ACTUALLY 515 00:21:33,959 --> 00:21:35,961 SEE THESE DOUBLE EXPRESSING 516 00:21:36,028 --> 00:21:36,161 CELLS. 517 00:21:36,228 --> 00:21:37,729 THIS IS AGAIN VERY PRELIMINARY, 518 00:21:37,796 --> 00:21:38,764 WE DO NOT KNOW WHAT FUNCTION 519 00:21:38,830 --> 00:21:40,432 THESE CELLS CARRY OUT, SO THESE 520 00:21:40,499 --> 00:21:45,470 ARE BASICALLY IL4 INTERFERON 521 00:21:45,537 --> 00:21:49,074 GAMMA DUAL EX-P EXPRESSERS. 522 00:21:49,141 --> 00:21:51,943 SO IF YOU LOOK AT EXPRESSION OF 523 00:21:52,010 --> 00:21:54,980 IL4 AND INTERFERON GAMMA IN 524 00:21:55,047 --> 00:21:56,515 ENDEMIC NORMALS, CONTROL 525 00:21:56,581 --> 00:21:57,716 INDIVIDUALS, AND STRONGY 526 00:21:57,783 --> 00:22:00,018 INFECTED INDIVIDUALS, YOU'LL SEE 527 00:22:00,085 --> 00:22:02,320 THIS DUAL -- PRESENTED IN THE 528 00:22:02,387 --> 00:22:03,288 STRONGY INFECTED INDIVIDUALS 529 00:22:03,355 --> 00:22:05,390 THAT ARE NOT SEEN IN CONTROL 530 00:22:05,457 --> 00:22:05,924 INDIVIDUALS. 531 00:22:05,991 --> 00:22:08,760 AND IT TURNS OUT THAT THEY 532 00:22:08,827 --> 00:22:12,064 EXPRESS -- CO-EXPRESS -- AND 533 00:22:12,130 --> 00:22:13,265 GATA3 AS WELL, SO THAT'S ONE OF 534 00:22:13,331 --> 00:22:14,232 THE OTHER INTERESTING FINDINGS 535 00:22:14,299 --> 00:22:15,767 THAT WE SEE IN STRONGY 536 00:22:15,834 --> 00:22:18,070 INFECTION. 537 00:22:18,136 --> 00:22:20,806 SO WITH THIS, WE BASICALLY THEN 538 00:22:20,872 --> 00:22:22,340 WANTED TO ASK THE QUESTION, HOW 539 00:22:22,407 --> 00:22:24,109 ARE THESE RESPONSES ACTUALLY 540 00:22:24,176 --> 00:22:27,813 BEING REGULATED IN STRONGYLOIDES 541 00:22:27,879 --> 00:22:29,014 INFECTION? 542 00:22:29,081 --> 00:22:30,449 I TOLD YOU AT THE BEGINNING THAT 543 00:22:30,515 --> 00:22:31,516 HELMINTH INFECTIONS, AND THIS IS 544 00:22:31,583 --> 00:22:35,587 TRUE OF TRON STRONGY INFECTIONS 545 00:22:35,654 --> 00:22:37,956 WELL, ARE CLASSICAL INDUCERS OF 546 00:22:38,023 --> 00:22:40,926 TH REGULATING CYTOKINES, BUT IN 547 00:22:40,992 --> 00:22:43,995 ADDITION, THEY ARE ALSO REALLY 548 00:22:44,062 --> 00:22:48,133 STRONG AND -- COINHIBITORY 549 00:22:48,200 --> 00:22:50,135 RECEPTORS, AND PD-1, SO THE 550 00:22:50,202 --> 00:22:52,504 QUESTION WE ASKED IS, DO ANY OF 551 00:22:52,571 --> 00:22:55,373 THESE REGULATORY CYTOKINES OR 552 00:22:55,440 --> 00:22:57,442 COINHIBITORS PLAY A ROLE IN 553 00:22:57,509 --> 00:22:58,577 MODULATING THE DIFFERENTIATION 554 00:22:58,643 --> 00:23:01,113 OF T-CELL SUBSETS THAT WE SEE IN 555 00:23:01,179 --> 00:23:02,681 OUR STRONGY INFECTED 556 00:23:02,748 --> 00:23:03,115 INDIVIDUALS. 557 00:23:03,181 --> 00:23:04,349 AND THE ANSWER IS INDEED IT IS 558 00:23:04,416 --> 00:23:06,084 TRUE, SO IF YOU LOOK AT IL10 IN 559 00:23:06,151 --> 00:23:08,386 THIS PARTICULAR CASE, SO WE'RE 560 00:23:08,453 --> 00:23:11,890 BASICALLY DOING RETRO CULTURES, 561 00:23:11,957 --> 00:23:14,626 AGAIN, WHOLE BLOOD, BLOCKING -- 562 00:23:14,693 --> 00:23:17,462 AND THEN LOOKING AT THE 563 00:23:17,529 --> 00:23:18,997 PRODUCTION OF -- COEXPRESSION OF 564 00:23:19,064 --> 00:23:22,934 DIFFERENT CYTOKINES IN THE 565 00:23:23,001 --> 00:23:25,871 T-CELL -- CD4 T-CELL 566 00:23:25,937 --> 00:23:26,304 COMPARTMENTS. 567 00:23:26,371 --> 00:23:28,206 WHAT WE FIND IS THERE IS A 568 00:23:28,273 --> 00:23:31,576 SIGNIFICANT UPREGULATION OF 569 00:23:31,643 --> 00:23:35,380 TH1 SUBSETS, AS WELL AS A 570 00:23:35,447 --> 00:23:38,650 MINIMAL EFFECT ON TH17 -- SO 571 00:23:38,717 --> 00:23:40,085 IL-17 PRETTY MUCH SEEMS TO 572 00:23:40,152 --> 00:23:41,653 REGULATE TH1 CELLS BUT NOT SO 573 00:23:41,720 --> 00:23:44,589 MUCH THE TH17 COMPARTMENT. 574 00:23:44,656 --> 00:23:47,526 IN CONTRAST, IL10 ACTUALLY 575 00:23:47,592 --> 00:23:51,029 REGULATES BOTH THE TH2 AND THE 576 00:23:51,096 --> 00:23:53,231 TH9 CELLS, SO HERE IF YOU LOOK 577 00:23:53,298 --> 00:23:56,067 AT THE EXPRESSION OF IL4 AND 578 00:23:56,134 --> 00:23:57,502 IL13, THEY ARE BOTH 579 00:23:57,569 --> 00:23:59,237 SIGNIFICANTLY DIMINISHED UPON 580 00:23:59,304 --> 00:24:01,973 IL10 BLOCKADE AND THE DOUBLE 581 00:24:02,040 --> 00:24:02,974 EXPRESSERS ARE ALSO 582 00:24:03,041 --> 00:24:04,476 SIGNIFICANTLY DIMINISHED. 583 00:24:04,543 --> 00:24:06,878 THE SAME IS TRUE WHEN YOU LOOK 584 00:24:06,945 --> 00:24:11,049 AT TH9 CELLS, SO -- DUAL 585 00:24:11,116 --> 00:24:12,250 EXPRESSERS OF IL9. 586 00:24:12,317 --> 00:24:13,685 BUT WHAT WE DID FIND WHICH IS 587 00:24:13,752 --> 00:24:14,753 VERY INTERESTING AND AGAIN WE 588 00:24:14,820 --> 00:24:16,188 STILL ARE TRYING TO UNDERSTAND 589 00:24:16,254 --> 00:24:18,757 THE MECHANISM BEHIND THIS IS 590 00:24:18,824 --> 00:24:20,358 THAT -- ALONE SEEMS TO HAVE A 591 00:24:20,425 --> 00:24:21,660 DIFFERENTIAL RESPONSE SO THERE 592 00:24:21,726 --> 00:24:23,962 IS A SIGNIFICANT UPREGULATION OF 593 00:24:24,029 --> 00:24:25,797 IL5 WHEN WE LOOK AT IL10 594 00:24:25,864 --> 00:24:27,132 BLOCKADE IN THESE PARTICULAR 595 00:24:27,199 --> 00:24:29,201 INDIVIDUALS. 596 00:24:29,267 --> 00:24:31,703 TGF BETA HAS NO EFFECT ON 597 00:24:31,770 --> 00:24:35,774 DH1 CELLS AND ON DH17 CELLS, SO 598 00:24:35,841 --> 00:24:37,976 BLOCKING TGF BAY DA DOES NOT 599 00:24:38,043 --> 00:24:40,045 MODULATE THE FREQUENCIES OF 600 00:24:40,111 --> 00:24:41,546 THESE COMPARTMENTS. 601 00:24:41,613 --> 00:24:44,549 HOWEVER, TGF BETA SIGNIFICANTLY 602 00:24:44,616 --> 00:24:47,819 DOES REGULATE CERTAIN SUBSETS OF 603 00:24:47,886 --> 00:24:49,888 TH2 CELLS, SO -- I LSM 13 604 00:24:49,955 --> 00:24:51,723 EXPRESSERS BUT SIGNIFICANTLY MOD 605 00:24:51,790 --> 00:24:53,258 LATES TH9 CELLS. 606 00:24:53,325 --> 00:24:55,894 SO THERE IS A SIGNIFICANT 607 00:24:55,961 --> 00:24:58,864 DECREASE UPON THE EXPRESSION OF 608 00:24:58,930 --> 00:24:59,931 IL9 SIGNAL EXPRESSERS AS WELL AS 609 00:24:59,998 --> 00:25:04,202 THE IL9 AND IL4 OR IL9/IL10 DUAL 610 00:25:04,269 --> 00:25:06,071 EXPRESSERS IN STRONGY INFECTIONS 611 00:25:06,137 --> 00:25:11,309 UPON BLOCKADE OF TGF BETA. 612 00:25:11,376 --> 00:25:14,346 SO WHEN WE LOOK AT COINHIBITORS 613 00:25:14,412 --> 00:25:15,814 AND ASK THE QUESTION WHAT ROLE 614 00:25:15,881 --> 00:25:19,251 DO THESE COINHIBITORS PLAY IN 615 00:25:19,317 --> 00:25:25,891 THE REGULATION OF THESE TH C 616 00:25:25,957 --> 00:25:28,059 CD4 POSITIVE -- WE FIND THAT 617 00:25:28,126 --> 00:25:30,028 CTLA4 LAS A VERY SIGNIFICANT 618 00:25:30,095 --> 00:25:33,632 EFFECT IN THAT BLOCKING 619 00:25:33,698 --> 00:25:36,301 CTLA4 SIGNIFICANTLY UPREGULATES 620 00:25:36,368 --> 00:25:37,802 BOTH MONO FUNCTIONAL AND DUAL 621 00:25:37,869 --> 00:25:40,305 FUNCTIONAL TH1 CELLS, AS WELL AS 622 00:25:40,372 --> 00:25:44,676 UPREGULATING THE TH17 SUBSETS IN 623 00:25:44,743 --> 00:25:51,349 RESPONSE TO -- CTLA4 ALSO HAS AN 624 00:25:51,416 --> 00:25:54,753 EFFECT IN DOWNMODULATING THE 625 00:25:54,819 --> 00:25:56,922 IMMUNE RESPONSES IN TH2 OR 626 00:25:56,988 --> 00:26:01,426 REGULATING THE RESPONSES OF -- 627 00:26:01,493 --> 00:26:06,765 COMPARTMENT, SO BLOCKADE OF 628 00:26:06,831 --> 00:26:09,601 CTLA4 DOWNMODULATES THE -- AS 629 00:26:09,668 --> 00:26:14,105 WELL AS THE ECK PRETION OF 630 00:26:14,172 --> 00:26:16,308 THE -- 9 CELLS. 631 00:26:16,374 --> 00:26:18,710 PD-1, AGAIN, EVEN PD-1 HAS -- SO 632 00:26:18,777 --> 00:26:20,545 THERE SEEMS TO BE THESE 633 00:26:20,612 --> 00:26:22,948 MULTIPRONGED APPROACH THAT 634 00:26:23,014 --> 00:26:24,616 HELMINTH INFECTION LIKE STRONGY 635 00:26:24,683 --> 00:26:27,085 USES BECAUSE THERE ARE MULTIPLE 636 00:26:27,152 --> 00:26:28,320 MECHANISMS BY WHICH THESE 637 00:26:28,386 --> 00:26:29,754 PATHWAYS SEEM TO BE REGULATED, 638 00:26:29,821 --> 00:26:33,692 SO PD-1 ALSO REGULATES THE 639 00:26:33,758 --> 00:26:35,327 EXPRESSION OF MONO FUNCTIONAL 640 00:26:35,393 --> 00:26:37,529 AND DUAL FUNCTIONAL TH1 CELLS, 641 00:26:37,595 --> 00:26:42,867 VERY SIMILAR EFFECT IN THE THE 642 00:26:42,934 --> 00:26:46,604 EXPRESSION OF TH17 CELLS, AND IN 643 00:26:46,671 --> 00:26:49,007 CONTRAST, THE DIFFERENTIAL 644 00:26:49,074 --> 00:26:51,409 EFFECT IN TERMS OF DOWN 645 00:26:51,476 --> 00:26:57,782 MODULATING THE EXPRESSION OF THE 646 00:26:57,849 --> 00:27:00,719 TH9 EXPRESSING T CELLS. 647 00:27:00,785 --> 00:27:02,787 IL9 EXPRESSING T CELLS. 648 00:27:02,854 --> 00:27:04,322 SO HAVING SHOWN THAT THERE IS A 649 00:27:04,389 --> 00:27:05,857 WIDE VARIETY OF IMMUNE 650 00:27:05,924 --> 00:27:10,428 REGULATION THAT STRONGY -- IN 651 00:27:10,495 --> 00:27:12,397 HUMANS AND THAT THESE RESPONSES 652 00:27:12,464 --> 00:27:15,033 HAVE A PROFOUND EFFECT -- WE 653 00:27:15,100 --> 00:27:16,134 NEXT WANTED TO ASK THE QUESTION, 654 00:27:16,201 --> 00:27:20,839 DOES THIS TRANSLATE INTO SYSTEM 655 00:27:20,905 --> 00:27:23,241 CYTOKINE RESPONSES AND WILL THAT 656 00:27:23,308 --> 00:27:24,876 HAVE ANY SORT OF EFFECT BECAUSE 657 00:27:24,943 --> 00:27:28,046 AS I MENTIONED BEFORE, WE DON'T 658 00:27:28,113 --> 00:27:30,782 HAVE THE INTERACTION OF STRONGY 659 00:27:30,849 --> 00:27:31,983 WITH COEXISTING DISORDERS. 660 00:27:32,050 --> 00:27:35,053 SO TO DO THIS, WE JUST BASICALLY 661 00:27:35,120 --> 00:27:44,462 LOOKED AT -- INCLUDING TH1, TH17 662 00:27:44,529 --> 00:27:47,399 CYTOKINES, AS WELL AS 663 00:27:47,465 --> 00:27:50,468 CH2 CYTOKINES -- SO WHEN WE DO 664 00:27:50,535 --> 00:27:53,872 THIS, WHAT WE FIND IS THAT IN 665 00:27:53,938 --> 00:27:55,607 THE SYSTEMIC CIRCULATION, YOU 666 00:27:55,673 --> 00:27:58,576 REALLY DON'T SEE MUCH OF AN 667 00:27:58,643 --> 00:28:02,380 EFFECT WITH A FEW EXCEPTIONS 668 00:28:02,447 --> 00:28:03,648 WITH PRO-INFLAMMATORY CYTOKINES, 669 00:28:03,715 --> 00:28:05,016 SO THERE IS A REDUCTION IN THE 670 00:28:05,083 --> 00:28:06,651 CIRCULATING LEVELS OF INTERFERON 671 00:28:06,718 --> 00:28:12,791 GAMMA AND TNF ALPHA AND -- BUT 672 00:28:12,857 --> 00:28:15,427 WHAT WE DO FIND INTERESTING IS 673 00:28:15,493 --> 00:28:18,463 IF YOU ACTUALLY LOOK SIX MONTH 674 00:28:18,530 --> 00:28:20,565 FOLLOWING TREATMENT OF STRONGY 675 00:28:20,632 --> 00:28:21,933 INFECTION, ALTHOUGH AT BASELINE 676 00:28:22,000 --> 00:28:23,201 THERE WERE NO DIFFERENCES IN 677 00:28:23,268 --> 00:28:25,370 THESE CYTOKINES. 678 00:28:25,437 --> 00:28:26,604 EVERY SINGLE -- PRETTY MUCH THAT 679 00:28:26,671 --> 00:28:29,641 WE LOOKED AT WAS SIGNIFICANTLY 680 00:28:29,707 --> 00:28:30,742 UPREGULATED AT SIX MONTHS, 681 00:28:30,809 --> 00:28:34,679 SUGGESTING, AGAIN, THAT THAT 682 00:28:34,746 --> 00:28:37,315 COULDN'T HAVE -- THAT WAS NOT 683 00:28:37,382 --> 00:28:38,616 MANIFEST EXCLUSIVELY JUST BY 684 00:28:38,683 --> 00:28:40,018 LOOKING AT THE CIRCULATION. 685 00:28:40,085 --> 00:28:40,919 BUT MORE INTERESTINGLY, IF YOU 686 00:28:40,985 --> 00:28:44,189 LOOK AT TH2 REGULATORY AS WELL 687 00:28:44,255 --> 00:28:45,857 AS -- THERE IS A PROFOUND EFFECT 688 00:28:45,924 --> 00:28:47,025 OF STRONGY INFECTION, SO WHEN 689 00:28:47,092 --> 00:28:49,661 YOU LOOK AT STRONGY INFECTION 690 00:28:49,727 --> 00:28:51,529 COMPARED TO CONTROLS, THE 691 00:28:51,596 --> 00:28:57,769 CIRCULATING LEVELS OF IL4, 5, 692 00:28:57,836 --> 00:28:59,170 10, 13 -- ARE ALL SIGNIFICANTLY 693 00:28:59,237 --> 00:29:00,605 HIGHER IN STRONGY INFECTED 694 00:29:00,672 --> 00:29:01,473 INDIVIDUALS COMPARED TO 695 00:29:01,539 --> 00:29:02,140 CONTROLS. 696 00:29:02,207 --> 00:29:04,642 AND ALL OF THESE PRETTY MUCH FOR 697 00:29:04,709 --> 00:29:08,580 THE MOST PART ARE SIGNIFICANTLY 698 00:29:08,646 --> 00:29:09,147 DOWN MODULATED. 699 00:29:09,214 --> 00:29:10,915 WHEN YOU TREAT THESE INDIVIDUALS 700 00:29:10,982 --> 00:29:12,550 AND THEN LOOK AT THEM SIX MONTHS 701 00:29:12,617 --> 00:29:14,352 LATER. 702 00:29:14,419 --> 00:29:18,323 AND FINALLY, STRONGY IS AGAIN 703 00:29:18,389 --> 00:29:20,091 ONE OF THE FEW HELMINTH HUMAN 704 00:29:20,158 --> 00:29:21,526 MODELS WHICH ACTUALLY IS 705 00:29:21,593 --> 00:29:26,865 ASSOCIATED WITH INDUCTION OF IL. 706 00:29:26,931 --> 00:29:29,167 SO WHEN WE LOOK AT THE -- WE SEE 707 00:29:29,234 --> 00:29:36,040 THERE IS A SIGNIFICANT LAMBDA 1, 708 00:29:36,107 --> 00:29:41,412 LAMBDA 2 AND -- SO TO SUMMARIZE 709 00:29:41,479 --> 00:29:44,582 THE SECOND PART OF MY TALK, 710 00:29:44,649 --> 00:29:49,087 STRONGY -- HAS THE ABILITY TO 711 00:29:49,154 --> 00:29:51,456 HAVE A COMPLEX INTERPLAY WITH 712 00:29:51,523 --> 00:29:53,791 THE HOST -- HUMAN-HOST IMMUNE 713 00:29:53,858 --> 00:29:54,092 SYSTEM. 714 00:29:54,159 --> 00:30:00,331 IT CAUSES EXPANSION OF TH2 AND 715 00:30:00,398 --> 00:30:05,937 TH9 CELLS -- THERE'S A -- 716 00:30:06,004 --> 00:30:07,872 SIMILAR DIFFERENTIAL MODULATION 717 00:30:07,939 --> 00:30:11,709 BASICALLY FOR PD-1, POTENTIALLY 718 00:30:11,776 --> 00:30:15,647 NOVEL TH2/1 T-CELL SUBSET AND 719 00:30:15,713 --> 00:30:17,582 FINALLY THESE SYSTEMIC CYTOKINES 720 00:30:17,649 --> 00:30:18,483 FOR THE MOST PART REFLECT THE 721 00:30:18,550 --> 00:30:20,351 CHANGES IN THE T-CELL 722 00:30:20,418 --> 00:30:21,352 COMPARTMENT IN WHICH THERE ARE 723 00:30:21,419 --> 00:30:23,087 HEIGHTENED LEVELS OF TYPE 724 00:30:23,154 --> 00:30:24,289 2 REGULATORY AND 725 00:30:24,355 --> 00:30:25,823 ANTI-INFLAMMATORY CYTOKINES. 726 00:30:25,890 --> 00:30:28,426 SO HAVING TALKED EXTENSIVELY 727 00:30:28,493 --> 00:30:31,396 ABOUT THE RESPONSES THAT STRONGY 728 00:30:31,462 --> 00:30:34,566 INFECTION CAUSES, WE THEN WANTED 729 00:30:34,632 --> 00:30:37,302 TO ASK THE PRESENCE OF THIS 730 00:30:37,368 --> 00:30:39,504 INFECTION, IT SEEMS TO MODULATE 731 00:30:39,571 --> 00:30:41,573 SO MANY DIFFERENT ARMS OF THE 732 00:30:41,639 --> 00:30:44,108 IMMUNE SYSTEM. 733 00:30:44,175 --> 00:30:45,510 HOW MANY -- BY STANDER 734 00:30:45,577 --> 00:30:46,411 INFECTIONS. 735 00:30:46,477 --> 00:30:48,146 SO THE FIRST INFECTION THAT I'M 736 00:30:48,213 --> 00:30:51,316 GOING TO LOOK AT, ONE THAT I'M 737 00:30:51,382 --> 00:30:53,384 GOING TO BE TALKING ABOUT TODAY 738 00:30:53,451 --> 00:30:55,053 IS MYCOBACTERIUM TUBERCULOSIS, 739 00:30:55,119 --> 00:30:56,254 AND THE REASON WHY WE ARE 740 00:30:56,321 --> 00:30:58,089 INTERESTED IN HELMINTH TB 741 00:30:58,156 --> 00:31:00,525 INTERACTIONS IS VERY SIMPLE. 742 00:31:00,592 --> 00:31:02,160 THIS IS BASICALLY ANSWERED BY 743 00:31:02,227 --> 00:31:04,696 LOOKING AT THIS GEOGRAPHIC MAP. 744 00:31:04,762 --> 00:31:07,332 SO IF YOU LOOK AT AREAS OF THE 745 00:31:07,398 --> 00:31:10,468 WORLD WHERE HELMINTH AND TB 746 00:31:10,535 --> 00:31:13,204 COINFECTION EXIST, THE PURPLE 747 00:31:13,271 --> 00:31:16,274 AREAS ARE THE ONES WHICH 748 00:31:16,341 --> 00:31:17,709 PREDOMINANTLY HAVE BOTH HELMINTH 749 00:31:17,775 --> 00:31:20,445 AND TB COINFECTIONS AND IF YOU 750 00:31:20,511 --> 00:31:23,715 ACTUALLY LOOK AT THE RAW DATA, 751 00:31:23,781 --> 00:31:25,250 INDIA HAS THE HIGHEST NUMBER OF 752 00:31:25,316 --> 00:31:26,784 TB CASES IN THE WORLD AND ALSO 753 00:31:26,851 --> 00:31:28,319 HAS PRETTY MUCH ONE OF THE 754 00:31:28,386 --> 00:31:29,654 HIGHEST PREVALENCE OF HELMINTH 755 00:31:29,721 --> 00:31:31,589 INFECTION SO THE QUESTION THAT 756 00:31:31,656 --> 00:31:33,291 IS -- SO IF THESE INFECTIONS 757 00:31:33,358 --> 00:31:34,759 TEFL ARE NOT EXISTING 758 00:31:34,826 --> 00:31:35,326 INDEPENDENTLY, THEN THERE'S 759 00:31:35,393 --> 00:31:36,461 GOING TO BE A LOT OF INDIVIDUALS 760 00:31:36,527 --> 00:31:38,696 WHO ARE GOING TO BE COINFECTED 761 00:31:38,763 --> 00:31:40,331 AND WHAT SORT OF AN IMMUNE 762 00:31:40,398 --> 00:31:42,333 RESPONSE ARE WE GOING TO EXPECT 763 00:31:42,400 --> 00:31:44,702 IN THE CONTEXT OF THESE 764 00:31:44,769 --> 00:31:45,703 INFECTIONS COEXISTING WITH EACH 765 00:31:45,770 --> 00:31:49,007 OTHER. 766 00:31:49,073 --> 00:31:51,075 SO THE OTHER REASON WE ARE 767 00:31:51,142 --> 00:31:55,446 INTERESTED ALSO IS BECAUSE THE 768 00:31:55,513 --> 00:31:57,181 RESPONSE -- IS DRASTICALLY 769 00:31:57,248 --> 00:32:01,686 DIFFERENT FROM WHAT A PAIR SPITE 770 00:32:01,753 --> 00:32:03,121 LIKE STRONGYLOIDES INDUCES IN 771 00:32:03,187 --> 00:32:04,222 THE HUMAN HOST. 772 00:32:04,289 --> 00:32:13,197 SO AS MOST OF YOU KNOW, THE 773 00:32:13,264 --> 00:32:18,870 INDUCTION OF TH1 AND TL17 774 00:32:18,936 --> 00:32:21,773 REDUCES ARE CRUCIAL AND IT IS 775 00:32:21,839 --> 00:32:24,542 THE INDUCTION OF THESE CELL 776 00:32:24,609 --> 00:32:26,444 COMPARTMENTS IN CONJUNCTION WITH 777 00:32:26,511 --> 00:32:28,946 CD8 T CELLS AS WELL AS A VARIETY 778 00:32:29,013 --> 00:32:31,015 OF OTHER INNATE IMMUNE CELLS AND 779 00:32:31,082 --> 00:32:33,685 B CELLS THAT ESSENTIALLY RESULT 780 00:32:33,751 --> 00:32:36,721 IN THE PRODUCTION OF PROTECTIVE 781 00:32:36,788 --> 00:32:38,456 SOLID GRANULOMA, WHICH HELPS 782 00:32:38,523 --> 00:32:40,658 CONTAIN THE TB WITHIN THE LUNG, 783 00:32:40,725 --> 00:32:44,929 AND LEADS TO WHAT WE CALL A 784 00:32:44,996 --> 00:32:45,797 LATENT INFECTION IN HUMANS. 785 00:32:45,863 --> 00:32:47,932 IN CONTRAST, IN THE PRESENCE OF 786 00:32:47,999 --> 00:32:49,400 THE SUPPRESSION OF THESE IMMUNE 787 00:32:49,467 --> 00:32:51,402 RESPONSES, EITHER THROUGH 788 00:32:51,469 --> 00:32:52,704 REGULATORY NETWORKS OR THROUGH A 789 00:32:52,770 --> 00:32:56,407 VARIETY OF OTHER MECHANISMS, 790 00:32:56,474 --> 00:33:02,613 THIS -- THAT GRANULOMA -- THE 791 00:33:02,680 --> 00:33:04,282 BACTERIA ARE NOW TRAVERSED INTO 792 00:33:04,349 --> 00:33:08,319 THE LUNG AND THIS RESULTS IN 793 00:33:08,386 --> 00:33:09,954 ACTIVE DISEASE. 794 00:33:10,021 --> 00:33:12,523 SO IN THIS CONTEXT, WE WANTED TO 795 00:33:12,590 --> 00:33:18,062 LOOK AT THE EFFECT OF 796 00:33:18,129 --> 00:33:19,364 STRONGYLOIDES COINFECTION, SO 797 00:33:19,430 --> 00:33:20,565 THE FIRST PART IS GOING TO BE 798 00:33:20,631 --> 00:33:22,233 ACTUALLY LOOKING AT DISEASE 799 00:33:22,300 --> 00:33:23,735 IMMUNITY AND TB TREATMENT 800 00:33:23,801 --> 00:33:24,102 OUTCOMES. 801 00:33:24,168 --> 00:33:27,171 THIS IS PURELY ASKING THE 802 00:33:27,238 --> 00:33:28,673 QUESTION IF YOU HAVE STRONGY, DO 803 00:33:28,740 --> 00:33:30,441 YOU HAVE AN EFFECT ON THE 804 00:33:30,508 --> 00:33:31,743 CLINICAL PICTURE OF 805 00:33:31,809 --> 00:33:32,076 TUBERCULOSIS. 806 00:33:32,143 --> 00:33:33,478 AND SECONDLY WE ARE THEN GOING 807 00:33:33,544 --> 00:33:35,680 TO ASK THE QUESTION, IS THERE 808 00:33:35,747 --> 00:33:39,717 ANY IMMUNOMODULATION THAT TB 809 00:33:39,784 --> 00:33:42,120 ENGENDERS OR -- MODULATION OF 810 00:33:42,186 --> 00:33:49,127 RESPONSES. 811 00:33:49,193 --> 00:33:52,864 SO HERE THE STUDY COHORT IS ALL 812 00:33:52,930 --> 00:33:53,631 TUBERCULOSIS PATIENTS SCREENED 813 00:33:53,698 --> 00:33:55,166 IN ONE OF OUR STUDIES, SO THESE 814 00:33:55,233 --> 00:34:02,473 ARE ALL NEWLY DIAGNOSED CULTURE 815 00:34:02,540 --> 00:34:04,242 POSITIVE PATIENTS WHO ARE DRUG 816 00:34:04,308 --> 00:34:04,776 SENSITIVE. 817 00:34:04,842 --> 00:34:07,945 THESE PATIENTS TYPICALLY GET PUT 818 00:34:08,012 --> 00:34:10,915 ON AN -- WHAT WE ARE DOING IN 819 00:34:10,982 --> 00:34:12,250 THESE PATIENTS WHICH ARE AROUND 820 00:34:12,316 --> 00:34:14,519 400 IN NUMBER IS FOLLOWING THEM 821 00:34:14,585 --> 00:34:17,155 UP AT BASELINE AND THEN UP TO A 822 00:34:17,221 --> 00:34:18,890 PERIOD OF 18 MONTHS. 823 00:34:18,956 --> 00:34:20,324 SO SIX MONTHS OF TREATMENT AND 824 00:34:20,391 --> 00:34:23,861 ONE YEAR OF FOLLOW-UP FOLLOWING 825 00:34:23,928 --> 00:34:25,563 THE END EVER TREATMENT, AND 826 00:34:25,630 --> 00:34:31,402 ASKING THE QUESTION, IS THERE 827 00:34:31,469 --> 00:34:33,905 CLINICAL BACTERIAL AND 828 00:34:33,971 --> 00:34:35,072 IMMUNOLOGICAL EFFECT OF 829 00:34:35,139 --> 00:34:41,312 COEXISTING STRONGY ON PT PATH 830 00:34:41,379 --> 00:34:41,779 JEP CYST. 831 00:34:41,846 --> 00:34:44,382 PATHOGENESIS. 832 00:34:44,449 --> 00:34:51,889 SO IN THIS COHORT, WE HAD -- WE 833 00:34:51,956 --> 00:34:54,892 LOOK AT THE DISEASE -- IN TERMS 834 00:34:54,959 --> 00:34:57,195 OF LUNG LESIONS, WHETHER IT'S 835 00:34:57,261 --> 00:35:01,232 UNILATERAL OR BILATERAL, SO 836 00:35:01,299 --> 00:35:07,605 BILATERAL DISEASE IS -- BECAUSE 837 00:35:07,672 --> 00:35:11,742 IT IS THE FORM OF LUNG DISEASE 838 00:35:11,809 --> 00:35:14,579 THAT ACTUALLY CONTRIBUTES TO 839 00:35:14,645 --> 00:35:16,113 TRANSMISSION AND DISEASE 840 00:35:16,180 --> 00:35:19,717 IMMUNITY, AND FINALLY WHAT THE 841 00:35:19,784 --> 00:35:21,118 MYCOBACTERIUM BURDENS REALLY 842 00:35:21,185 --> 00:35:21,686 ARE. 843 00:35:21,752 --> 00:35:23,554 WE ALSO ARE GOING TO BE LOOKING 844 00:35:23,621 --> 00:35:26,290 AT FOLLOW-UP TO LOOK FOR WHAT WE 845 00:35:26,357 --> 00:35:28,693 CALL UNFAVORABLE TB TREATMENTS. 846 00:35:28,759 --> 00:35:30,661 SO TB TREATMENT OUTCOMES IN 847 00:35:30,728 --> 00:35:32,196 TERMS OF WHAT HAPPENS IS ABOUT 848 00:35:32,263 --> 00:35:41,272 EIGHT'80 TO 85% UNDER STANDARD N 849 00:35:41,339 --> 00:35:42,874 UNDERGO CLINICAL CURE, BUT ABOUT 850 00:35:42,940 --> 00:35:46,711 10 TO 15% UNDERGO UNFAVORABLE 851 00:35:46,777 --> 00:35:48,579 TREATMENT OUTCOMES, AND THESE 852 00:35:48,646 --> 00:35:50,014 INCLUDE TREATMENT FAILURES WHICH 853 00:35:50,081 --> 00:35:51,215 MEANS THEY ARE BASICALLY NOT 854 00:35:51,282 --> 00:35:54,519 RESPONDING TO TREATMENT, 855 00:35:54,585 --> 00:35:56,587 MORTALITY, DEATH DURING 856 00:35:56,654 --> 00:35:59,090 TREATMENT, OR WHAT WE CALL A 857 00:35:59,156 --> 00:36:00,324 RELAPSE OR REINFECTION, THEY GET 858 00:36:00,391 --> 00:36:03,594 CURED AT THE END OF SIX MONTHS, 859 00:36:03,661 --> 00:36:05,396 VERY QUICKLY THAN ONE TO TWO 860 00:36:05,463 --> 00:36:06,764 YEARS AFTER TREATMENT. 861 00:36:06,831 --> 00:36:08,332 SO -- AND THEN WE'D BASICALLY 862 00:36:08,399 --> 00:36:09,834 WANT SOMEONE TO LOOK AT THE 863 00:36:09,901 --> 00:36:11,569 MODULATION OF IMMUNE RESPONSES. 864 00:36:11,636 --> 00:36:15,072 SO IN TERMS OF DISEASE -- AND 865 00:36:15,139 --> 00:36:16,507 TREATMENT FAILURE THE PUNCH LINE 866 00:36:16,574 --> 00:36:18,376 IS HERE, IT JUST ONE SLIDE THAT 867 00:36:18,442 --> 00:36:19,343 SUMMARIZES ALL THE DATA THAT 868 00:36:19,410 --> 00:36:21,546 WE'VE DONE SO FAR, AND WHAT WE 869 00:36:21,612 --> 00:36:23,414 ARE BASICALLY SHOWING YOU IS THE 870 00:36:23,481 --> 00:36:26,050 ODDS RATIO OR THE RISK OF WHAT 871 00:36:26,117 --> 00:36:30,621 HAPPENS TO EITHER THE SPUTUM 872 00:36:30,688 --> 00:36:32,523 SMEAR GRADE OR TREATMENT 873 00:36:32,590 --> 00:36:38,195 OUTCOMES IF YOU HAVE STRONGY 874 00:36:38,262 --> 00:36:39,196 IN -- DO NOT HAVE STRONGY 875 00:36:39,263 --> 00:36:39,931 INFECTION. 876 00:36:39,997 --> 00:36:42,900 SO INDIVIDUALS WITH STRONGY 877 00:36:42,967 --> 00:36:44,535 INFECTION, WHEN COMPARED TO 878 00:36:44,602 --> 00:36:49,574 THOSE WITHOUT, ALL OF THESE -- 879 00:36:49,640 --> 00:36:51,609 TUBERCULOSIS PATIENTS HAVE AN 880 00:36:51,676 --> 00:36:53,411 EIGHT FOLD INCREASED RISK OF 881 00:36:53,477 --> 00:36:55,913 HAVING A MUCH HIGHER SPEAR GRADE 882 00:36:55,980 --> 00:36:58,316 COMPARED TO THOSE WITHOUT. 883 00:36:58,382 --> 00:37:01,586 SIMILARLY THOSE WITH STRONGY 884 00:37:01,652 --> 00:37:03,154 HAVE A FIVE TOLD INCREASED RISK 885 00:37:03,221 --> 00:37:06,324 OF HAVING BILATERAL -- COMPARED 886 00:37:06,390 --> 00:37:09,794 TO THOSE WITHOUT STRONGY. 887 00:37:09,860 --> 00:37:12,763 AND IN ORDER -- ONE OF THE MOST 888 00:37:12,830 --> 00:37:13,864 IMPORTANT DRIVERS OF 889 00:37:13,931 --> 00:37:14,532 TRANSMISSION. 890 00:37:14,599 --> 00:37:17,568 WE ALSO FIND THAT IF YOU HAVE 891 00:37:17,635 --> 00:37:23,274 STRONGY, YOU ARE FIVE TO SIX 892 00:37:23,341 --> 00:37:25,242 FOLD HIGHER RISK COMPARED TO 893 00:37:25,309 --> 00:37:26,544 THOSE THAT DON'T HAVE STRONGY. 894 00:37:26,611 --> 00:37:27,945 FINALLY WHAT YOU THINK IS ALSO 895 00:37:28,012 --> 00:37:29,614 VERY IMPORTANT, ALTHOUGH IT'S A 896 00:37:29,680 --> 00:37:32,183 MILD PEESKT, IS THAT EVEN IN 897 00:37:32,250 --> 00:37:35,086 TERMS OF UNFAVORABLE TREATMENT 898 00:37:35,152 --> 00:37:36,621 OUTCOMES, THERE IS AN INCREASED 899 00:37:36,687 --> 00:37:47,131 RISK OF HAVING STRONGY, -- 900 00:37:50,635 --> 00:37:53,471 1.22 -- ADVERSE TREATMENT 901 00:37:53,537 --> 00:37:54,038 OUTCOMES. 902 00:37:54,105 --> 00:37:55,339 SO ESSENTIALLY WHAT I'M TRYING 903 00:37:55,406 --> 00:37:56,741 TO TELL YOU HERE IS JUST LIKE 904 00:37:56,807 --> 00:38:00,044 OTHER KNOWN FACTORS, RISK 905 00:38:00,111 --> 00:38:02,113 FACTORS FOR DISEASE SEVERITY AND 906 00:38:02,179 --> 00:38:05,616 TREATMENT OUTCOMES IN TB, THE 907 00:38:05,683 --> 00:38:09,687 COMMONLY KNOWN ONES ARE HIB, 908 00:38:09,754 --> 00:38:10,988 DIABETES, MALNUTRITION, 909 00:38:11,055 --> 00:38:13,190 ALCOHOLISM AND SMOKING, SOCIAL 910 00:38:13,257 --> 00:38:14,925 FACTORS, WE THINK HELMINTH 911 00:38:14,992 --> 00:38:16,894 INFECTIONS COULD ALSO HAVE A 912 00:38:16,961 --> 00:38:21,165 VERY SIGNIFICANT ROLE IN 913 00:38:21,232 --> 00:38:23,668 ALTERING THE CLINICAL PICTURE OR 914 00:38:23,734 --> 00:38:26,537 WORSER ENING THE CLINICAL 915 00:38:26,604 --> 00:38:28,172 PICTURE WITH PULMONARY 916 00:38:28,239 --> 00:38:28,506 TUBERCULOSIS. 917 00:38:28,572 --> 00:38:29,807 OF COURSE ALL OF THIS NEEDS TO 918 00:38:29,874 --> 00:38:32,109 BE CONFIRMED IN LARGER COHORTS 919 00:38:32,176 --> 00:38:33,978 AND THAT IS WHAT WE'RE LOOKING 920 00:38:34,045 --> 00:38:35,613 AT BUT HAVING LOOKED AT ABOUT 921 00:38:35,680 --> 00:38:36,814 500 PATIENTS, WHICH IS A PRETTY 922 00:38:36,881 --> 00:38:38,582 LARGE SAMPLE SIZE FOR A TB 923 00:38:38,649 --> 00:38:40,051 STUDY, WE ARE QUITE CONFIDENT 924 00:38:40,117 --> 00:38:43,487 THAT THIS SHOULD BE REPLICATED 925 00:38:43,554 --> 00:38:50,961 IN EVEN -- SO HOW DOES STR STROY 926 00:38:51,028 --> 00:38:51,629 DO THIS? 927 00:38:51,696 --> 00:38:53,030 ONE OF THE WAYS WE THINK IS 928 00:38:53,097 --> 00:38:55,566 LOOKING BY IMMUNE RESPONSES, TB 929 00:38:55,633 --> 00:39:00,938 AND ANTIGEN SPECIFIC RESPONSES. 930 00:39:01,005 --> 00:39:04,675 FOSO HERE WE ARE LOOKING AT 931 00:39:04,742 --> 00:39:06,944 COINFECTED PEOPLE, STRONGY AND 932 00:39:07,011 --> 00:39:09,680 TB TOGETHER, SHOWN IN RED, OR TB 933 00:39:09,747 --> 00:39:10,981 ALONE WHICH IS SHOWN IN BLUE, 934 00:39:11,048 --> 00:39:15,119 AND LOOKING AT MONO FUNCTIONAL 935 00:39:15,186 --> 00:39:18,856 OR DUAL -- FROM -- SO VERY 936 00:39:18,923 --> 00:39:20,191 IMPORTANT IN THE CONTROL OF TB 937 00:39:20,257 --> 00:39:22,827 IN TERMS OF ELIMINATING TB 938 00:39:22,893 --> 00:39:24,795 DISEASE SEVERITY, AND POSSIBLY 939 00:39:24,862 --> 00:39:28,432 ALSO IN TERMS OF TREATMENT 940 00:39:28,499 --> 00:39:31,268 OUTCOMES. 941 00:39:31,335 --> 00:39:33,904 WHEN WE LOOK AT -- 10, WE SEE A 942 00:39:33,971 --> 00:39:35,973 SIGNIFICANT DOWN MODULATION OF 943 00:39:36,040 --> 00:39:40,678 MONO FUNCTION, DUAL FUNCTION 944 00:39:40,745 --> 00:39:42,179 AND -- IN THESE COINFECTED 945 00:39:42,246 --> 00:39:43,647 INDIVIDUALS COMPARED TO THE TB 946 00:39:43,714 --> 00:39:44,415 ALONE INDIVIDUALS. 947 00:39:44,482 --> 00:39:47,485 AND THIS IS TRUE EVEN WHEN WE 948 00:39:47,551 --> 00:39:50,988 LOOK AT DIFFERENT -- WE'RE 949 00:39:51,055 --> 00:39:54,024 LOOKING AT -- WE AGAIN SEE A 950 00:39:54,091 --> 00:39:56,994 SIGNIFICANT DIMINUTION IN MONO 951 00:39:57,061 --> 00:40:01,499 FUNCTION -- IN RESPONSE TO 952 00:40:01,565 --> 00:40:06,971 THE -- IN RESPONSE TO -- 953 00:40:07,037 --> 00:40:08,372 6 PEPTIDE -- EXPRESSION. 954 00:40:08,439 --> 00:40:10,608 IF YOU LOOK AT TH17 CELLS, AGAIN 955 00:40:10,674 --> 00:40:12,443 WE SEE A VERY SIMILAR EFFECT. 956 00:40:12,510 --> 00:40:15,946 THEY'RE NOT AS STRONG BUT 957 00:40:16,013 --> 00:40:16,447 SIGNIFICANT NEFORT LELS. 958 00:40:16,514 --> 00:40:23,120 SO YOU SEE -- CD4 POSITIVE T 959 00:40:23,187 --> 00:40:24,054 CELLS, IN THE COINFECTED 960 00:40:24,121 --> 00:40:26,590 INDIVIDUALS COMPARED TO THE TB 961 00:40:26,657 --> 00:40:29,326 ALONE INDIVIDUALS, AND FINALLY 962 00:40:29,393 --> 00:40:32,830 THERE'S A VERY SIMILAR PATTERN 963 00:40:32,897 --> 00:40:34,899 WITH -- VERY STRONGLY SUGGESTING 964 00:40:34,965 --> 00:40:37,101 THAT ONE OF THE MAJOR MECHANISMS 965 00:40:37,168 --> 00:40:38,969 BY WHICH STRONGY MOD LATES 966 00:40:39,036 --> 00:40:41,605 IMMUNE RESPONSES THROUGH TB IS 967 00:40:41,672 --> 00:40:43,774 BY DOWN MODULATING OR DOWN 968 00:40:43,841 --> 00:40:44,809 REGULATING IMMUNE RESPONSES TO 969 00:40:44,875 --> 00:40:47,945 TWO OF THE CLASSICAL 970 00:40:48,012 --> 00:40:49,180 IMMUNODOMINANT THAT TB RESPONDS 971 00:40:49,246 --> 00:40:49,980 TO. 972 00:40:50,047 --> 00:40:52,583 AND INTERESTINGLY, IT NOT JUST 973 00:40:52,650 --> 00:40:53,584 THE T-CELL RESPONSE. 974 00:40:53,651 --> 00:40:56,654 IF YOU ACTUALLY LOOK AT THE -- 975 00:40:56,720 --> 00:40:57,822 REMEMBER I TOLD YOU ONE OF THE 976 00:40:57,888 --> 00:40:58,756 THINGS WE WERE VERY INTERESTED 977 00:40:58,823 --> 00:41:00,925 IN IN STRONGY IS THAT THE T-CELL 978 00:41:00,991 --> 00:41:02,693 RESPONSE ACTUALLY TRANSLATES TO 979 00:41:02,760 --> 00:41:04,361 THE SYSTEMIC CYTOKINE LEVELS AS 980 00:41:04,428 --> 00:41:04,695 WELL. 981 00:41:04,762 --> 00:41:06,530 WHEN WE LOOK AT PROTECTIVE 982 00:41:06,597 --> 00:41:07,865 LEVELS OF CYTOKINES OR 983 00:41:07,932 --> 00:41:09,533 CIRCULATING LEVELS OF PROTECTOR 984 00:41:09,600 --> 00:41:11,468 SITE KIEPS, SO IN THIS CASE A 985 00:41:11,535 --> 00:41:14,538 DIFFERENT GAMMA, IL2 AND IL-17 986 00:41:14,605 --> 00:41:20,978 A, WE SEE THAT COINFECTED -- IN 987 00:41:21,045 --> 00:41:22,746 COMPARISON WITH INDIVIDUALS WITH 988 00:41:22,813 --> 00:41:26,150 TB ALONE, IN CONTRAST, TWO OF 989 00:41:26,217 --> 00:41:27,885 THE DETRIMENTAL CYTOKINES THAT 990 00:41:27,952 --> 00:41:30,087 BASICALLY DRIVE PATHOLOGY -- 991 00:41:30,154 --> 00:41:33,791 DRIESTLES PATHOLOGY -- IN TB, 992 00:41:33,858 --> 00:41:39,063 INTERFERON ALPHA AND BAIT TA, AE 993 00:41:39,129 --> 00:41:40,831 AT SIGNIFICANTLY HIGHER LEVELS 994 00:41:40,898 --> 00:41:46,403 IN THE CIRCULATION AND THE 995 00:41:46,470 --> 00:41:48,939 COINFECTED -- THAN TB INFECTED 996 00:41:49,006 --> 00:41:52,343 INDIVIDUALS A. 997 00:41:52,409 --> 00:41:55,512 IF YOU LOOK AT IL4, IL5, IL13, 998 00:41:55,579 --> 00:41:59,450 THE TH2 CYTOKINES, AS WELL AS 999 00:41:59,516 --> 00:42:03,520 THE UPSTREAM CYTOKINES OF TH2, 1000 00:42:03,587 --> 00:42:05,256 IL25, IL-33 AS WELL AS THE 1001 00:42:05,322 --> 00:42:07,024 REGULATORY CYTOKINE IL10, ALL OF 1002 00:42:07,091 --> 00:42:09,426 THESE ARE SIGNIFICANTLY 1003 00:42:09,493 --> 00:42:14,698 INCREASED THAT HAVE STR STRONGY 1004 00:42:14,765 --> 00:42:15,132 COINFECTIONS. 1005 00:42:15,199 --> 00:42:21,472 AND FINALLY WE ALSO FIND THAT 1006 00:42:21,538 --> 00:42:24,208 CERTAIN -- FACTORS KNOWN TO 1007 00:42:24,275 --> 00:42:26,944 DRIVE DISEASE PATHOLOGY, 1008 00:42:27,011 --> 00:42:32,416 INCLUDING EGF -- SIGNIFICANTLY 1009 00:42:32,483 --> 00:42:33,517 HEIGHTENED LEVELS IN THE 1010 00:42:33,584 --> 00:42:35,719 CIRCULATION COMPARED TO THE 1011 00:42:35,786 --> 00:42:37,488 UNINFECTED INDIVIDUALS OR 1012 00:42:37,554 --> 00:42:38,322 TB-ALONE INDIVIDUALS, 1013 00:42:38,389 --> 00:42:39,757 SUGGESTING, AGAIN, THAT THERE 1014 00:42:39,823 --> 00:42:42,526 ARE MULTIPLE MECHANISMS BY WHICH 1015 00:42:42,593 --> 00:42:50,734 THE COEXISTING HELMINTH AR -- SO 1016 00:42:50,801 --> 00:42:51,769 I'LL BASICALLY CONCLUDE THIS 1017 00:42:51,835 --> 00:42:53,470 PART OF MY TALK BY SAYING THAT 1018 00:42:53,537 --> 00:42:55,406 HELMINTHS AND TB INTERACTIONS IS 1019 00:42:55,472 --> 00:42:57,641 A VERY DETRIMENTAL INTERACTION. 1020 00:42:57,708 --> 00:43:01,378 IN TERMS OF A TB -- TB 1021 00:43:01,445 --> 00:43:04,648 RESPONSES, BOTH CLINICAL AS WELL 1022 00:43:04,715 --> 00:43:05,616 AS IMMUNOLOGICAL. 1023 00:43:05,683 --> 00:43:08,252 IN THIS CASE STRONGY -- AND I 1024 00:43:08,319 --> 00:43:12,656 DIDN'T SWR DATA TO SHOW ALL THE 1025 00:43:12,723 --> 00:43:15,059 DIFFERENT DATA HAS BEEN SHOWN TO 1026 00:43:15,125 --> 00:43:17,261 DECREASE ANTIGEN PRESENTATION 1027 00:43:17,328 --> 00:43:20,097 AND THIS CELL ACTIVATION. 1028 00:43:20,164 --> 00:43:22,333 STRONGLY PROMOTE -- AND 1029 00:43:22,399 --> 00:43:25,369 INCREASES PROTECTIVE CYTOKINES, 1030 00:43:25,436 --> 00:43:26,904 INCREASES SE VAIRD OF TB DISEASE 1031 00:43:26,971 --> 00:43:29,306 AND ENHANCED BACTERIAL BURDENS, 1032 00:43:29,373 --> 00:43:31,608 THERE BY PROMOTING TRANSMISSION. 1033 00:43:31,675 --> 00:43:34,578 HAS RESULTS OF AN INCREASED RISK 1034 00:43:34,645 --> 00:43:36,447 OF UNFAVORABLE TB TREATMENT 1035 00:43:36,513 --> 00:43:37,648 PROGRAMS AND AGAIN PRELIMINARY, 1036 00:43:37,715 --> 00:43:39,183 PRELIMINARY, THAT WE'LL BE 1037 00:43:39,249 --> 00:43:43,253 LOOKING AT PROGRESSERS OF LTBI 1038 00:43:43,320 --> 00:43:46,090 TO TB, THE PRESENCE OF HELMINTH 1039 00:43:46,156 --> 00:43:49,159 COINFECTIONS MIGHT HAVE A DET 1040 00:43:49,226 --> 00:43:52,329 MENTAL ROAD. 1041 00:43:52,396 --> 00:44:02,906 SO THE FINAL PART OF MY TALK, 1042 00:44:04,174 --> 00:44:05,909 I'M GOING TO BE FOCUSING ON 1043 00:44:05,976 --> 00:44:06,643 SOMETHING COMPLETELY DIFFERENT, 1044 00:44:06,710 --> 00:44:08,479 IN THIS CASE LOOKING AT THE 1045 00:44:08,545 --> 00:44:11,281 EFFECT OF ONE INFECTION ON A 1046 00:44:11,348 --> 00:44:19,289 COMPLETELY -- THE ANSWER AGAIN 1047 00:44:19,356 --> 00:44:22,893 IS SHOWN IN THIS GEOGRAPHIC MAP. 1048 00:44:22,960 --> 00:44:26,196 SHOWN ABOVE IS THE PREVALENCE OF 1049 00:44:26,263 --> 00:44:28,599 HELMINTH INFECTIONS WORLDWIDE, 1050 00:44:28,665 --> 00:44:30,234 ALL SHOWN IN RED, AND SHOWN 1051 00:44:30,300 --> 00:44:32,436 BELOW IS THE PREVALENCE OF TYPE 1052 00:44:32,503 --> 00:44:32,870 2 DIABETES. 1053 00:44:32,936 --> 00:44:33,971 ONE THING THAT YOU CAN NOTICE 1054 00:44:34,038 --> 00:44:35,839 RIGHT OFF THE BAT IF YOU LOOK AT 1055 00:44:35,906 --> 00:44:38,675 PLACES LIKE NORTH AMERICA OR 1056 00:44:38,742 --> 00:44:40,411 EUROPE, THERE IS NO RED IN TERMS 1057 00:44:40,477 --> 00:44:41,378 OF HELMINTH INFECTION. 1058 00:44:41,445 --> 00:44:43,080 SO AREAS WHICH HAVE BOTH 1059 00:44:43,147 --> 00:44:44,948 HELMINTH INFECTIONS PRETTY MUCH 1060 00:44:45,015 --> 00:44:45,916 HAVE SIGNIFICANTLY HIGHER 1061 00:44:45,983 --> 00:44:48,218 PREVALENCE OF TYPE 2 DIABETES. 1062 00:44:48,285 --> 00:44:50,621 SO THIS HERE INDICATES TYPE 1063 00:44:50,687 --> 00:44:50,988 2 DIABETES. 1064 00:44:51,055 --> 00:44:53,690 IN CONTRAST, PLACES LIKE AFRICA, 1065 00:44:53,757 --> 00:44:56,126 WHERE YOU HAVE SIGNIFICANTLY 1066 00:44:56,193 --> 00:44:59,063 HIGH LEVELS, HIGH PREVALENCE OF 1067 00:44:59,129 --> 00:45:03,867 HELMINTH INFECTIONS HAVE -- VERY 1068 00:45:03,934 --> 00:45:06,537 LOW LEVEL OF PRECEDENCE FOR TYPE 1069 00:45:06,603 --> 00:45:08,372 2 DIABETES. 1070 00:45:08,439 --> 00:45:11,108 -- BETWEEN HELMINTH INFECTIONS 1071 00:45:11,175 --> 00:45:12,543 AND A METABOLIC DISORDER, IN 1072 00:45:12,609 --> 00:45:14,578 THIS CASE TYPE 2 DIABETES, AND 1073 00:45:14,645 --> 00:45:17,681 IN ADDITION TO THIS, WE NOTICED 1074 00:45:17,748 --> 00:45:19,683 SOMETHING THAT I ALLUDED TO IN 1075 00:45:19,750 --> 00:45:21,018 THE FIRST PART OF MY TALK, AND 1076 00:45:21,085 --> 00:45:23,921 THAT IS IF YOU LOOKED AT OUR 1077 00:45:23,987 --> 00:45:24,621 4,000 DIFFERENT INDIVIDUALS THAT 1078 00:45:24,688 --> 00:45:29,593 WE SCREENED, INCLUDING THE 1,300 1079 00:45:29,660 --> 00:45:31,095 INDIVIDUALS WITH STRONGY, WE HAD 1080 00:45:31,161 --> 00:45:34,298 DETERMINED OR WE HAD SHOWN THAT 1081 00:45:34,364 --> 00:45:36,366 THERE IS A SIGNIFICANT LOWERING 1082 00:45:36,433 --> 00:45:39,269 IN THE PARAMETERS THAT DICTATE 1083 00:45:39,336 --> 00:45:43,740 TYPE 2 DIABETES, BOTH BLOOD 1084 00:45:43,807 --> 00:45:45,943 GLUCOSE AND A1C, SO 1085 00:45:46,009 --> 00:45:48,045 SIGNIFICANTLY LOWER LEVELS OF 1086 00:45:48,112 --> 00:45:51,215 RANDOM BLOOD GLUCOSE AS WELL AS 1087 00:45:51,281 --> 00:45:54,952 A1C NOTICED IN STRONGY INFECTED 1088 00:45:55,018 --> 00:45:56,820 INDIVIDUALS, SO NOT JUST 1089 00:45:56,887 --> 00:45:57,488 DIABETIC INDIVIDUALS ALONE. 1090 00:45:57,554 --> 00:45:58,922 SO WE WANTED TO ASK THE 1091 00:45:58,989 --> 00:46:01,325 QUESTION, IF YOU NOW LOOK AT 1092 00:46:01,391 --> 00:46:03,861 TYPE 2 DIABETES WITHOUT STRONGY 1093 00:46:03,927 --> 00:46:05,229 INFECTION, WHAT ARE THE CHANGES 1094 00:46:05,295 --> 00:46:10,200 THAT STRONGY DOES IN THIS 1095 00:46:10,267 --> 00:46:11,735 PARTICULAR CO-MORBIDITY. 1096 00:46:11,802 --> 00:46:13,403 SO AS I SAID, WE WANTED TO STUDY 1097 00:46:13,470 --> 00:46:14,705 THE INTERACTION BETWEEN STRONGY 1098 00:46:14,771 --> 00:46:16,974 AND TYPE 2 DIABETES, AND LOOK AT 1099 00:46:17,040 --> 00:46:20,777 A VARIETY OF BIOCHEMICAL, 1100 00:46:20,844 --> 00:46:21,845 HORMONAL AND BIOLOGICAL 1101 00:46:21,912 --> 00:46:22,946 PARAMETERS THAT AFFECT TWO 1102 00:46:23,013 --> 00:46:25,082 DIFFERENT PHASES OF TYPE 1103 00:46:25,149 --> 00:46:25,382 2 DIABETES. 1104 00:46:25,449 --> 00:46:29,753 ONE IS LOOKING AT PATHOGENESIS 1105 00:46:29,820 --> 00:46:33,824 OF THE -- AND CONTROL. 1106 00:46:33,891 --> 00:46:35,359 PEOPLE WITH DIABETES USUALLY ARE 1107 00:46:35,425 --> 00:46:36,560 MUCH -- HIGHLY PRONE FOR A 1108 00:46:36,627 --> 00:46:40,497 VARIETY OF COMPLICATIONS, MAINLY 1109 00:46:40,564 --> 00:46:43,834 MICROVASCULAR, MICROVASCULAR -- 1110 00:46:43,901 --> 00:46:45,235 WE WANT TO LOOK AT THE 1111 00:46:45,302 --> 00:46:50,240 PARAMETERS THAT COULD -- SO THE 1112 00:46:50,307 --> 00:46:54,144 PROTOCOL IS BASICALLY LOOKING AT 1113 00:46:54,211 --> 00:46:55,846 60 STRONG GEE INFECTED PATIENTS 1114 00:46:55,913 --> 00:46:59,550 AND 58 CONTROLS. 1115 00:46:59,616 --> 00:47:01,084 WE COLLECT PLASMA AND LOOK AT A 1116 00:47:01,151 --> 00:47:03,287 VARIETY OF PARAMETERS THAT WE 1117 00:47:03,353 --> 00:47:07,824 KNOW DRIVES DIABETES SEVERITY. 1118 00:47:07,891 --> 00:47:09,026 AND BASICALLY ASKED THE QUESTION 1119 00:47:09,092 --> 00:47:11,094 WHAT DOES THE BASELINE LEVELS OF 1120 00:47:11,161 --> 00:47:12,996 THESE PARAMETERS IN THESE 1121 00:47:13,063 --> 00:47:14,097 STRONGY INFECTED INDIVIDUALS 1122 00:47:14,164 --> 00:47:15,832 COMPARED TO CONTROLS, AND ALSO 1123 00:47:15,899 --> 00:47:19,903 ASK THE QUESTION, IF YOU TREAT 1124 00:47:19,970 --> 00:47:21,238 STRONGY, DOES IT ACTUALLY HELP 1125 00:47:21,305 --> 00:47:24,841 OR WORSEN THE PICTURE FOR TYPE . 1126 00:47:24,908 --> 00:47:26,376 SO THAT'S BASICALLY WHAT WE ARE 1127 00:47:26,443 --> 00:47:30,881 LOOKING AT. 1128 00:47:30,948 --> 00:47:34,585 SO THE FIRST THING WE NOTICED IN 1129 00:47:34,651 --> 00:47:36,853 THIS FIRST ROUND OF PATIENT IS 1130 00:47:36,920 --> 00:47:38,455 REMEMBER ALL OF THESE PATIENTS 1131 00:47:38,522 --> 00:47:40,090 ARE TYPE 2 DIABETIC, SO ALL OF 1132 00:47:40,157 --> 00:47:44,061 THEM WILL HAVE HIGH LEVELS OF 1133 00:47:44,127 --> 00:47:47,898 RANDOM LEVEL -- IT HAS A VERY -- 1134 00:47:47,965 --> 00:47:50,300 PEOPLE WITH STRONGY WHO ARE 1135 00:47:50,367 --> 00:47:53,570 SHOWN HERE IN RED HAVE 1136 00:47:53,637 --> 00:47:55,672 SIGNIFICANT LOWER OF -- COMPARED 1137 00:47:55,739 --> 00:47:57,674 TO THE UNINFECTED TYPE 1138 00:47:57,741 --> 00:47:59,076 2 DIABETIC PATIENTS SHOWN IN 1139 00:47:59,142 --> 00:48:00,744 GREEN, AND SIGNIFICANTLY LOWER 1140 00:48:00,811 --> 00:48:04,348 LEVELS OF RANDOM BLOOD GLUCOSE. 1141 00:48:04,414 --> 00:48:06,316 INTERESTINGLY, WE ALSO SEE 1142 00:48:06,383 --> 00:48:07,417 SIGNIFICANTLY LOW LEVELS OF 1143 00:48:07,484 --> 00:48:10,954 CIRCULATING INSULIN AS WELL AS 1144 00:48:11,021 --> 00:48:13,257 GLUCAGON, TWO PA PANCREATIC 1145 00:48:13,323 --> 00:48:15,125 HORMONES THAT DRIVE THE TYPE 1146 00:48:15,192 --> 00:48:16,860 2 DIABETES PHENOTYPE, BUT MORE 1147 00:48:16,927 --> 00:48:18,662 INTERESTINGLY IF YOU ACTUALLY 1148 00:48:18,729 --> 00:48:21,265 TREAT TRON GEE AND THEN LOOK AT 1149 00:48:21,331 --> 00:48:22,699 THESE PARAMETERS SIX MONTHS 1150 00:48:22,766 --> 00:48:24,268 LATER, YOU ACTUALLY SEE THERE IS 1151 00:48:24,334 --> 00:48:28,305 AN INCREASE IN A1C, INCREASE IN 1152 00:48:28,372 --> 00:48:30,474 INSULIN AND INCREASE IN 1153 00:48:30,540 --> 00:48:31,041 GLUCAGON. 1154 00:48:31,108 --> 00:48:34,144 SO ESSENTIALLY WHAT I'M SHARING 1155 00:48:34,211 --> 00:48:35,545 WITH YOU, THE CONTROL AS WELL AS 1156 00:48:35,612 --> 00:48:38,515 THE SEVERITY OF DIABETES IS 1157 00:48:38,582 --> 00:48:42,252 SIGNIFICANTLY BETTER IF YOU HAVE 1158 00:48:42,319 --> 00:48:43,220 STRONGY COINFECTION, AND GETTING 1159 00:48:43,287 --> 00:48:44,655 RID OF STRONGY IN THIS 1160 00:48:44,721 --> 00:48:45,522 PARTICULAR CONTEXT IS ACTUALLY 1161 00:48:45,589 --> 00:48:47,758 NOT GOOD FOR YOU, BECAUSE YOU 1162 00:48:47,824 --> 00:48:48,625 ACTUALLY WORSEN YOUR CONTROL OF 1163 00:48:48,692 --> 00:48:52,562 TYPE 2 DIABETES. 1164 00:48:52,629 --> 00:48:53,764 AND WHY IS THAT? 1165 00:48:53,830 --> 00:48:55,232 THERE APPEARS TO BE MULTIPLE 1166 00:48:55,299 --> 00:48:56,300 DIFFERENT PARAMETERS THAT GET 1167 00:48:56,366 --> 00:48:57,934 ALTERED BY STRONGY AND THESE ARE 1168 00:48:58,001 --> 00:49:00,504 ALL, AGAIN, ASSOCIATION DATA. 1169 00:49:00,570 --> 00:49:03,240 WE DON'T HAVE A CAUSE AND EFFECT 1170 00:49:03,307 --> 00:49:04,107 RELATIONSHIP, IT'S VERY HARD TO 1171 00:49:04,174 --> 00:49:06,109 DETERMINE THAT IN HUMANS, BUT WE 1172 00:49:06,176 --> 00:49:07,878 THINK THAT BY MODULATING A 1173 00:49:07,944 --> 00:49:10,480 VARIETY OF DIFFERENT PARAMETERS 1174 00:49:10,547 --> 00:49:12,249 THAT DRIVE DIABETES OR DIABETES 1175 00:49:12,316 --> 00:49:13,684 SEVERITY AND COMPLICATIONS THAT 1176 00:49:13,750 --> 00:49:14,785 STRONGY CAN MODULATE THIS. 1177 00:49:14,851 --> 00:49:20,190 SO THE FIRST ONE IS LOOKING AT 1178 00:49:20,257 --> 00:49:21,591 ADIPOCYTOKINES, BASICALLY 1179 00:49:21,658 --> 00:49:24,094 HORMONES PRODUCED BY ADIPOSE 1180 00:49:24,161 --> 00:49:25,862 TISSUE AND CAN DRIVE THE 1181 00:49:25,929 --> 00:49:27,331 PROGRESSION OF PATHOGENESIS OF 1182 00:49:27,397 --> 00:49:29,299 METABOLIC DISORDERS, AND WE FIND 1183 00:49:29,366 --> 00:49:34,471 THAT TRON GEE BASICALLY DOWN 1184 00:49:34,538 --> 00:49:36,973 REGULATES, WHICH ARE BOTH 1185 00:49:37,040 --> 00:49:38,275 PATHOGENIC FACTORS DRIVERRING 1186 00:49:38,342 --> 00:49:43,580 DRIVING TYPE2 DIABETES AND THISS 1187 00:49:43,647 --> 00:49:44,448 REVERSED DURING TREATMENT. 1188 00:49:44,514 --> 00:49:45,415 THEN IF YOU LOOK AT THE OTHER 1189 00:49:45,482 --> 00:49:48,051 SET OF HORMONAL MEDIATORS, IN 1190 00:49:48,118 --> 00:49:51,355 THIS PARTICULAR CASE, WHAT ARE 1191 00:49:51,421 --> 00:49:52,556 CALLED -- THESE ARE BASICALLY 1192 00:49:52,622 --> 00:49:53,990 MOLECULES THAT ARE ACTUALLY GOOD 1193 00:49:54,057 --> 00:49:54,991 FOR YOU BECAUSE THEY ARE THE 1194 00:49:55,058 --> 00:49:57,661 ONES THAT DRIVE PROTECTION 1195 00:49:57,728 --> 00:49:58,795 AGAINST METABOLIC DISORDERS AND 1196 00:49:58,862 --> 00:50:01,131 IN FACT SOME OF THESE ARE NOW 1197 00:50:01,198 --> 00:50:02,566 BEING USED WORLDWIDE FOR 1198 00:50:02,632 --> 00:50:05,001 TREATMENT OF OBESITY AND TYPE 1199 00:50:05,068 --> 00:50:05,869 2 DIABETES. 1200 00:50:05,936 --> 00:50:10,941 SO IF YOU LOOK AT GHRELIN, GI 1201 00:50:11,007 --> 00:50:15,746 P&G LP-1 YOU'LL SEE STRONGY IS 1202 00:50:15,812 --> 00:50:17,381 SIGNIFICANTED WITH HIGHER 1203 00:50:17,447 --> 00:50:19,349 LEVELS -- AGAIN IF YOU TREAT 1204 00:50:19,416 --> 00:50:22,119 THESE PATIENTS, YOU'RE ACTUALLY 1205 00:50:22,185 --> 00:50:23,987 WORSE OFF BECAUSE YOU DON'T 1206 00:50:24,054 --> 00:50:29,226 MODULATE THESE VERY -- 1207 00:50:29,292 --> 00:50:29,960 MODULATORS. 1208 00:50:30,026 --> 00:50:31,561 SO TYPE 2 DIABETES IS ALSO, 1209 00:50:31,628 --> 00:50:32,529 ALTHOUGH NOT CLASSICALLY THOUGHT 1210 00:50:32,596 --> 00:50:36,032 OF AS SUCH, IS ALSO VERY 1211 00:50:36,099 --> 00:50:37,834 INFLAMMATORY DISORDER, 1212 00:50:37,901 --> 00:50:39,369 CLASSICALLY ASSOCIATED WITH 1213 00:50:39,436 --> 00:50:41,104 INFLAMMATION, IN THIS PARTICULAR 1214 00:50:41,171 --> 00:50:43,807 CASE, A TERM THAT IS COMMONLY 1215 00:50:43,874 --> 00:50:50,414 USED IS METAINFLAMMATION, AND IT 1216 00:50:50,480 --> 00:50:53,583 IS -- SO WITH THE QUESTION WE 1217 00:50:53,650 --> 00:50:55,919 ASKED, DOES TRON GEE DO ANYTHING 1218 00:50:55,986 --> 00:50:57,454 TO DAMPEN THE INFORMATION AND 1219 00:50:57,521 --> 00:50:58,655 THE ANSWER IS CLEARLY YES, 1220 00:50:58,722 --> 00:51:00,724 BECAUSE IF YOU LOOK AT PRETTY 1221 00:51:00,791 --> 00:51:03,093 MUCH MOST -- EVERY CYTOKINE THAT 1222 00:51:03,160 --> 00:51:08,465 WE'LL EXAMINE, WITH THE 1223 00:51:08,532 --> 00:51:11,201 EXCEPTION OF IL22, BECAUSE 1224 00:51:11,268 --> 00:51:12,636 IL22 IS ONE OF THE FEW FACTORS 1225 00:51:12,702 --> 00:51:14,938 WHICH ACTUALLY ARE PROTECTIVE 1226 00:51:15,005 --> 00:51:15,872 AGAINST METABOLIC DISORDERS. 1227 00:51:15,939 --> 00:51:17,874 THAT IS THE ONLY ONE THAT IS 1228 00:51:17,941 --> 00:51:18,875 ACTUALLY SIGNIFICANTLY ELEVATED 1229 00:51:18,942 --> 00:51:20,744 IN STRONGY BUT EVERYTHING ELSE 1230 00:51:20,811 --> 00:51:25,048 IS DOWN MODULATED. 1231 00:51:25,115 --> 00:51:28,084 SO STRONGY CLEARLY HELPS IN DOWN 1232 00:51:28,151 --> 00:51:28,985 MODULATING THE PRO-INFLAMMATORY 1233 00:51:29,052 --> 00:51:30,654 MILIEU THAT EXISTS IN TYPE 1234 00:51:30,720 --> 00:51:33,723 2 DIABETES AND PERHAPS HELPS IN 1235 00:51:33,790 --> 00:51:40,297 ALLEVIATING DISEASE SEVERITY. 1236 00:51:40,363 --> 00:51:45,669 IL1 ALPHA AND IL1 BETA ARE -- 1237 00:51:45,735 --> 00:51:47,204 THAT OCCURS IN TYPE 2 DIABETES, 1238 00:51:47,270 --> 00:51:49,072 BOTH OF THEM ARE SIGNIFICANTLY 1239 00:51:49,139 --> 00:51:52,275 LOWER, AND IL-6 -- THAT ARE ALSO 1240 00:51:52,342 --> 00:51:54,444 SIGNIFICANTLY LOWER. 1241 00:51:54,511 --> 00:51:56,413 AND FINALLY STRONGY ALSO, 1242 00:51:56,480 --> 00:51:58,014 BECAUSE THIS IS A CLASSICAL 1243 00:51:58,081 --> 00:52:00,617 INDUCER OF TH2 OR TYPE 1244 00:52:00,684 --> 00:52:02,252 2 CYTOKINE RESPONSES ALSO DRIVES 1245 00:52:02,319 --> 00:52:08,859 THE UPREGULATION OF IL4, IL5, 1246 00:52:08,925 --> 00:52:12,462 IL13 -- ALL OF THESE COMBINED 1247 00:52:12,529 --> 00:52:19,135 POSSIBLY IS ABLE TO ALLEVIATE -- 1248 00:52:19,202 --> 00:52:20,370 AS WELL AS GLUCOSE CONTROL IN 1249 00:52:20,437 --> 00:52:21,304 DIABETES. 1250 00:52:21,371 --> 00:52:26,476 FINALLY, SO THE QUESTION THEN WE 1251 00:52:26,543 --> 00:52:29,246 WE -- STRONGY APPEARS IN 1252 00:52:29,312 --> 00:52:30,780 INDIVIDUALS WHO ALREADY HAVE 1253 00:52:30,847 --> 00:52:33,083 TYPE 2 DIABETES, STRONGY IS 1254 00:52:33,149 --> 00:52:34,618 ACTUALLY DOING YOU GOOD. 1255 00:52:34,684 --> 00:52:38,388 BUT IT ALSO HAS PROPHYLACTIC 1256 00:52:38,455 --> 00:52:41,858 EFFECT IN -- TO DO THIS WE 1257 00:52:41,925 --> 00:52:44,928 BASICALLY LOOKED AT A VARIETY OF 1258 00:52:44,995 --> 00:52:46,530 DIFFERENT PARAMETERS THAT DRIVE 1259 00:52:46,596 --> 00:52:48,265 THESE COMPLICATING PATHWAYS 1260 00:52:48,331 --> 00:52:54,938 INCLUDING ACUTE PHASE PROTEI 1261 00:52:55,005 --> 00:52:56,006 PROTEINS, -- I'M GOING TO 1262 00:52:56,072 --> 00:52:57,374 QUICKLY GO THROUGH THIS AND TELL 1263 00:52:57,440 --> 00:52:59,876 YOU THAT PRETTY MUCH MOST OF THE 1264 00:52:59,943 --> 00:53:01,511 FACTORS THAT WE LOOKED AT, SO IN 1265 00:53:01,578 --> 00:53:08,251 THIS CASE ACUTE PHASE PROTEIN -- 1266 00:53:08,318 --> 00:53:10,220 ALL OF THESE ARE SIGNIFICANTLY 1267 00:53:10,287 --> 00:53:15,292 DOWN MODULATED IN TR STRONGY 1268 00:53:15,358 --> 00:53:17,027 INFECTED INDIVIDUALS WHO HAVE 1269 00:53:17,093 --> 00:53:17,827 TYPE 2 DIABETES COMPARED TO 1270 00:53:17,894 --> 00:53:19,095 THOSE WHO DON'T HAVE STRONGY, 1271 00:53:19,162 --> 00:53:20,463 AND THIS GETS REVERSED UPON 1272 00:53:20,530 --> 00:53:22,866 TREATMENT OF STRONGY INFECTION. 1273 00:53:22,933 --> 00:53:25,569 SIMILARLY, MICROBIAL MARKERS 1274 00:53:25,635 --> 00:53:28,939 WHICH ARE A REFLECTION OF -- 1275 00:53:29,005 --> 00:53:31,007 DYSBIOSIS AND GUT DAMAGE IN 1276 00:53:31,074 --> 00:53:33,209 DIABETIC PATIENTS, ALSO GETS 1277 00:53:33,276 --> 00:53:36,112 DOWN MODULATING, MOST OF THESE 1278 00:53:36,179 --> 00:53:39,916 ARE DOWN MODULATED WITH -- 1279 00:53:39,983 --> 00:53:44,521 TREATMENT, AND IMPORTANT DRIVERS 1280 00:53:44,588 --> 00:53:52,862 OF THE VASCULAR COMPLICATIO 1281 00:53:52,929 --> 00:53:55,098 COMPLICATIONS -- -- ARE ALL DOWN 1282 00:53:55,165 --> 00:53:56,833 MODULATED IN TYPE 2 DIABETIC 1283 00:53:56,900 --> 00:53:59,035 PATIENTS WITH STRONGY 1284 00:53:59,102 --> 00:54:02,872 COINFECTION, AND FINALLY -- 1285 00:54:02,939 --> 00:54:04,841 LIGANDS AS COMPLEMENT PATHWAYS 1286 00:54:04,908 --> 00:54:06,610 WHICH ARE IMPORTANT IN DRIVING 1287 00:54:06,676 --> 00:54:08,612 THE COMPLICATIONS OF TYPE 1288 00:54:08,678 --> 00:54:09,913 2 DIABETES ARE ALSO DOWN 1289 00:54:09,980 --> 00:54:10,246 MODULATED. 1290 00:54:10,313 --> 00:54:11,681 SO STRONGY, AGAIN, JUST LIKE IT 1291 00:54:11,748 --> 00:54:13,717 DOES IN TERMS OF MODULATING THE 1292 00:54:13,783 --> 00:54:16,486 IMMUNE SYSTEM IN THE DIFFERENT 1293 00:54:16,553 --> 00:54:20,523 ARMS, APPEARED -- A VARIETY OF 1294 00:54:20,590 --> 00:54:28,298 DIFFERENT PATHWAYS THAT -- SO 1295 00:54:28,365 --> 00:54:30,367 BASICALLY THE CONCLUSION HERE IS 1296 00:54:30,433 --> 00:54:33,336 THAT WE THINK THAT HELMINTHS ARE 1297 00:54:33,403 --> 00:54:34,471 NOT ALL BAD. 1298 00:54:34,537 --> 00:54:37,340 IN THIS PARTICULAR CASE, 1299 00:54:37,407 --> 00:54:40,243 HELMINTH BENEFITS, SO STRONGY 1300 00:54:40,310 --> 00:54:42,012 MIGHT ACTUALLY DO YOU A LOT OF 1301 00:54:42,078 --> 00:54:43,113 GOOD BUT DEPENDING ON THE 1302 00:54:43,179 --> 00:54:44,814 CONTEXT IN WHICH IT IS PRESENT. 1303 00:54:44,881 --> 00:54:47,550 SO WITH THAT, I'M GOING TO 1304 00:54:47,617 --> 00:54:53,523 BASICALLY END BY ACKNOWLEDGING 1305 00:54:53,590 --> 00:54:55,592 THE LAB TEAM, THE FIELD TEAM, 1306 00:54:55,659 --> 00:54:58,628 BOTH PAST AND PRESENT, 1307 00:54:58,695 --> 00:55:05,602 ESPECIALLY THREE INDIVIDUALS, AS 1308 00:55:05,669 --> 00:55:07,671 WELL AS A PREVIOUS LAB MEMBER, 1309 00:55:07,737 --> 00:55:09,739 DR. GEORGE, WHO HAVE BEEN -- WHO 1310 00:55:09,806 --> 00:55:12,876 WERE INSTRUMENTAL IN STUDIES IN 1311 00:55:12,942 --> 00:55:17,681 THE STRONGY FIELD. 1312 00:55:17,747 --> 00:55:20,517 ALSO ACKNOWLEDGE MY MENTOR, AS 1313 00:55:20,583 --> 00:55:23,453 WELL AS COLLABORATORS HERE AT 1314 00:55:23,520 --> 00:55:26,423 NIH, AND PREVIOUSLY -- AS WELL 1315 00:55:26,489 --> 00:55:29,959 AS A VARIETY OF COLLABORATORS 1316 00:55:30,026 --> 00:55:31,728 ACROSS INDIA AND SPECIFICALLY I 1317 00:55:31,795 --> 00:55:33,663 WOULD ALSO LIKE TO ESPECIALLY 1318 00:55:33,730 --> 00:55:36,032 EXTEND MY THANKS TO OUR HOST 1319 00:55:36,099 --> 00:55:36,599 INSTITUTE, THE NATIONAL 1320 00:55:36,666 --> 00:55:39,135 INSTITUTE OF RESEARCH IN 1321 00:55:39,202 --> 00:55:43,139 TUBERCULOSIS, ESPECIALLY THE -- 1322 00:55:43,206 --> 00:55:46,009 WHO HAVE BEEN INSTRUMENTAL IN 1323 00:55:46,076 --> 00:55:48,545 HELPING US DO THESE SORT OF 1324 00:55:48,611 --> 00:55:50,080 BASIC RESEARCH, CLINICAL 1325 00:55:50,146 --> 00:55:52,182 RESEARCH AND ANIMAL RESEARCH 1326 00:55:52,248 --> 00:55:55,919 STUDIES IN SOUTH INDIA. 1327 00:55:55,985 --> 00:56:02,058 AND I'D ALSO LIKE TO BASICALLY 1328 00:56:02,125 --> 00:56:03,359 END BY SAYING THAT WE HAVE OVER 1329 00:56:03,426 --> 00:56:05,595 THE PAST COUPLE OF DECADES 1330 00:56:05,662 --> 00:56:09,065 ESTABLISHED A VERY EXTENSIVE 1331 00:56:09,132 --> 00:56:10,300 INDIA RESEARCH NETWORK. 1332 00:56:10,366 --> 00:56:12,635 WE HAVE CLINICAL COLLABORATORS 1333 00:56:12,702 --> 00:56:14,270 FROM OVER 30 DIFFERENT 1334 00:56:14,337 --> 00:56:15,572 INSTITUTIONS AND WE HAVE THUS 1335 00:56:15,638 --> 00:56:18,842 FAR CONDUCTED ABOUT 32 DIFFERENT 1336 00:56:18,908 --> 00:56:22,412 CLINICAL TRIALS, SO I WOULD BE 1337 00:56:22,479 --> 00:56:25,815 VERY HAPPY TO, YOU KNOW, CONNECT 1338 00:56:25,882 --> 00:56:27,884 WITH ANY NIH OR FDA INVESTIGATOR 1339 00:56:27,951 --> 00:56:31,421 WHO IS INTERESTED IN DOING 1340 00:56:31,488 --> 00:56:34,290 EITHER BASIC CLINICAL OR 1341 00:56:34,357 --> 00:56:36,893 IMMUNOLOGICAL STUDIES IN INDIA. 1342 00:56:36,960 --> 00:56:38,261 AND THIS IS MY CONTACT 1343 00:56:38,328 --> 00:56:38,995 INFORMATION. 1344 00:56:39,062 --> 00:56:41,865 AND FINALLY, ALSO LIKE TO THANK 1345 00:56:41,931 --> 00:56:48,238 THE NIAID SUPPORT FOR ICER, 1346 00:56:48,304 --> 00:56:48,838 SPECIFICALLY MARK, CHRIS, AND 1347 00:56:48,905 --> 00:56:50,240 OTHERS. 1348 00:56:50,306 --> 00:56:52,041 WITH THAT, I'M HAPPY TO CONCLUDE 1349 00:56:52,108 --> 00:56:52,976 AND TAKE ANY QUESTIONS. 1350 00:56:53,042 --> 00:56:53,743 THANK YOU SO MUCH. 1351 00:56:53,810 --> 00:57:03,987 [APPLAUSE] 1352 00:57:05,655 --> 00:57:08,591 >> HI, SUBASH, THAT WAS GREAT. 1353 00:57:08,658 --> 00:57:10,894 I HAVE THREE QUESTIONS. 1354 00:57:10,960 --> 00:57:14,197 WITH YOUR STRONGY TYPE 1355 00:57:14,264 --> 00:57:17,167 2 DIABETES ASSOCIATION, SO I 1356 00:57:17,233 --> 00:57:18,468 PRESUME THIS PARASITE RESIDES IN 1357 00:57:18,535 --> 00:57:21,471 THE GUT, AND THERE IS GUT 1358 00:57:21,538 --> 00:57:23,673 PATHOLOGY INVOLVED, AND ALSO THE 1359 00:57:23,740 --> 00:57:25,642 PARASITE ITSELF MOST LIKELY IS 1360 00:57:25,708 --> 00:57:27,710 CONSUMING SOME OF THE FOOD THAT 1361 00:57:27,777 --> 00:57:28,411 THE PATIENT -- 1362 00:57:28,478 --> 00:57:29,946 >> CAN YOU SPEAK INTO THE MIC? 1363 00:57:30,013 --> 00:57:31,748 I'M SORRY, I'M HEARING IMPAIRED. 1364 00:57:31,815 --> 00:57:32,949 >> CAN YOU HEAR ME NOW? 1365 00:57:33,016 --> 00:57:33,283 OKAY. 1366 00:57:33,349 --> 00:57:36,452 SO I WAS JUST WONDERING, THE 1367 00:57:36,519 --> 00:57:37,887 METABOLIC CHANGES THAT YOU HAVE 1368 00:57:37,954 --> 00:57:39,289 SEEN AFTER STRONGY INFECTION, 1369 00:57:39,355 --> 00:57:41,424 HOW MUCH IS IT BECAUSE THE 1370 00:57:41,491 --> 00:57:43,393 PATIENTS DON'T HAVE GOOD FOOD 1371 00:57:43,459 --> 00:57:44,828 ABSORPTION DUE TO THE GUT 1372 00:57:44,894 --> 00:57:46,029 PATHOLOGY AND THE PARASITE 1373 00:57:46,095 --> 00:57:48,932 ITSELF WILL BE CONSUMING SOME OF 1374 00:57:48,998 --> 00:57:51,534 THE FOOD, SO WHEN YOU TREATED 1375 00:57:51,601 --> 00:57:55,605 THE PATIENTS, DOES THEIR FOOD 1376 00:57:55,672 --> 00:57:59,909 ABSORPTION ALSO IMPROVE, AND ARE 1377 00:57:59,976 --> 00:58:02,745 THESE CHANGES INDUCED BY TYPE 1378 00:58:02,812 --> 00:58:05,248 2 CYTOKINES OR MEA IT BE LIGHTS 1379 00:58:05,315 --> 00:58:06,850 THAT HAVE -- SO WHEN YOU TREATED 1380 00:58:06,916 --> 00:58:07,951 THE PATIENTS AND REMOVE THE 1381 00:58:08,017 --> 00:58:10,153 PARASITE DO YOU ALSO SEE A VERY 1382 00:58:10,220 --> 00:58:12,956 FAST DROP IN TH2 CYTOKINES? 1383 00:58:13,022 --> 00:58:15,191 >> SO I THINK I SHOWED THAT A 1384 00:58:15,258 --> 00:58:18,294 LITTLE BIT IN THE EARLIER SLIDE, 1385 00:58:18,361 --> 00:58:20,964 SO YES, THE FIRST PART OF YOUR 1386 00:58:21,030 --> 00:58:22,932 QUESTION IS HOW MUCH IS IT 1387 00:58:22,999 --> 00:58:24,133 ATTRIBUTABLE TO FOOD INTAKE AND 1388 00:58:24,200 --> 00:58:26,069 THE LOWERING OF FOOD ABSORPTION. 1389 00:58:26,135 --> 00:58:29,572 I THINK THAT'S A GREAT QUESTION. 1390 00:58:29,639 --> 00:58:32,408 IT PROBABLY HAS AN EFFECT BUT 1391 00:58:32,475 --> 00:58:34,210 STRONGY IS NOT ONE OF THOSE 1392 00:58:34,277 --> 00:58:36,412 PATHOGENS THAT BASICALLY INDUCE 1393 00:58:36,479 --> 00:58:40,717 MALL ABSORPTIMALABSORPTION TO AT 1394 00:58:40,783 --> 00:58:41,918 EX-STENT SO WE DON'T THINK IT'S 1395 00:58:41,985 --> 00:58:43,553 DIRECTLY AN EFFECT OF JUST 1396 00:58:43,620 --> 00:58:48,157 LOWERING OF CALORIE-RICH INTAKE. 1397 00:58:48,224 --> 00:58:49,726 WE THINK IT'S A MULTIPRONGED 1398 00:58:49,792 --> 00:58:51,928 CHANGE THAT HAPPENS, STRONGY 1399 00:58:51,995 --> 00:58:53,663 BECAUSE IT'S PRESENT OF ITS 1400 00:58:53,730 --> 00:58:55,064 ABILITY TO BE IN THE CIRCULATION 1401 00:58:55,131 --> 00:58:56,432 CAN ACTUALLY AFFECT THE 1402 00:58:56,499 --> 00:58:58,635 DIFFERENT ORGAN SYSTEMS, 1403 00:58:58,701 --> 00:58:59,602 INCLUDING DIRECT EFFECT NOT JUST 1404 00:58:59,669 --> 00:59:01,537 ON THE GUT BUT ON ADIPOSE TISSUE 1405 00:59:01,604 --> 00:59:02,972 AS WELL, BUT HAVING SAID THAT, 1406 00:59:03,039 --> 00:59:05,475 TO ANSWER YOUR SECOND QUESTION, 1407 00:59:05,541 --> 00:59:08,912 YES, WE DO SEE SIGNIFICANT DOWN 1408 00:59:08,978 --> 00:59:10,780 MODULATION OF TYPE 2 CYTOKINES 1409 00:59:10,847 --> 00:59:12,215 AS WELL AS REGULATORY CYTOKINES 1410 00:59:12,282 --> 00:59:13,283 FOLLOWING TREATMENT IN THESE 1411 00:59:13,349 --> 00:59:16,552 PATIENTS. 1412 00:59:16,619 --> 00:59:17,487 SO PRETTY MUCH -- 1413 00:59:17,553 --> 00:59:19,455 >> AND I'LL JUST ASK ONE MORE 1414 00:59:19,522 --> 00:59:23,493 QUESTION BECAUSE I SEE -- WITH 1415 00:59:23,559 --> 00:59:25,128 THE TUBERCULOSIS COINFECTIONS, 1416 00:59:25,194 --> 00:59:27,730 THAT ASSOCIATION, SO I NOTICED 1417 00:59:27,797 --> 00:59:30,733 THERE'S REALLY HIGH LEVELS OF 1418 00:59:30,800 --> 00:59:35,204 IL12 IN COINFECTED PATIENTS, BUT 1419 00:59:35,271 --> 00:59:36,639 YOUR IL10 LEVELS ARE ALSO 1420 00:59:36,706 --> 00:59:37,740 ELEVATED. 1421 00:59:37,807 --> 00:59:40,143 SO IS IT POSSIBLE IT'S THE IL10 1422 00:59:40,209 --> 00:59:43,880 THAT IS DECREASING TH1 RESPONSE? 1423 00:59:43,947 --> 00:59:45,114 I DON'T KNOW IF YOU CAN TAKE THE 1424 00:59:45,181 --> 00:59:46,416 CELLS OUT OF THE PATIENTS AND 1425 00:59:46,482 --> 00:59:48,985 BLOCK IL10 AND SEE WHETHER THEIR 1426 00:59:49,052 --> 00:59:50,386 GAMMA GOES BACK TO THE NORMAL 1427 00:59:50,453 --> 00:59:51,621 LEVELS. 1428 00:59:51,688 --> 00:59:54,757 >> SO WE HAVEN'T DONE THAT. 1429 00:59:54,824 --> 00:59:57,560 YES, SO IN OUR -- IN INDIAN 1430 00:59:57,627 --> 01:00:00,730 PATIENTS IN GENERAL, IN PRIMARY 1431 01:00:00,797 --> 01:00:02,131 TUBERCULOSIS, WE DO FIND VERY 1432 01:00:02,198 --> 01:00:03,399 SIGNIFICANTLY HIGH LEVELS OF 1433 01:00:03,466 --> 01:00:04,334 CIRCULATING CYTOKINES. 1434 01:00:04,400 --> 01:00:05,201 THAT IS SOMETHING THAT I'VE BEEN 1435 01:00:05,268 --> 01:00:07,437 ASKED ABOUT BEFORE. 1436 01:00:07,503 --> 01:00:08,905 SO INTERFERON GAMMA LEVELS ARE 1437 01:00:08,972 --> 01:00:13,076 ARETYPICALLY MUCH HIGHER THAN 1438 01:00:13,142 --> 01:00:14,444 PEOPLE IN OTHER AREAS. 1439 01:00:14,510 --> 01:00:16,212 IL12 AS YOU NOTICED IS 1440 01:00:16,279 --> 01:00:16,846 SIGNIFICANTLY HIGH. 1441 01:00:16,913 --> 01:00:18,982 WE DO NOT KNOW IF IT IS -- HOW 1442 01:00:19,048 --> 01:00:21,617 MUCH OF IT IS DETERMINED 1443 01:00:21,684 --> 01:00:23,152 GENETICALLY AND HOW MUCH OF IT 1444 01:00:23,219 --> 01:00:26,956 IS EXPOSURE TO THESE VARIETY OF 1445 01:00:27,023 --> 01:00:30,193 PATHOGENS THAT THE INDIAN 1446 01:00:30,259 --> 01:00:30,660 POPULATION UNDERGOES. 1447 01:00:30,727 --> 01:00:34,464 WHAT WE DO KNOW IS THAT THERE IS 1448 01:00:34,530 --> 01:00:37,300 THE LEVEL OF INFLAMMATORY 1449 01:00:37,367 --> 01:00:39,769 CYTOKINES, ESPECIALLY IN THE 1450 01:00:39,836 --> 01:00:41,404 CONTEXT OF TBS VERY, VERY HIGH. 1451 01:00:41,471 --> 01:00:42,605 TO ANSWER YOUR QUESTION ABOUT 1452 01:00:42,672 --> 01:00:48,011 WHETHER IL10 IS DOWN MODULATING 1453 01:00:48,077 --> 01:00:49,545 THE IL12 RESPONSES, I WOULD 1454 01:00:49,612 --> 01:00:51,080 EXPECT TO BE SO BECAUSE WHAT WE 1455 01:00:51,147 --> 01:00:54,050 DO FIND IN TB INFECTION, JUST TB 1456 01:00:54,117 --> 01:00:56,352 ALONE, IS THAT IL10 IS 1457 01:00:56,419 --> 01:00:57,887 SIGNIFICANTLY DOWN MODULATED 1458 01:00:57,954 --> 01:00:59,922 BOTH IN THE LEVEL OF T-CELL 1459 01:00:59,989 --> 01:01:00,890 PRODUCTION OR IF YOU LOOK AT 1460 01:01:00,957 --> 01:01:03,292 OTHER IL10 PRODUCERS OR IF YOU 1461 01:01:03,359 --> 01:01:06,295 LOOK AT CIRCULATORY LEVELS, SO I 1462 01:01:06,362 --> 01:01:09,465 THINK ONE OF THE REASONS WHY TB 1463 01:01:09,532 --> 01:01:12,368 DRIVES SUCH A PRO-INFLAMMATORY 1464 01:01:12,435 --> 01:01:13,703 RESPONSE, BY ITSELF I THINK IT 1465 01:01:13,770 --> 01:01:15,004 CAN DOWN MODULATE IL10. 1466 01:01:15,071 --> 01:01:18,408 >> OKAY, THANK YOU. 1467 01:01:18,474 --> 01:01:21,177 >> HI. 1468 01:01:21,244 --> 01:01:25,348 VERY IMPORTANT CLINICAL RESEARCH 1469 01:01:25,415 --> 01:01:26,015 AND DATA. 1470 01:01:26,082 --> 01:01:29,185 SO I'M KIND OF INTERESTED IN THE 1471 01:01:29,252 --> 01:01:32,155 LAST PART, THE INTERACTION 1472 01:01:32,221 --> 01:01:34,190 BETWEEN THE HELMINTH INK FEX 1473 01:01:34,257 --> 01:01:35,691 AND -- SO THERE ARE MICE 1474 01:01:35,758 --> 01:01:37,427 EXPERIMENT WHICH IS NOT QUITE 1475 01:01:37,493 --> 01:01:38,628 LIKE HUMANS THAT HAVE SHOWN THAT 1476 01:01:38,694 --> 01:01:41,330 IF YOU TAKE AWAY -- YOU SEE AN 1477 01:01:41,397 --> 01:01:46,035 INCREASE IN WEIGHT IN MICE -- 1478 01:01:46,102 --> 01:01:49,072 IMPORTANT IN -- WEIGHT AND I WAS 1479 01:01:49,138 --> 01:01:50,473 JUST THINKING DO YOU HAVE ANY 1480 01:01:50,540 --> 01:01:55,711 DATA ON ILC2s IN THE CONTEXT 1481 01:01:55,778 --> 01:02:00,450 OF STRONG LLO STRONGYLOIDES INFS 1482 01:02:00,516 --> 01:02:02,985 THERE ANY EFFORT IN LOOKING AT 1483 01:02:03,052 --> 01:02:09,058 TISSUES, IS NATI ANY TISSUE SITE 1484 01:02:09,125 --> 01:02:10,026 AVAILABLE IN THESE PATIENTS BUT 1485 01:02:10,093 --> 01:02:11,694 CAN YOU COMMENT ON WHAT YOU 1486 01:02:11,761 --> 01:02:11,928 THINK -- 1487 01:02:11,994 --> 01:02:15,398 >> SO YOU'RE TALKING ABOUT IL22? 1488 01:02:15,465 --> 01:02:19,502 >> GROUP 2 INNATE LYMPHOID 1489 01:02:19,569 --> 01:02:19,702 CELLS? 1490 01:02:19,769 --> 01:02:21,370 >> ILC2s. 1491 01:02:21,437 --> 01:02:23,940 >> SO WE HAVEN'T ACTUALLY LOOKED 1492 01:02:24,006 --> 01:02:27,610 AT ILC2s DIRECTLY, SO AS YOU 1493 01:02:27,677 --> 01:02:29,812 KNOW VERY WELL, ILC2s ARE 1494 01:02:29,879 --> 01:02:31,347 TYPICALLY INDUCED IN HELMINTH 1495 01:02:31,414 --> 01:02:32,982 INFECTIONS BOTH IN HUMANS AND IN 1496 01:02:33,049 --> 01:02:34,684 ANIMAL MODELS, AND AS YOU 1497 01:02:34,750 --> 01:02:36,185 RIGHTLY SAID, ANIMAL MODEL 1498 01:02:36,252 --> 01:02:37,487 EXPERIMENTS CLEARLY SHOW THAT 1499 01:02:37,553 --> 01:02:40,289 THE INDUCTION OF ILC2 HAS A 1500 01:02:40,356 --> 01:02:40,857 BENEFICIAL EFFECT AGAINST 1501 01:02:40,923 --> 01:02:42,158 METABOLIC DISORDERS, MAINLY 1502 01:02:42,225 --> 01:02:43,826 BECAUSE OF THE ABILITY OF 1503 01:02:43,893 --> 01:02:45,161 ILC2s TO GO INTO THE ADIPOSE 1504 01:02:45,228 --> 01:02:47,930 TISSUE AND BASICALLY, YOU KNOW, 1505 01:02:47,997 --> 01:02:50,299 CHANGE THE -- OF THE FAT, 1506 01:02:50,366 --> 01:02:51,467 INFLAMMATORY MILIEU, ET CETERA, 1507 01:02:51,534 --> 01:02:53,436 AND IN ADDITION, WITH 1508 01:02:53,503 --> 01:02:58,708 EOSINOPHILS AS WELL, SO -- WHICH 1509 01:02:58,774 --> 01:03:00,576 ALSO OCCUPY ADIPOSE TISSUE AND 1510 01:03:00,643 --> 01:03:02,712 CAUSE MODULATION OF THE 1511 01:03:02,778 --> 01:03:04,447 THERMOGENESIS OF -- METABOLISM. 1512 01:03:04,514 --> 01:03:06,682 WE UNFORTUNATELY HAVEN'T LOOKED 1513 01:03:06,749 --> 01:03:10,086 DIRECTLY AT ILC2 IN OUR 1514 01:03:10,153 --> 01:03:12,155 PATIENTS, BUT PEOPLE WHO ARE 1515 01:03:12,221 --> 01:03:14,891 LOOKING AT HELMINTH INFECTION IN 1516 01:03:14,957 --> 01:03:17,059 THE CONTEXT OF METABOLIC 1517 01:03:17,126 --> 01:03:20,129 DISORDERS DO SEE SIGNIFICANT 1518 01:03:20,196 --> 01:03:21,964 CONCENTRATION OF ILC2, THAT'S 1519 01:03:22,031 --> 01:03:22,165 KNOWN. 1520 01:03:22,231 --> 01:03:23,199 >> NICE TALK, SUBASH. 1521 01:03:23,266 --> 01:03:25,701 THANK 1522 01:03:25,768 --> 01:03:26,202 >> THANK YOU. 1523 01:03:26,269 --> 01:03:29,071 >> ANOTHER HALLMARK OF THE 1524 01:03:29,138 --> 01:03:31,641 STRONGY INFECTION ARE THOSE 1525 01:03:31,707 --> 01:03:32,208 EOSINOPHIL NUMBERS. 1526 01:03:32,275 --> 01:03:36,345 I WAS WONDERING DID IT LOOK -- 1527 01:03:36,412 --> 01:03:41,450 EOSINOPHIL NUMBERS OF THOSE 1528 01:03:41,517 --> 01:03:43,419 STRONGY INFECTED PATIENTS -- 1529 01:03:43,486 --> 01:03:44,387 COMPLETELY DETRIMENTAL OR 1530 01:03:44,453 --> 01:03:45,788 BENEFICIAL AND I WAS WONDERING 1531 01:03:45,855 --> 01:03:48,624 IF THERE WAS ANY CORRELATION 1532 01:03:48,691 --> 01:03:51,194 BETWEEN THE EOSINOPHIL LEVELS OF 1533 01:03:51,260 --> 01:03:53,362 THE STRONGY WITH THE CLINICAL 1534 01:03:53,429 --> 01:03:57,667 OUTCOMES IN THE TB OR IN THE 1535 01:03:57,733 --> 01:03:58,601 TYPE 2 DIABETES. 1536 01:03:58,668 --> 01:03:59,835 >> THAT'S A GREAT QUESTION. 1537 01:03:59,902 --> 01:04:01,270 SO I DON'T HAVE AN ANSWER TO 1538 01:04:01,337 --> 01:04:03,406 YOUR QUESTION BECAUSE WE 1539 01:04:03,472 --> 01:04:06,442 ACTUALLY NEVER FOCUSED IN ON 1540 01:04:06,509 --> 01:04:09,512 EOSINOPHIL -- WE SEE -- WE WERE 1541 01:04:09,579 --> 01:04:11,981 ONE OF THE FEW GROUPS THAT 1542 01:04:12,048 --> 01:04:15,151 ACTUALLY SAW THAT EOSINOPHIL 1543 01:04:15,218 --> 01:04:17,687 DERIVED PROTEINS ARE 1544 01:04:17,753 --> 01:04:18,988 SIGNIFICANTLY UPREGULATED IN 1545 01:04:19,055 --> 01:04:23,426 STRONGY, INCLUDING EBN AND THE 1546 01:04:23,492 --> 01:04:25,928 OTHER EOSINOPHIL MEDIATORS. 1547 01:04:25,995 --> 01:04:27,663 WHAT WE HAVEN'T LOOKED AT IS 1548 01:04:27,730 --> 01:04:28,731 WHETHER ANY OF THIS HAS AN 1549 01:04:28,798 --> 01:04:30,600 EFFECT ON ANY OF THE BYSTANDER 1550 01:04:30,666 --> 01:04:31,467 RESPONSES THAT WE'VE SEEN. 1551 01:04:31,534 --> 01:04:32,635 SO I DON'T HAVE AN ANSWER TO 1552 01:04:32,702 --> 01:04:34,937 YOUR QUESTION. 1553 01:04:35,004 --> 01:04:36,672 >> I THINK ANOTHER RELATED 1554 01:04:36,739 --> 01:04:42,445 QUESTION IS IF THE CHRONICITY OF 1555 01:04:42,511 --> 01:04:44,180 THE HELMINTH INFECTION MATTERS, 1556 01:04:44,247 --> 01:04:46,916 THEY ALWAYS GET THE 1557 01:04:46,983 --> 01:04:48,884 HYPERRESPONSIVENESS BUT THAT 1558 01:04:48,951 --> 01:04:50,353 DEPENDENT ON HOW CHRONIC THE 1559 01:04:50,419 --> 01:04:52,822 PATIENTS ARE MATTERS? 1560 01:04:52,888 --> 01:04:53,556 >> GOOD QUESTION. 1561 01:04:53,623 --> 01:04:55,625 HAVEN'T LOOKED AT THAT BUT WE 1562 01:04:55,691 --> 01:05:03,599 CAN CERTAINLY LOOK AT THAT. 1563 01:05:03,666 --> 01:05:05,901 [APPLAUSE] 1564 01:05:05,968 >> THANK YOU.