>> SO IT GIVES ME GREAT PLEASURE
TO INTRODUCE TO YOU A
LONG-STANDING COLLEAGUE AND
FRIEND, SUBASH BABU, WHO'S GOING
TO GIVE TODAY'S IIG SEMINAR.
A LITTLE BIT ABOUT SUBASH, HE
RECEIVED HIS -- FROM INDIA AND
EARNED A PH.D. IN IMMUNOLOGY AT
THE UNIVERSITY OF CONNECTICUT.
DURING HIS TIME AS A GRADUATE
STUDENT, HE MADE THESE
INCREDIBLE SEMINOLE
CONTRIBUTIONS TO THE
UNDERSTANDING OF FILARIAL
INFECTIONS, SOMETHING THAT'S
NEAR AND DEAR TO MY HEART, USING
MOUSE MODELS.
AND THESE REALLY LED TO A GREAT
LEAP FORWARD GENERALLY IN THE
FIELD.
THEN WE WERE REALLY LUCKY TO
RECRUIT HIM AFTER HIS PH.D. AT
THE HELMINTH IMMUNOLOGY SECTION
IN THE NIAID, WHERE HE WAS A
VISITING FELLOW FOR ABOUT FIVE
YEARS AND HE CONDUCTED RESEARCH
ON HUMAN RESPONSES TO FILARIAL
INFECTIONS.
AND THEN AFTER AN INCREDIBLY
PRODUCTIVE FIVE YEARS, HE BECAME
A STAFF SCIENTIST HERE, BUT SOON
THEREAFTER, MOVED TO AND HELPED
ESTABLISH WHAT WAS THE LPD ICMR
CHENNAI ICER, THESE ARE
INTERNATIONAL CENTERS FOR
EXCELLENCE IN RESEARCH.
AND HE'S ACTUALLY BEEN THERE ON
THE GROUND SINCE THEN, AND IS
CURRENTLCURRENTLY ITS SCIENTIFIC
DIRECTOR.
OVER THESE LAST 20 YEARS,
ALMOST, HE AND HIS COLLEAGUES IN
INDIA HAVE MADE INCREDIBLE
CONTRIBUTIONS TO THE IMMUNOLOGY
OF HUMAN HELMINTH INFECTIONS AS
WELL AS IMMUNOLOGY OF TB IN
HUMANS.
HE HAD THREE SORT OF BROAD AREAS
OF RESEARCH, ONE SORT OF
MECHANISM UNDERLYING
PATHOGENESIS OF FILARIAL
INFECTIONS, A SECOND ABOUT THE
INFLUENCE OF SOIL TRANSMITTED
HELMINTHS ON THE OUTCOMES OF
METABOLIC DISORDERS AND OTHER
INFECTIOUS NON-PARASITIC
INFECTIOUS DISORDERS, AND THEN
THE INTERFACE BETWEEN TB AND
HELMINTH INFECTIONS AS WELL AS
DIABETES.
SO THROUGHOUT THE 20 YEARS THAT
I'VE KNOWN HIM, HE'S COMMITTED
HIMSELF TO KIND OF APPLYING BOTH
BASIC AND TRANSLATIONAL RESEARCH
TO IMPORTANT PUBLIC HEALTH
IMPLICATIONS, AND AS A
CONSEQUENCE OR WHILE DOING THIS,
HE'S MENTORED AN EXTRAORDINARY
NUMBER OF GRADUATE STUDENTS AND
MASTERS STUDENTS AND
UNDERGRADUATES IN INDIA, AND AS
A CONSEQUENCE, HAS RECEIVED
MULTIPLE AWARDS FOR HIS WORK.
SO HE'S BACK HERE, AND SO IT
GIVES ME REALLY GREAT PLEASURE
TO HAVE HIM GIVE TODAY'S IIG
LECTURE.
SO THANKS.
[APPLAUSE]
>> GOOD AFTERNOON, EVERYONE.
THANK YOU FOR COMING.
THANK YOU SO MUCH, TOM, FOR THE
KIND INTRODUCTION, AND THANKS TO
JULIE FOR HELPING ME OUT WITH
ALL THE ARRANGEMENTS FOR THIS
TALK TODAY.
SO AS TOM MENTIONED, I'M GOING
TO BE TALKING ABOUT IMMUNE
RESPONSES, HUMAN IMMUNE
RESPONSES, SPECIFICALLY
PARASITIC INFECTION FOR
STRONGYLOIDES STERCORALIS AND
IMPLICATIONS FOR THE IMMUNE
RESPONSE BY HELMINTH ON BOTH THE
CLINICAL PICTURE AS WELL AS
IMMUNE RESPONSES, TWO VERY
DIVERSE DISEASE PROCESSES,
TUBERCULOSIS AND TYPE
2 DIABETES.
SO BEFORE I GO ON, I JUST WANTED
TO GIVE A BRIEF INTRODUCTION OF
OUR PROGRAM.
SO THE INTERNATIONAL CENTER FOR
EXCELLENCE IN RESEARCH IN INDIA
WERE ESTABLISHED IN THE 2000s,
WE ARE BASICALLY LOCATED IN
CHENNAI, A CITY IN SOUTH INDIA
WITH THE POPULATION OF ABOUT
12 MILLION PEOPLE.
OUR RESEARCH MISSION IS TO BE A
SECTOR FOR RESEARCH ON PARASITIC
INFECTIONS, TUBERCULOSIS, HIV
AND OTHER DISEASES, WITH A MAJOR
FOCUS ON DISEASE INTERACTIONS.
AND THIS CENTER IS BASICALLY A
COLLABORATION BETWEEN NIAID AND
THE INDIAN COUNCIL OF MEDICAL
RESEARCH, WHICH IS THE -- PRETTY
MUCH THE NIH EQUAL OF INDIA.
AS TOM MENTIONED, WE WORK ON A
VARIETY OF RESEARCH AREAS.
OUR RESEARCH PORTFOLIO MAINLY
FOCUSED ON HELMINTHS, STARTING
OFF WITH LYMPHATIC FILARIASIS.
WE ALSO DO A LOT OF WORK ON
TUBERCULOSIS, MAINLY LOOKING AT
IMMUNOLOGY AS WELL AS BIOMARKER
DISCOVERY IN PULMONARY AND EXTRA
PULMONARY FORMS OF TB.
WE WORK ON VIROLOGY AS WELL,
VIRAL INFECTIONS INCLUDING
COVID-19, HIV, AND A VARIETY OF
VIRAL COINFECTIONS, AND AS WELL
AS MISCELLANEOUS -- MULTISYSTEM
INFLAMMATORY SYNDROME IN
CHILDREN.
OUR NICHE AREA IS LOOKING AT
COINFECTIONS AND COMORBIDITIES,
WHEREIN WE DON'T LACK AT -- IN
SILO BUT RATHER DISEASE
INTERACTIONS BETWEEN INFECTIONS
AND OTHER MORBIDITIES.
A FEW EXAMPLES OF THAT ARE DM
AND TB, UNDERNUTRITION AND TB,
HEL MIHELMINTHS AND TB, HELMINTD
DM AND SI VIRUSES AND TB.
THE TWO MAJOR VACCINES THAT WE
WORK ON, ONE IS BCG, THE VACCINE
AGAINST TUBERCULOSIS, AND THE
OTHER, THE TWO MAJOR COVID-19
VACCINES THAT ARE ADMINISTERED
IN INDIA, COVAXIN AND
COVISHIELD.
SO WITH THAT BACKGROUND, MY TALK
IS GOING TO BE FOCUSED ON FOUR
MAJOR RESEARCH AREAS.
SO INITIALLY I'M GOING TO WALK
YOU THROUGH A BACKGROUND ON
STRONGYLOIDES STERCORALIS
INFECTION BECAUSE THIS IS NOT
SOMETHING THAT IS COMMONLY
UNDERSTOOD.
I'M GOING TO TALK A GREAT DEAL
WITH THE HUMAN RESPONSE TO
STRONGYLOIDES STERCORALIS
INFECTION AND THEN TALK TO YOU A
LITTLE BIT ABOUT THE BYSTANDER
EFFECT ON TUBERCULOSIS AND TYPE
2 DIABETES.
SO AS MOST OF YOU MIGHT ALREADY
KNOW, HELMINTH INFECTIONS ARE A
MAJOR AFFLICTION IN TERMS OF THE
INFECTIONS AFFECTING THE GLOBAL
HEALTH MAJORITY, SO HELMINTH
INFECTIONS AFFECT ABOUT
2 BILLION PEOPLE WORLDWIDE AND
ARE BROADLY CLASSIFIED INTO
THREE TYPES, INCLUDING EC HMENT
INOCOCCUS TAENIA, AND WHAT I AM
PARTICULARLY INTERESTED IN, THE
HOOK WORMS, FILARIAL WORMS, ALL
OF WHICH AFFECT ANYWHERE FROM
500 MILLION PEOPLE TO
800 MILLION PEOPLE, SO IT'S A
HUGE PROBLEM GLOBALLY.
AND HELMINTH INFECTIONS ARE ALSO
INTERESTING TO IMMUNOLOGISTS
MAINLY BECAUSE OF THE
STEREOTYPICAL RESPONSES TO THE
USUALLY -- THE HOST.
SO THE INTERACTION BETWEEN THE
EARLY STAGE LARVAE OR EGGS OF
THE PARASITE WITH THE HOST
IMMUNE SYSTEM TYPICALLY INDUCES
A CLASSICAL ALARMED RESPONSE
WITH THE PRODUCTION OF THE THREE
CYTOKINES, DSLP, IL25 AND IL-33,
WHICH THEN, IN FACT, WITH A
VARIETY OF CELL TYPES IN THE
HOST INCLUDING DENDRITIC CELLS,
MACROPHAGES, EOSINOPHILS,
BASOPHILS AND INNATE LYMPHOID
CELLS SETTING IN MOTION A
CASCADE OF CYTOKINE PRODUCTION
THAT THEN DRIVES T-CELL AND B
CELL DIFFERENTIATION.
SO T-CELL DIFFERENTIATION, CLASS
CLICK ASSOCIATED WITH THE
TH2 PHENOTYPE AND THIS IS
IMPORTANT IN -- MASTOCYTOSIS AS
WELL AS IMMUNE MODULATION AND
REGULATING NETWORKS WHICH
INCLUDE IL10, TGF BETA, T
REGULATORY CELLS, AND SO ON.
AND FINALLY, B CELL PRODUCTION
OF THE ANTIBODY -- PREDOMINANTLY
IGG 4 AND IGE IN HUMANS.
SO WHY ARE WE INTERESTED IN
STRONGYLOIDES?
IT ACTUALLY CONSIDERED ONE OF
THE MOST NEGLECTED AMONG THE
TROPICAL DISEASES BECAUSE VERY
LITTLE IS KNOWN IN TERMS OF
VIRULENCE AND THE PATHOGEN
ASSISTED -- ABOUT A COUPLE OF
YEARS AGO, IF YOU HAD LOOKED AT
THE PREVALENCE, MOST LITERATURE
WOULD HAVE SAID THAT IT INFECTS
AROUND 30 TO 100 MILLION PEOPLE
WORLDWIDE.
NOW THEY HAVE COMPLETELY REVISED
THE ESTIMATES TO AS MANY AS
600 MILLION PEOPLE WORLDWIDE SO
THERE'S THIS HUGE JUMP IN WHAT
WAS THOUGHT TO BE AND THAT
CLEARLY SHOWS HOW NEGLECTED THE
INFECTION IS AROUND THE WORLD.
THE REASON WHY IS BECAUSE IT
USUALLY OCCURS ONLY IN LOW AND
MIDDLE INCOME COUNTRIES SUCH AS
ASIA, AFRICA, LATIN AMERICA, AND
ALSO BECAUSE FOR THE MOST PART,
IT IS ASYMPTOMATIC.
S IS ONLY DURING
IMMUNOCOMPROMISE THAT IT
ACTUALLY MANIFESTS AS A
POTENTIALLY FATAL CONDITION.
DIAGNOSIS OFTEN INVOLVES
SEROLOGY AND STOOL EXAMINATION,
AND TREATMENT TYPICALLY
COMPRISES OF THE DRUG
IVERMECTIN.
AND AS I ALREADY MENTIONED,
IMMUNOSUPPRESSION, WHETHER DUE
TO MEDICATION LIKE
CORTICOSTEROIDS OR INFECTIONS
SUCH AS HTLV OR HIV
SIGNIFICANTLY INCREASES THE RISK
OF HYPERINFECTION SYNDROME AND
DISSEMINATED STRONG LOW DIASIS.
I WANT YOU TO FOCUS ON THE RED
AREAS ON THIS GLOBAL MAP.
WHAT YOU CAN CLEARLY SEE IS IT'S
PREDOMINANTLY PREVALENT -- SO
THE LIFECYCLE OF STRONGY IS VERY
COMPLEX, I'M NOT GOING TO GO
INTO THE TEE TAILS OF THIS
EXCEPT TO TELL YOU THAT THERE
ARE TWO STAGES, TWO DIFFERENT
CYCLES WUFNLT IS A FREE-LIVING
CYCLE AND PARASITIC CYCLE, AND
STRONGY INFECTION USUALLY BEGINS
WITH THE INFECTIOUS LARVAE
PENETRATING THE SKIN, GETTING TO
THE CIRCULATION, AND THEN GOING
INTO THE -- TREE WHERE IT ENDS
UP IN THE LUNGS DUE TO MIGRATION
INTO THE LUNG PARENCHYMA.
STRONGY -- GET COUGHED UP,
ASPIRATED AND THEN BASICALLY
REGURGITATED OR INTO THE
GASTROINTESTINAL TRACT, WHERE
THE ADULT FEMALE WORMS SETTLE
AND USUALLY CONTINUE THE
LIFECYCLE.
SO THE LIFECYCLE CAN ACTUALLY
TAKE AS I SAID TWO FORMS.
YOU CAN HAVE LARVAE WHICH ARE
PRODUCED DIRECTLY FROM THE
PATHOGENIC FEMALE AND THESE
LARVAE -- OF THE CAPACITY TO
CAUSE AUTO INFECTION, AND THIS
IS ONE OF THE REALLY UNIQUE
MECHANISMS BY WHICH STRONGY IS
ABLE TO ESTABLISH LONG-STANDING
CHRONIC INFECTIONS IN THE HOST.
DIAGNOSIS IS MAINLY THROUGH --
THE PATHOLOGY FROM STRONGY
USUALLY IS A REFLECTION OF THE
MIGRATION STAGES.
SO THE SKIN PHASE IS BECAUSE OF
THE INVASION OF THE LARVAE, THE
RESPIRATORY PHASE BECAUSE OF THE
MIGRATION OF THE LARVAE AND
TISSUE DESTRUCTION.
THE CLINICAL MANIFESTATIONS OF
STRONGY CAN BE SUBDIVIDED INTO
ACUTE AND CHRONIC STRONGYLOIDES
AND BASICALLY PREDOMINANTLY SKIN
MANIFESTATIONS, ABDOMINAL
MANIFESTATION AND PULMONARY
MANIFESTATIONS BASED ON THE
MIGRATION STAGE OF THE PARASITE.
SO WITH THAT BACKGROUND I WOULD
NOW LIKE TO FOCUS OUR ATTENTION
ON OUR WORK ON HUMAN IMMUNE
RESPONSES.
AND I'D LIKE TO BASICALLY TELL
YOU HERE THAT WE HAVE BEEN STU
STUDYING STRONGY FOR OVER A
DECADE NOW, WE'VE HAD THREE
LARGE PROTOCOLS IN WHICH WE'VE
DONE SCREENING ACROSS THE SOUTH
INDIAN POPULATION AND THE SAMPLE
SIZES OF THE DIFFERENT STUDIES
ARE SHOWN HERE.
SO BASED ON THIS, WE USUALLY
UTILIZE THE SEROLOGY TEST FOR
DIAGNOSING STRONGY, AND WHAT WE
FOUND IS THAT WHEN WE SCREENED
ABOUT 4,700 THUS FAR, THE ZERO
POSITIVITY IN THIS POPULATION IS
AROUND 29%.
THIS IS THE AGE AND GENDER
DISTRIBUTION OF STRONGY.
SO WITH THESE COHORTS THAT WE
HAVE, WE HAVE WANTED TO GO AHEAD
AND EXAMINE CERTAIN OBJECTIVES
LOOK AT CERTAIN OBJECTIVES.
ONE WAS TO CHARACTERIZE THE
BASELINE HEMATOLOGICAL AND
BIOCHEMICAL PARAMETERS IN THESE
INDIVIDUALS, TO CHARACTERIZE THE
REGULATION OF CD4 SUBSETS IN
THESE INFECTIONS, AND TO
CHARACTERIZE THE SYSTEMIC
CYTOKINE RESPONSES IN
STRONGYLOIDES STERCORALIS
INFECTION AND DELINEATE THE
CHANGES THAT HAPPENED AFTER
TREATING THE STRONGY PATIENT.
SO IF YOU LOOK AT HEMATOLOGY IN
STRONGY INFECTION -- TYPICALLY
ASSOCIATED -- AND INDEED IF YOU
LOOK AT EITHER ABSOLUTE NUMBERS
SHOWN ON THE UPPER PANEL OR
FREQUENCIES SHOWN IN THE LOWER
PANEL, YOU'LL SEE THAT STRONGY
INFECTED INDIVIDUALS INDEED DO
HAVE A SIGNIFICANTLY HIGHER
NUMBER OF EOSINOPHILS COMPARED
TO THE UNINFECTED INDIVIDUALS.
BUT ALSO INTERESTINGLY, WE ALSO
FOUND THAT THERE IS AN INCREASE
IN THE NUMBERS OF MONOCYTES AS
WELL AS BASOPHILS IN THE STRONGY
INFECTED IN OUR COHORT, THIS IS
ACCOMPANIED BY A CO CONCOMITANT
DECREASE IN THE NUMBER OF
LYMPHOCYTES.
WHEN WE LOOK AT -- HERE AGAIN WE
ARE LOOKING AT THE LIVER
FUNCTION TESTS, RENAL FUNCTION
TESTS AS WELL AS BLOOD GLUCOSE
INDICES, WHAT BA BASICALLY STOOD
OUT WAS THAT STRONGY POSITIVE
EOSIN FILLS WERE SIGNIFICANTLY
ASSOCIATED WITH A DECREASE IN
THE RANDOM BLOOD GLUCOSE LEVEL
AS WELL AS THE HEMOGLOBIN A1C
LEVELS, BOTH OF WHICH ARE
INDICATORS OF CONTROL OF
DIABETES OR THE OCCURRENCE OF
DIABETES.
AND SO I'M GOING TO COME BACK TO
THIS PARTICULAR FINDING IN THE
LATER PART OF MY TALK.
SO IN TERMS OF THE IMMUNOLOGY OF
CD4 T CELLS AND THEIR RESPONSES,
WE BASICALLY USE WHOLE BLOOD
CULTURES FROM STRONGY INFECTED
OR CONTROL INFECTED PEOPLE AN
AND -- NIE OR CONTROL ANDROGENS
PPD AND -- AND ASKED THE
QUESTION WHAT SORT OF T-CELL
SUBSET DIFFERENTIATION RESPONSE
DO YOU FIND IN THESE HUMANS WITH
STRONGY INFECTION.
THIS IS SHOWING THE EXPRESSION
OF TH1 CYTOKINES, EITHER AT
BASELINE SHOWN IN THE UPPER
PANEL ANTIGEN STIMULATION IN THE
MIDDLE OR IN THE -- OR
FOLLOWING -- AND LOOKING AT THE
EXPRESSION OF INTERFERON GAMMA,
TNF ALPHA AND IL2.
WHEN WE DO THIS, WHAT WE FIND IS
INTERESTINGLY EVEN AT BASELINE
IN STRONGY INFECTED INDIVIDUALS,
THE FREQUENCY OF BOTH MONO
FUNCTIONAL AS WELL AS DUAL
FUNCTIONAL TH1 CELLS IS
SIGNIFICANTLY LOWER IN STRONGY
INFECTED INDIVIDUALS COMPARED TO
THE UNINFECTED INDIVIDUALS, AND
THIS ACTUALLY GETS SIGNIFICANTLY
AUGMENTED WHEN WE LOOK AT
ANTIGEN STIMULATION, SO EITHER
LOOKING AT SOMATIC ANTIGEN ON
THE TOP OR THE RECOMBINANT
ANTIGEN IN THE BOTTOM, WE FIND
TH1 MONO FUNCTIONAL, DUAL
FUNCTIONAL -- OF CELLS, THE
FREQUENCY OF THESE CELLS ARE
SIGNIFICANTLY LOWER IN STRONGY
INFECTED INDIVIDUALS COMPARED TO
UNINFECTED INDIVIDUALS.
INTERESTINGLY, IF YOU LOOK AT
CONTROL ANTIGEN STIMULATION
OR -- THIS DIFFERENTIAL RESPONSE
DOES NOT HOLD SO THAT THIS
RESPONSE APPEARS TO BE ONLY AT
BASELINE OR AFTER PARASITE
ANTIGEN INFECTION.
BUT WHAT ABOUT ABO ABOUT TH2 A,
LOOKING FOR IL4, IL5 AND IL13
PRODUCTION.
SO WHEN WE LOOK AT MONO
FUNCTIONAL OR DUAL FUNCTIONAL
TH2 CELLS, AGAIN WE SEE THIS
VERY DIFFERENT TREND OF WHAT WE
SAW WITH TH1 CELLS BUT WHAT YOU
WOULD EXPECT BASED ON WHAT
HELMINTH INFECTION -- IN THAT
THERE IS A SIGNIFICANTLY
INCREASED FREQUENCY EVEN AT
BASELINE WITHOUT ANY STIMULATION
OF MONO FUNCTIONAL AND DUAL
FUNCTIONAL TH2 CELLS, AND THIS
IS AGAIN SIGNIFICANTLY AUGMENTED
OR ENHANCED UPON ANTIGEN
STIMULATION, SO YOU SEE
SIGNIFICANTLY HIGHER FREQUENCIES
OF BOTH MONO AND DUAL FUNCTIONAL
TH2 CELLS IN RESPONSE TO -- OR
IN RESPONSE TO -- AND WHAT WE
SAW WITH TH1 CELLS, NO
SIGNIFICANT DIFFERENCE UPON --
STIMULATION OR IF YOU STIMULATED
WITH CONTROL --.
SO THE NEXT THING WE WANTED
TO -- NEXT T-CELL SUBSET WE
WANTED TO LOOK AT WAS TH9 CELLS.
SO THERE HAS NOT BEEN A LOT OF
LITERATURE DESCRIBING THE
EXPRESSION PATTERNS OF TH9 CELLS
IN HUMAN HELMINTH INFECTIONS, SO
WHEN WE DID THIS, WHAT WE FIND
IS THAT -- SO THIS IS BASICALLY
A CONTOUR PLOT LOOKING AT
EXPRESSION OF IL4, IL9 AND IL10
AND WE BASICALLY DEFINE
TH9 CELLS IN THIS CASE AS
IL9 POSITIVE, IL10 POSITIVE OR
NEGATIVE BUT IL4 NEGATIVE.
SO IN ORDER TO DIFFERENTIATE
THEM FROM CLASSICAL TH2 CELLS.
WHEN WE DO THIS, WE FIND THAT
EITHER THE SINGLE -- CELLS OR
THE IL11 DOUBLE -- CELLS ARE
SIGNIFICANTLY INCREASED IN
FREQUENCY IN STRONGY INFECTION
AT BASELINE, AND THIS IS
ACTUALLY TRUE WHEN WE LOOK AT
ANTIGEN STIMULATION AS WELL, SO
IF YOU LOOK AT IL9 -- -- YOU SEE
A SIGNIFICANT ENHANCEMENT IN THE
EXPANSION AND FREQUENCY OF THESE
SUBSETS.
AGAIN YOU DON'T SEE ANY
DIFFERENCE IN RESPONSE TO --.
FINALLY, WHEN WE LOOK AT TH17
CELLS, IN RESPONSE TO EITHER
TRON GEE INFSTRONGY INFECTED IN.
WE FIND A BASELINE INCREASE IN
TH17 CELLS, BUT SURPRISINGLY THE
BABASELINE INCREASE IS ACTUALLY
NOT REFLECTED WHEN WE LOOK AT
ANTIGEN STIMULATION, SO WHEN WE
LOOK AT ANTIGEN STIMULATED
CELLS, WE ACTUALLY START
SEEING -- WE SEE A SIGNIFICANT
CONTRACTION IN THE FREQUENCY OF
THESE TH17 CELLS IN RESPONSE TO
STRONGY INFECTION.
-- DUAL FUNCTIONAL TH17 CELLS.
AND AGAIN, SAME RESPONSE IN --
WITH RESPECT TO CONTROL ANTIGEN.
FINALLY, ONE OTHER INTERESTING
FEATURE THAT WE NOTICED IN
STRONGY INFECTION IS THAT
STRONGY INFECTION IS ONE OF THE
FEW HUMAN HEALTH -- HELMINTH
INFECTIONS IN WHICH WE ACTUALLY
SEE THESE DOUBLE EXPRESSING
CELLS.
THIS IS AGAIN VERY PRELIMINARY,
WE DO NOT KNOW WHAT FUNCTION
THESE CELLS CARRY OUT, SO THESE
ARE BASICALLY IL4 INTERFERON
GAMMA DUAL EX-P EXPRESSERS.
SO IF YOU LOOK AT EXPRESSION OF
IL4 AND INTERFERON GAMMA IN
ENDEMIC NORMALS, CONTROL
INDIVIDUALS, AND STRONGY
INFECTED INDIVIDUALS, YOU'LL SEE
THIS DUAL -- PRESENTED IN THE
STRONGY INFECTED INDIVIDUALS
THAT ARE NOT SEEN IN CONTROL
INDIVIDUALS.
AND IT TURNS OUT THAT THEY
EXPRESS -- CO-EXPRESS -- AND
GATA3 AS WELL, SO THAT'S ONE OF
THE OTHER INTERESTING FINDINGS
THAT WE SEE IN STRONGY
INFECTION.
SO WITH THIS, WE BASICALLY THEN
WANTED TO ASK THE QUESTION, HOW
ARE THESE RESPONSES ACTUALLY
BEING REGULATED IN STRONGYLOIDES
INFECTION?
I TOLD YOU AT THE BEGINNING THAT
HELMINTH INFECTIONS, AND THIS IS
TRUE OF TRON STRONGY INFECTIONS
WELL, ARE CLASSICAL INDUCERS OF
TH REGULATING CYTOKINES, BUT IN
ADDITION, THEY ARE ALSO REALLY
STRONG AND -- COINHIBITORY
RECEPTORS, AND PD-1, SO THE
QUESTION WE ASKED IS, DO ANY OF
THESE REGULATORY CYTOKINES OR
COINHIBITORS PLAY A ROLE IN
MODULATING THE DIFFERENTIATION
OF T-CELL SUBSETS THAT WE SEE IN
OUR STRONGY INFECTED
INDIVIDUALS.
AND THE ANSWER IS INDEED IT IS
TRUE, SO IF YOU LOOK AT IL10 IN
THIS PARTICULAR CASE, SO WE'RE
BASICALLY DOING RETRO CULTURES,
AGAIN, WHOLE BLOOD, BLOCKING --
AND THEN LOOKING AT THE
PRODUCTION OF -- COEXPRESSION OF
DIFFERENT CYTOKINES IN THE
T-CELL -- CD4 T-CELL
COMPARTMENTS.
WHAT WE FIND IS THERE IS A
SIGNIFICANT UPREGULATION OF
TH1 SUBSETS, AS WELL AS A
MINIMAL EFFECT ON TH17 -- SO
IL-17 PRETTY MUCH SEEMS TO
REGULATE TH1 CELLS BUT NOT SO
MUCH THE TH17 COMPARTMENT.
IN CONTRAST, IL10 ACTUALLY
REGULATES BOTH THE TH2 AND THE
TH9 CELLS, SO HERE IF YOU LOOK
AT THE EXPRESSION OF IL4 AND
IL13, THEY ARE BOTH
SIGNIFICANTLY DIMINISHED UPON
IL10 BLOCKADE AND THE DOUBLE
EXPRESSERS ARE ALSO
SIGNIFICANTLY DIMINISHED.
THE SAME IS TRUE WHEN YOU LOOK
AT TH9 CELLS, SO -- DUAL
EXPRESSERS OF IL9.
BUT WHAT WE DID FIND WHICH IS
VERY INTERESTING AND AGAIN WE
STILL ARE TRYING TO UNDERSTAND
THE MECHANISM BEHIND THIS IS
THAT -- ALONE SEEMS TO HAVE A
DIFFERENTIAL RESPONSE SO THERE
IS A SIGNIFICANT UPREGULATION OF
IL5 WHEN WE LOOK AT IL10
BLOCKADE IN THESE PARTICULAR
INDIVIDUALS.
TGF BETA HAS NO EFFECT ON
DH1 CELLS AND ON DH17 CELLS, SO
BLOCKING TGF BAY DA DOES NOT
MODULATE THE FREQUENCIES OF
THESE COMPARTMENTS.
HOWEVER, TGF BETA SIGNIFICANTLY
DOES REGULATE CERTAIN SUBSETS OF
TH2 CELLS, SO -- I LSM 13
EXPRESSERS BUT SIGNIFICANTLY MOD
LATES TH9 CELLS.
SO THERE IS A SIGNIFICANT
DECREASE UPON THE EXPRESSION OF
IL9 SIGNAL EXPRESSERS AS WELL AS
THE IL9 AND IL4 OR IL9/IL10 DUAL
EXPRESSERS IN STRONGY INFECTIONS
UPON BLOCKADE OF TGF BETA.
SO WHEN WE LOOK AT COINHIBITORS
AND ASK THE QUESTION WHAT ROLE
DO THESE COINHIBITORS PLAY IN
THE REGULATION OF THESE TH C
CD4 POSITIVE -- WE FIND THAT
CTLA4 LAS A VERY SIGNIFICANT
EFFECT IN THAT BLOCKING
CTLA4 SIGNIFICANTLY UPREGULATES
BOTH MONO FUNCTIONAL AND DUAL
FUNCTIONAL TH1 CELLS, AS WELL AS
UPREGULATING THE TH17 SUBSETS IN
RESPONSE TO -- CTLA4 ALSO HAS AN
EFFECT IN DOWNMODULATING THE
IMMUNE RESPONSES IN TH2 OR
REGULATING THE RESPONSES OF --
COMPARTMENT, SO BLOCKADE OF
CTLA4 DOWNMODULATES THE -- AS
WELL AS THE ECK PRETION OF
THE -- 9 CELLS.
PD-1, AGAIN, EVEN PD-1 HAS -- SO
THERE SEEMS TO BE THESE
MULTIPRONGED APPROACH THAT
HELMINTH INFECTION LIKE STRONGY
USES BECAUSE THERE ARE MULTIPLE
MECHANISMS BY WHICH THESE
PATHWAYS SEEM TO BE REGULATED,
SO PD-1 ALSO REGULATES THE
EXPRESSION OF MONO FUNCTIONAL
AND DUAL FUNCTIONAL TH1 CELLS,
VERY SIMILAR EFFECT IN THE THE
EXPRESSION OF TH17 CELLS, AND IN
CONTRAST, THE DIFFERENTIAL
EFFECT IN TERMS OF DOWN
MODULATING THE EXPRESSION OF THE
TH9 EXPRESSING T CELLS.
IL9 EXPRESSING T CELLS.
SO HAVING SHOWN THAT THERE IS A
WIDE VARIETY OF IMMUNE
REGULATION THAT STRONGY -- IN
HUMANS AND THAT THESE RESPONSES
HAVE A PROFOUND EFFECT -- WE
NEXT WANTED TO ASK THE QUESTION,
DOES THIS TRANSLATE INTO SYSTEM
CYTOKINE RESPONSES AND WILL THAT
HAVE ANY SORT OF EFFECT BECAUSE
AS I MENTIONED BEFORE, WE DON'T
HAVE THE INTERACTION OF STRONGY
WITH COEXISTING DISORDERS.
SO TO DO THIS, WE JUST BASICALLY
LOOKED AT -- INCLUDING TH1, TH17
CYTOKINES, AS WELL AS
CH2 CYTOKINES -- SO WHEN WE DO
THIS, WHAT WE FIND IS THAT IN
THE SYSTEMIC CIRCULATION, YOU
REALLY DON'T SEE MUCH OF AN
EFFECT WITH A FEW EXCEPTIONS
WITH PRO-INFLAMMATORY CYTOKINES,
SO THERE IS A REDUCTION IN THE
CIRCULATING LEVELS OF INTERFERON
GAMMA AND TNF ALPHA AND -- BUT
WHAT WE DO FIND INTERESTING IS
IF YOU ACTUALLY LOOK SIX MONTH
FOLLOWING TREATMENT OF STRONGY
INFECTION, ALTHOUGH AT BASELINE
THERE WERE NO DIFFERENCES IN
THESE CYTOKINES.
EVERY SINGLE -- PRETTY MUCH THAT
WE LOOKED AT WAS SIGNIFICANTLY
UPREGULATED AT SIX MONTHS,
SUGGESTING, AGAIN, THAT THAT
COULDN'T HAVE -- THAT WAS NOT
MANIFEST EXCLUSIVELY JUST BY
LOOKING AT THE CIRCULATION.
BUT MORE INTERESTINGLY, IF YOU
LOOK AT TH2 REGULATORY AS WELL
AS -- THERE IS A PROFOUND EFFECT
OF STRONGY INFECTION, SO WHEN
YOU LOOK AT STRONGY INFECTION
COMPARED TO CONTROLS, THE
CIRCULATING LEVELS OF IL4, 5,
10, 13 -- ARE ALL SIGNIFICANTLY
HIGHER IN STRONGY INFECTED
INDIVIDUALS COMPARED TO
CONTROLS.
AND ALL OF THESE PRETTY MUCH FOR
THE MOST PART ARE SIGNIFICANTLY
DOWN MODULATED.
WHEN YOU TREAT THESE INDIVIDUALS
AND THEN LOOK AT THEM SIX MONTHS
LATER.
AND FINALLY, STRONGY IS AGAIN
ONE OF THE FEW HELMINTH HUMAN
MODELS WHICH ACTUALLY IS
ASSOCIATED WITH INDUCTION OF IL.
SO WHEN WE LOOK AT THE -- WE SEE
THERE IS A SIGNIFICANT LAMBDA 1,
LAMBDA 2 AND -- SO TO SUMMARIZE
THE SECOND PART OF MY TALK,
STRONGY -- HAS THE ABILITY TO
HAVE A COMPLEX INTERPLAY WITH
THE HOST -- HUMAN-HOST IMMUNE
SYSTEM.
IT CAUSES EXPANSION OF TH2 AND
TH9 CELLS -- THERE'S A --
SIMILAR DIFFERENTIAL MODULATION
BASICALLY FOR PD-1, POTENTIALLY
NOVEL TH2/1 T-CELL SUBSET AND
FINALLY THESE SYSTEMIC CYTOKINES
FOR THE MOST PART REFLECT THE
CHANGES IN THE T-CELL
COMPARTMENT IN WHICH THERE ARE
HEIGHTENED LEVELS OF TYPE
2 REGULATORY AND
ANTI-INFLAMMATORY CYTOKINES.
SO HAVING TALKED EXTENSIVELY
ABOUT THE RESPONSES THAT STRONGY
INFECTION CAUSES, WE THEN WANTED
TO ASK THE PRESENCE OF THIS
INFECTION, IT SEEMS TO MODULATE
SO MANY DIFFERENT ARMS OF THE
IMMUNE SYSTEM.
HOW MANY -- BY STANDER
INFECTIONS.
SO THE FIRST INFECTION THAT I'M
GOING TO LOOK AT, ONE THAT I'M
GOING TO BE TALKING ABOUT TODAY
IS MYCOBACTERIUM TUBERCULOSIS,
AND THE REASON WHY WE ARE
INTERESTED IN HELMINTH TB
INTERACTIONS IS VERY SIMPLE.
THIS IS BASICALLY ANSWERED BY
LOOKING AT THIS GEOGRAPHIC MAP.
SO IF YOU LOOK AT AREAS OF THE
WORLD WHERE HELMINTH AND TB
COINFECTION EXIST, THE PURPLE
AREAS ARE THE ONES WHICH
PREDOMINANTLY HAVE BOTH HELMINTH
AND TB COINFECTIONS AND IF YOU
ACTUALLY LOOK AT THE RAW DATA,
INDIA HAS THE HIGHEST NUMBER OF
TB CASES IN THE WORLD AND ALSO
HAS PRETTY MUCH ONE OF THE
HIGHEST PREVALENCE OF HELMINTH
INFECTION SO THE QUESTION THAT
IS -- SO IF THESE INFECTIONS
TEFL ARE NOT EXISTING
INDEPENDENTLY, THEN THERE'S
GOING TO BE A LOT OF INDIVIDUALS
WHO ARE GOING TO BE COINFECTED
AND WHAT SORT OF AN IMMUNE
RESPONSE ARE WE GOING TO EXPECT
IN THE CONTEXT OF THESE
INFECTIONS COEXISTING WITH EACH
OTHER.
SO THE OTHER REASON WE ARE
INTERESTED ALSO IS BECAUSE THE
RESPONSE -- IS DRASTICALLY
DIFFERENT FROM WHAT A PAIR SPITE
LIKE STRONGYLOIDES INDUCES IN
THE HUMAN HOST.
SO AS MOST OF YOU KNOW, THE
INDUCTION OF TH1 AND TL17
REDUCES ARE CRUCIAL AND IT IS
THE INDUCTION OF THESE CELL
COMPARTMENTS IN CONJUNCTION WITH
CD8 T CELLS AS WELL AS A VARIETY
OF OTHER INNATE IMMUNE CELLS AND
B CELLS THAT ESSENTIALLY RESULT
IN THE PRODUCTION OF PROTECTIVE
SOLID GRANULOMA, WHICH HELPS
CONTAIN THE TB WITHIN THE LUNG,
AND LEADS TO WHAT WE CALL A
LATENT INFECTION IN HUMANS.
IN CONTRAST, IN THE PRESENCE OF
THE SUPPRESSION OF THESE IMMUNE
RESPONSES, EITHER THROUGH
REGULATORY NETWORKS OR THROUGH A
VARIETY OF OTHER MECHANISMS,
THIS -- THAT GRANULOMA -- THE
BACTERIA ARE NOW TRAVERSED INTO
THE LUNG AND THIS RESULTS IN
ACTIVE DISEASE.
SO IN THIS CONTEXT, WE WANTED TO
LOOK AT THE EFFECT OF
STRONGYLOIDES COINFECTION, SO
THE FIRST PART IS GOING TO BE
ACTUALLY LOOKING AT DISEASE
IMMUNITY AND TB TREATMENT
OUTCOMES.
THIS IS PURELY ASKING THE
QUESTION IF YOU HAVE STRONGY, DO
YOU HAVE AN EFFECT ON THE
CLINICAL PICTURE OF
TUBERCULOSIS.
AND SECONDLY WE ARE THEN GOING
TO ASK THE QUESTION, IS THERE
ANY IMMUNOMODULATION THAT TB
ENGENDERS OR -- MODULATION OF
RESPONSES.
SO HERE THE STUDY COHORT IS ALL
TUBERCULOSIS PATIENTS SCREENED
IN ONE OF OUR STUDIES, SO THESE
ARE ALL NEWLY DIAGNOSED CULTURE
POSITIVE PATIENTS WHO ARE DRUG
SENSITIVE.
THESE PATIENTS TYPICALLY GET PUT
ON AN -- WHAT WE ARE DOING IN
THESE PATIENTS WHICH ARE AROUND
400 IN NUMBER IS FOLLOWING THEM
UP AT BASELINE AND THEN UP TO A
PERIOD OF 18 MONTHS.
SO SIX MONTHS OF TREATMENT AND
ONE YEAR OF FOLLOW-UP FOLLOWING
THE END EVER TREATMENT, AND
ASKING THE QUESTION, IS THERE
CLINICAL BACTERIAL AND
IMMUNOLOGICAL EFFECT OF
COEXISTING STRONGY ON PT PATH
JEP CYST.
PATHOGENESIS.
SO IN THIS COHORT, WE HAD -- WE
LOOK AT THE DISEASE -- IN TERMS
OF LUNG LESIONS, WHETHER IT'S
UNILATERAL OR BILATERAL, SO
BILATERAL DISEASE IS -- BECAUSE
IT IS THE FORM OF LUNG DISEASE
THAT ACTUALLY CONTRIBUTES TO
TRANSMISSION AND DISEASE
IMMUNITY, AND FINALLY WHAT THE
MYCOBACTERIUM BURDENS REALLY
ARE.
WE ALSO ARE GOING TO BE LOOKING
AT FOLLOW-UP TO LOOK FOR WHAT WE
CALL UNFAVORABLE TB TREATMENTS.
SO TB TREATMENT OUTCOMES IN
TERMS OF WHAT HAPPENS IS ABOUT
EIGHT'80 TO 85% UNDER STANDARD N
UNDERGO CLINICAL CURE, BUT ABOUT
10 TO 15% UNDERGO UNFAVORABLE
TREATMENT OUTCOMES, AND THESE
INCLUDE TREATMENT FAILURES WHICH
MEANS THEY ARE BASICALLY NOT
RESPONDING TO TREATMENT,
MORTALITY, DEATH DURING
TREATMENT, OR WHAT WE CALL A
RELAPSE OR REINFECTION, THEY GET
CURED AT THE END OF SIX MONTHS,
VERY QUICKLY THAN ONE TO TWO
YEARS AFTER TREATMENT.
SO -- AND THEN WE'D BASICALLY
WANT SOMEONE TO LOOK AT THE
MODULATION OF IMMUNE RESPONSES.
SO IN TERMS OF DISEASE -- AND
TREATMENT FAILURE THE PUNCH LINE
IS HERE, IT JUST ONE SLIDE THAT
SUMMARIZES ALL THE DATA THAT
WE'VE DONE SO FAR, AND WHAT WE
ARE BASICALLY SHOWING YOU IS THE
ODDS RATIO OR THE RISK OF WHAT
HAPPENS TO EITHER THE SPUTUM
SMEAR GRADE OR TREATMENT
OUTCOMES IF YOU HAVE STRONGY
IN -- DO NOT HAVE STRONGY
INFECTION.
SO INDIVIDUALS WITH STRONGY
INFECTION, WHEN COMPARED TO
THOSE WITHOUT, ALL OF THESE --
TUBERCULOSIS PATIENTS HAVE AN
EIGHT FOLD INCREASED RISK OF
HAVING A MUCH HIGHER SPEAR GRADE
COMPARED TO THOSE WITHOUT.
SIMILARLY THOSE WITH STRONGY
HAVE A FIVE TOLD INCREASED RISK
OF HAVING BILATERAL -- COMPARED
TO THOSE WITHOUT STRONGY.
AND IN ORDER -- ONE OF THE MOST
IMPORTANT DRIVERS OF
TRANSMISSION.
WE ALSO FIND THAT IF YOU HAVE
STRONGY, YOU ARE FIVE TO SIX
FOLD HIGHER RISK COMPARED TO
THOSE THAT DON'T HAVE STRONGY.
FINALLY WHAT YOU THINK IS ALSO
VERY IMPORTANT, ALTHOUGH IT'S A
MILD PEESKT, IS THAT EVEN IN
TERMS OF UNFAVORABLE TREATMENT
OUTCOMES, THERE IS AN INCREASED
RISK OF HAVING STRONGY, --
1.22 -- ADVERSE TREATMENT
OUTCOMES.
SO ESSENTIALLY WHAT I'M TRYING
TO TELL YOU HERE IS JUST LIKE
OTHER KNOWN FACTORS, RISK
FACTORS FOR DISEASE SEVERITY AND
TREATMENT OUTCOMES IN TB, THE
COMMONLY KNOWN ONES ARE HIB,
DIABETES, MALNUTRITION,
ALCOHOLISM AND SMOKING, SOCIAL
FACTORS, WE THINK HELMINTH
INFECTIONS COULD ALSO HAVE A
VERY SIGNIFICANT ROLE IN
ALTERING THE CLINICAL PICTURE OR
WORSER ENING THE CLINICAL
PICTURE WITH PULMONARY
TUBERCULOSIS.
OF COURSE ALL OF THIS NEEDS TO
BE CONFIRMED IN LARGER COHORTS
AND THAT IS WHAT WE'RE LOOKING
AT BUT HAVING LOOKED AT ABOUT
500 PATIENTS, WHICH IS A PRETTY
LARGE SAMPLE SIZE FOR A TB
STUDY, WE ARE QUITE CONFIDENT
THAT THIS SHOULD BE REPLICATED
IN EVEN -- SO HOW DOES STR STROY
DO THIS?
ONE OF THE WAYS WE THINK IS
LOOKING BY IMMUNE RESPONSES, TB
AND ANTIGEN SPECIFIC RESPONSES.
FOSO HERE WE ARE LOOKING AT
COINFECTED PEOPLE, STRONGY AND
TB TOGETHER, SHOWN IN RED, OR TB
ALONE WHICH IS SHOWN IN BLUE,
AND LOOKING AT MONO FUNCTIONAL
OR DUAL -- FROM -- SO VERY
IMPORTANT IN THE CONTROL OF TB
IN TERMS OF ELIMINATING TB
DISEASE SEVERITY, AND POSSIBLY
ALSO IN TERMS OF TREATMENT
OUTCOMES.
WHEN WE LOOK AT -- 10, WE SEE A
SIGNIFICANT DOWN MODULATION OF
MONO FUNCTION, DUAL FUNCTION
AND -- IN THESE COINFECTED
INDIVIDUALS COMPARED TO THE TB
ALONE INDIVIDUALS.
AND THIS IS TRUE EVEN WHEN WE
LOOK AT DIFFERENT -- WE'RE
LOOKING AT -- WE AGAIN SEE A
SIGNIFICANT DIMINUTION IN MONO
FUNCTION -- IN RESPONSE TO
THE -- IN RESPONSE TO --
6 PEPTIDE -- EXPRESSION.
IF YOU LOOK AT TH17 CELLS, AGAIN
WE SEE A VERY SIMILAR EFFECT.
THEY'RE NOT AS STRONG BUT
SIGNIFICANT NEFORT LELS.
SO YOU SEE -- CD4 POSITIVE T
CELLS, IN THE COINFECTED
INDIVIDUALS COMPARED TO THE TB
ALONE INDIVIDUALS, AND FINALLY
THERE'S A VERY SIMILAR PATTERN
WITH -- VERY STRONGLY SUGGESTING
THAT ONE OF THE MAJOR MECHANISMS
BY WHICH STRONGY MOD LATES
IMMUNE RESPONSES THROUGH TB IS
BY DOWN MODULATING OR DOWN
REGULATING IMMUNE RESPONSES TO
TWO OF THE CLASSICAL
IMMUNODOMINANT THAT TB RESPONDS
TO.
AND INTERESTINGLY, IT NOT JUST
THE T-CELL RESPONSE.
IF YOU ACTUALLY LOOK AT THE --
REMEMBER I TOLD YOU ONE OF THE
THINGS WE WERE VERY INTERESTED
IN IN STRONGY IS THAT THE T-CELL
RESPONSE ACTUALLY TRANSLATES TO
THE SYSTEMIC CYTOKINE LEVELS AS
WELL.
WHEN WE LOOK AT PROTECTIVE
LEVELS OF CYTOKINES OR
CIRCULATING LEVELS OF PROTECTOR
SITE KIEPS, SO IN THIS CASE A
DIFFERENT GAMMA, IL2 AND IL-17
A, WE SEE THAT COINFECTED -- IN
COMPARISON WITH INDIVIDUALS WITH
TB ALONE, IN CONTRAST, TWO OF
THE DETRIMENTAL CYTOKINES THAT
BASICALLY DRIVE PATHOLOGY --
DRIESTLES PATHOLOGY -- IN TB,
INTERFERON ALPHA AND BAIT TA, AE
AT SIGNIFICANTLY HIGHER LEVELS
IN THE CIRCULATION AND THE
COINFECTED -- THAN TB INFECTED
INDIVIDUALS A.
IF YOU LOOK AT IL4, IL5, IL13,
THE TH2 CYTOKINES, AS WELL AS
THE UPSTREAM CYTOKINES OF TH2,
IL25, IL-33 AS WELL AS THE
REGULATORY CYTOKINE IL10, ALL OF
THESE ARE SIGNIFICANTLY
INCREASED THAT HAVE STR STRONGY
COINFECTIONS.
AND FINALLY WE ALSO FIND THAT
CERTAIN -- FACTORS KNOWN TO
DRIVE DISEASE PATHOLOGY,
INCLUDING EGF -- SIGNIFICANTLY
HEIGHTENED LEVELS IN THE
CIRCULATION COMPARED TO THE
UNINFECTED INDIVIDUALS OR
TB-ALONE INDIVIDUALS,
SUGGESTING, AGAIN, THAT THERE
ARE MULTIPLE MECHANISMS BY WHICH
THE COEXISTING HELMINTH AR -- SO
I'LL BASICALLY CONCLUDE THIS
PART OF MY TALK BY SAYING THAT
HELMINTHS AND TB INTERACTIONS IS
A VERY DETRIMENTAL INTERACTION.
IN TERMS OF A TB -- TB
RESPONSES, BOTH CLINICAL AS WELL
AS IMMUNOLOGICAL.
IN THIS CASE STRONGY -- AND I
DIDN'T SWR DATA TO SHOW ALL THE
DIFFERENT DATA HAS BEEN SHOWN TO
DECREASE ANTIGEN PRESENTATION
AND THIS CELL ACTIVATION.
STRONGLY PROMOTE -- AND
INCREASES PROTECTIVE CYTOKINES,
INCREASES SE VAIRD OF TB DISEASE
AND ENHANCED BACTERIAL BURDENS,
THERE BY PROMOTING TRANSMISSION.
HAS RESULTS OF AN INCREASED RISK
OF UNFAVORABLE TB TREATMENT
PROGRAMS AND AGAIN PRELIMINARY,
PRELIMINARY, THAT WE'LL BE
LOOKING AT PROGRESSERS OF LTBI
TO TB, THE PRESENCE OF HELMINTH
COINFECTIONS MIGHT HAVE A DET
MENTAL ROAD.
SO THE FINAL PART OF MY TALK,
I'M GOING TO BE FOCUSING ON
SOMETHING COMPLETELY DIFFERENT,
IN THIS CASE LOOKING AT THE
EFFECT OF ONE INFECTION ON A
COMPLETELY -- THE ANSWER AGAIN
IS SHOWN IN THIS GEOGRAPHIC MAP.
SHOWN ABOVE IS THE PREVALENCE OF
HELMINTH INFECTIONS WORLDWIDE,
ALL SHOWN IN RED, AND SHOWN
BELOW IS THE PREVALENCE OF TYPE
2 DIABETES.
ONE THING THAT YOU CAN NOTICE
RIGHT OFF THE BAT IF YOU LOOK AT
PLACES LIKE NORTH AMERICA OR
EUROPE, THERE IS NO RED IN TERMS
OF HELMINTH INFECTION.
SO AREAS WHICH HAVE BOTH
HELMINTH INFECTIONS PRETTY MUCH
HAVE SIGNIFICANTLY HIGHER
PREVALENCE OF TYPE 2 DIABETES.
SO THIS HERE INDICATES TYPE
2 DIABETES.
IN CONTRAST, PLACES LIKE AFRICA,
WHERE YOU HAVE SIGNIFICANTLY
HIGH LEVELS, HIGH PREVALENCE OF
HELMINTH INFECTIONS HAVE -- VERY
LOW LEVEL OF PRECEDENCE FOR TYPE
2 DIABETES.
-- BETWEEN HELMINTH INFECTIONS
AND A METABOLIC DISORDER, IN
THIS CASE TYPE 2 DIABETES, AND
IN ADDITION TO THIS, WE NOTICED
SOMETHING THAT I ALLUDED TO IN
THE FIRST PART OF MY TALK, AND
THAT IS IF YOU LOOKED AT OUR
4,000 DIFFERENT INDIVIDUALS THAT
WE SCREENED, INCLUDING THE 1,300
INDIVIDUALS WITH STRONGY, WE HAD
DETERMINED OR WE HAD SHOWN THAT
THERE IS A SIGNIFICANT LOWERING
IN THE PARAMETERS THAT DICTATE
TYPE 2 DIABETES, BOTH BLOOD
GLUCOSE AND A1C, SO
SIGNIFICANTLY LOWER LEVELS OF
RANDOM BLOOD GLUCOSE AS WELL AS
A1C NOTICED IN STRONGY INFECTED
INDIVIDUALS, SO NOT JUST
DIABETIC INDIVIDUALS ALONE.
SO WE WANTED TO ASK THE
QUESTION, IF YOU NOW LOOK AT
TYPE 2 DIABETES WITHOUT STRONGY
INFECTION, WHAT ARE THE CHANGES
THAT STRONGY DOES IN THIS
PARTICULAR CO-MORBIDITY.
SO AS I SAID, WE WANTED TO STUDY
THE INTERACTION BETWEEN STRONGY
AND TYPE 2 DIABETES, AND LOOK AT
A VARIETY OF BIOCHEMICAL,
HORMONAL AND BIOLOGICAL
PARAMETERS THAT AFFECT TWO
DIFFERENT PHASES OF TYPE
2 DIABETES.
ONE IS LOOKING AT PATHOGENESIS
OF THE -- AND CONTROL.
PEOPLE WITH DIABETES USUALLY ARE
MUCH -- HIGHLY PRONE FOR A
VARIETY OF COMPLICATIONS, MAINLY
MICROVASCULAR, MICROVASCULAR --
WE WANT TO LOOK AT THE
PARAMETERS THAT COULD -- SO THE
PROTOCOL IS BASICALLY LOOKING AT
60 STRONG GEE INFECTED PATIENTS
AND 58 CONTROLS.
WE COLLECT PLASMA AND LOOK AT A
VARIETY OF PARAMETERS THAT WE
KNOW DRIVES DIABETES SEVERITY.
AND BASICALLY ASKED THE QUESTION
WHAT DOES THE BASELINE LEVELS OF
THESE PARAMETERS IN THESE
STRONGY INFECTED INDIVIDUALS
COMPARED TO CONTROLS, AND ALSO
ASK THE QUESTION, IF YOU TREAT
STRONGY, DOES IT ACTUALLY HELP
OR WORSEN THE PICTURE FOR TYPE .
SO THAT'S BASICALLY WHAT WE ARE
LOOKING AT.
SO THE FIRST THING WE NOTICED IN
THIS FIRST ROUND OF PATIENT IS
REMEMBER ALL OF THESE PATIENTS
ARE TYPE 2 DIABETIC, SO ALL OF
THEM WILL HAVE HIGH LEVELS OF
RANDOM LEVEL -- IT HAS A VERY --
PEOPLE WITH STRONGY WHO ARE
SHOWN HERE IN RED HAVE
SIGNIFICANT LOWER OF -- COMPARED
TO THE UNINFECTED TYPE
2 DIABETIC PATIENTS SHOWN IN
GREEN, AND SIGNIFICANTLY LOWER
LEVELS OF RANDOM BLOOD GLUCOSE.
INTERESTINGLY, WE ALSO SEE
SIGNIFICANTLY LOW LEVELS OF
CIRCULATING INSULIN AS WELL AS
GLUCAGON, TWO PA PANCREATIC
HORMONES THAT DRIVE THE TYPE
2 DIABETES PHENOTYPE, BUT MORE
INTERESTINGLY IF YOU ACTUALLY
TREAT TRON GEE AND THEN LOOK AT
THESE PARAMETERS SIX MONTHS
LATER, YOU ACTUALLY SEE THERE IS
AN INCREASE IN A1C, INCREASE IN
INSULIN AND INCREASE IN
GLUCAGON.
SO ESSENTIALLY WHAT I'M SHARING
WITH YOU, THE CONTROL AS WELL AS
THE SEVERITY OF DIABETES IS
SIGNIFICANTLY BETTER IF YOU HAVE
STRONGY COINFECTION, AND GETTING
RID OF STRONGY IN THIS
PARTICULAR CONTEXT IS ACTUALLY
NOT GOOD FOR YOU, BECAUSE YOU
ACTUALLY WORSEN YOUR CONTROL OF
TYPE 2 DIABETES.
AND WHY IS THAT?
THERE APPEARS TO BE MULTIPLE
DIFFERENT PARAMETERS THAT GET
ALTERED BY STRONGY AND THESE ARE
ALL, AGAIN, ASSOCIATION DATA.
WE DON'T HAVE A CAUSE AND EFFECT
RELATIONSHIP, IT'S VERY HARD TO
DETERMINE THAT IN HUMANS, BUT WE
THINK THAT BY MODULATING A
VARIETY OF DIFFERENT PARAMETERS
THAT DRIVE DIABETES OR DIABETES
SEVERITY AND COMPLICATIONS THAT
STRONGY CAN MODULATE THIS.
SO THE FIRST ONE IS LOOKING AT
ADIPOCYTOKINES, BASICALLY
HORMONES PRODUCED BY ADIPOSE
TISSUE AND CAN DRIVE THE
PROGRESSION OF PATHOGENESIS OF
METABOLIC DISORDERS, AND WE FIND
THAT TRON GEE BASICALLY DOWN
REGULATES, WHICH ARE BOTH
PATHOGENIC FACTORS DRIVERRING
DRIVING TYPE2 DIABETES AND THISS
REVERSED DURING TREATMENT.
THEN IF YOU LOOK AT THE OTHER
SET OF HORMONAL MEDIATORS, IN
THIS PARTICULAR CASE, WHAT ARE
CALLED -- THESE ARE BASICALLY
MOLECULES THAT ARE ACTUALLY GOOD
FOR YOU BECAUSE THEY ARE THE
ONES THAT DRIVE PROTECTION
AGAINST METABOLIC DISORDERS AND
IN FACT SOME OF THESE ARE NOW
BEING USED WORLDWIDE FOR
TREATMENT OF OBESITY AND TYPE
2 DIABETES.
SO IF YOU LOOK AT GHRELIN, GI
P&G LP-1 YOU'LL SEE STRONGY IS
SIGNIFICANTED WITH HIGHER
LEVELS -- AGAIN IF YOU TREAT
THESE PATIENTS, YOU'RE ACTUALLY
WORSE OFF BECAUSE YOU DON'T
MODULATE THESE VERY --
MODULATORS.
SO TYPE 2 DIABETES IS ALSO,
ALTHOUGH NOT CLASSICALLY THOUGHT
OF AS SUCH, IS ALSO VERY
INFLAMMATORY DISORDER,
CLASSICALLY ASSOCIATED WITH
INFLAMMATION, IN THIS PARTICULAR
CASE, A TERM THAT IS COMMONLY
USED IS METAINFLAMMATION, AND IT
IS -- SO WITH THE QUESTION WE
ASKED, DOES TRON GEE DO ANYTHING
TO DAMPEN THE INFORMATION AND
THE ANSWER IS CLEARLY YES,
BECAUSE IF YOU LOOK AT PRETTY
MUCH MOST -- EVERY CYTOKINE THAT
WE'LL EXAMINE, WITH THE
EXCEPTION OF IL22, BECAUSE
IL22 IS ONE OF THE FEW FACTORS
WHICH ACTUALLY ARE PROTECTIVE
AGAINST METABOLIC DISORDERS.
THAT IS THE ONLY ONE THAT IS
ACTUALLY SIGNIFICANTLY ELEVATED
IN STRONGY BUT EVERYTHING ELSE
IS DOWN MODULATED.
SO STRONGY CLEARLY HELPS IN DOWN
MODULATING THE PRO-INFLAMMATORY
MILIEU THAT EXISTS IN TYPE
2 DIABETES AND PERHAPS HELPS IN
ALLEVIATING DISEASE SEVERITY.
IL1 ALPHA AND IL1 BETA ARE --
THAT OCCURS IN TYPE 2 DIABETES,
BOTH OF THEM ARE SIGNIFICANTLY
LOWER, AND IL-6 -- THAT ARE ALSO
SIGNIFICANTLY LOWER.
AND FINALLY STRONGY ALSO,
BECAUSE THIS IS A CLASSICAL
INDUCER OF TH2 OR TYPE
2 CYTOKINE RESPONSES ALSO DRIVES
THE UPREGULATION OF IL4, IL5,
IL13 -- ALL OF THESE COMBINED
POSSIBLY IS ABLE TO ALLEVIATE --
AS WELL AS GLUCOSE CONTROL IN
DIABETES.
FINALLY, SO THE QUESTION THEN WE
WE -- STRONGY APPEARS IN
INDIVIDUALS WHO ALREADY HAVE
TYPE 2 DIABETES, STRONGY IS
ACTUALLY DOING YOU GOOD.
BUT IT ALSO HAS PROPHYLACTIC
EFFECT IN -- TO DO THIS WE
BASICALLY LOOKED AT A VARIETY OF
DIFFERENT PARAMETERS THAT DRIVE
THESE COMPLICATING PATHWAYS
INCLUDING ACUTE PHASE PROTEI
PROTEINS, -- I'M GOING TO
QUICKLY GO THROUGH THIS AND TELL
YOU THAT PRETTY MUCH MOST OF THE
FACTORS THAT WE LOOKED AT, SO IN
THIS CASE ACUTE PHASE PROTEIN --
ALL OF THESE ARE SIGNIFICANTLY
DOWN MODULATED IN TR STRONGY
INFECTED INDIVIDUALS WHO HAVE
TYPE 2 DIABETES COMPARED TO
THOSE WHO DON'T HAVE STRONGY,
AND THIS GETS REVERSED UPON
TREATMENT OF STRONGY INFECTION.
SIMILARLY, MICROBIAL MARKERS
WHICH ARE A REFLECTION OF --
DYSBIOSIS AND GUT DAMAGE IN
DIABETIC PATIENTS, ALSO GETS
DOWN MODULATING, MOST OF THESE
ARE DOWN MODULATED WITH --
TREATMENT, AND IMPORTANT DRIVERS
OF THE VASCULAR COMPLICATIO
COMPLICATIONS -- -- ARE ALL DOWN
MODULATED IN TYPE 2 DIABETIC
PATIENTS WITH STRONGY
COINFECTION, AND FINALLY --
LIGANDS AS COMPLEMENT PATHWAYS
WHICH ARE IMPORTANT IN DRIVING
THE COMPLICATIONS OF TYPE
2 DIABETES ARE ALSO DOWN
MODULATED.
SO STRONGY, AGAIN, JUST LIKE IT
DOES IN TERMS OF MODULATING THE
IMMUNE SYSTEM IN THE DIFFERENT
ARMS, APPEARED -- A VARIETY OF
DIFFERENT PATHWAYS THAT -- SO
BASICALLY THE CONCLUSION HERE IS
THAT WE THINK THAT HELMINTHS ARE
NOT ALL BAD.
IN THIS PARTICULAR CASE,
HELMINTH BENEFITS, SO STRONGY
MIGHT ACTUALLY DO YOU A LOT OF
GOOD BUT DEPENDING ON THE
CONTEXT IN WHICH IT IS PRESENT.
SO WITH THAT, I'M GOING TO
BASICALLY END BY ACKNOWLEDGING
THE LAB TEAM, THE FIELD TEAM,
BOTH PAST AND PRESENT,
ESPECIALLY THREE INDIVIDUALS, AS
WELL AS A PREVIOUS LAB MEMBER,
DR. GEORGE, WHO HAVE BEEN -- WHO
WERE INSTRUMENTAL IN STUDIES IN
THE STRONGY FIELD.
ALSO ACKNOWLEDGE MY MENTOR, AS
WELL AS COLLABORATORS HERE AT
NIH, AND PREVIOUSLY -- AS WELL
AS A VARIETY OF COLLABORATORS
ACROSS INDIA AND SPECIFICALLY I
WOULD ALSO LIKE TO ESPECIALLY
EXTEND MY THANKS TO OUR HOST
INSTITUTE, THE NATIONAL
INSTITUTE OF RESEARCH IN
TUBERCULOSIS, ESPECIALLY THE --
WHO HAVE BEEN INSTRUMENTAL IN
HELPING US DO THESE SORT OF
BASIC RESEARCH, CLINICAL
RESEARCH AND ANIMAL RESEARCH
STUDIES IN SOUTH INDIA.
AND I'D ALSO LIKE TO BASICALLY
END BY SAYING THAT WE HAVE OVER
THE PAST COUPLE OF DECADES
ESTABLISHED A VERY EXTENSIVE
INDIA RESEARCH NETWORK.
WE HAVE CLINICAL COLLABORATORS
FROM OVER 30 DIFFERENT
INSTITUTIONS AND WE HAVE THUS
FAR CONDUCTED ABOUT 32 DIFFERENT
CLINICAL TRIALS, SO I WOULD BE
VERY HAPPY TO, YOU KNOW, CONNECT
WITH ANY NIH OR FDA INVESTIGATOR
WHO IS INTERESTED IN DOING
EITHER BASIC CLINICAL OR
IMMUNOLOGICAL STUDIES IN INDIA.
AND THIS IS MY CONTACT
INFORMATION.
AND FINALLY, ALSO LIKE TO THANK
THE NIAID SUPPORT FOR ICER,
SPECIFICALLY MARK, CHRIS, AND
OTHERS.
WITH THAT, I'M HAPPY TO CONCLUDE
AND TAKE ANY QUESTIONS.
THANK YOU SO MUCH.
[APPLAUSE]
>> HI, SUBASH, THAT WAS GREAT.
I HAVE THREE QUESTIONS.
WITH YOUR STRONGY TYPE
2 DIABETES ASSOCIATION, SO I
PRESUME THIS PARASITE RESIDES IN
THE GUT, AND THERE IS GUT
PATHOLOGY INVOLVED, AND ALSO THE
PARASITE ITSELF MOST LIKELY IS
CONSUMING SOME OF THE FOOD THAT
THE PATIENT --
>> CAN YOU SPEAK INTO THE MIC?
I'M SORRY, I'M HEARING IMPAIRED.
>> CAN YOU HEAR ME NOW?
OKAY.
SO I WAS JUST WONDERING, THE
METABOLIC CHANGES THAT YOU HAVE
SEEN AFTER STRONGY INFECTION,
HOW MUCH IS IT BECAUSE THE
PATIENTS DON'T HAVE GOOD FOOD
ABSORPTION DUE TO THE GUT
PATHOLOGY AND THE PARASITE
ITSELF WILL BE CONSUMING SOME OF
THE FOOD, SO WHEN YOU TREATED
THE PATIENTS, DOES THEIR FOOD
ABSORPTION ALSO IMPROVE, AND ARE
THESE CHANGES INDUCED BY TYPE
2 CYTOKINES OR MEA IT BE LIGHTS
THAT HAVE -- SO WHEN YOU TREATED
THE PATIENTS AND REMOVE THE
PARASITE DO YOU ALSO SEE A VERY
FAST DROP IN TH2 CYTOKINES?
>> SO I THINK I SHOWED THAT A
LITTLE BIT IN THE EARLIER SLIDE,
SO YES, THE FIRST PART OF YOUR
QUESTION IS HOW MUCH IS IT
ATTRIBUTABLE TO FOOD INTAKE AND
THE LOWERING OF FOOD ABSORPTION.
I THINK THAT'S A GREAT QUESTION.
IT PROBABLY HAS AN EFFECT BUT
STRONGY IS NOT ONE OF THOSE
PATHOGENS THAT BASICALLY INDUCE
MALL ABSORPTIMALABSORPTION TO AT
EX-STENT SO WE DON'T THINK IT'S
DIRECTLY AN EFFECT OF JUST
LOWERING OF CALORIE-RICH INTAKE.
WE THINK IT'S A MULTIPRONGED
CHANGE THAT HAPPENS, STRONGY
BECAUSE IT'S PRESENT OF ITS
ABILITY TO BE IN THE CIRCULATION
CAN ACTUALLY AFFECT THE
DIFFERENT ORGAN SYSTEMS,
INCLUDING DIRECT EFFECT NOT JUST
ON THE GUT BUT ON ADIPOSE TISSUE
AS WELL, BUT HAVING SAID THAT,
TO ANSWER YOUR SECOND QUESTION,
YES, WE DO SEE SIGNIFICANT DOWN
MODULATION OF TYPE 2 CYTOKINES
AS WELL AS REGULATORY CYTOKINES
FOLLOWING TREATMENT IN THESE
PATIENTS.
SO PRETTY MUCH --
>> AND I'LL JUST ASK ONE MORE
QUESTION BECAUSE I SEE -- WITH
THE TUBERCULOSIS COINFECTIONS,
THAT ASSOCIATION, SO I NOTICED
THERE'S REALLY HIGH LEVELS OF
IL12 IN COINFECTED PATIENTS, BUT
YOUR IL10 LEVELS ARE ALSO
ELEVATED.
SO IS IT POSSIBLE IT'S THE IL10
THAT IS DECREASING TH1 RESPONSE?
I DON'T KNOW IF YOU CAN TAKE THE
CELLS OUT OF THE PATIENTS AND
BLOCK IL10 AND SEE WHETHER THEIR
GAMMA GOES BACK TO THE NORMAL
LEVELS.
>> SO WE HAVEN'T DONE THAT.
YES, SO IN OUR -- IN INDIAN
PATIENTS IN GENERAL, IN PRIMARY
TUBERCULOSIS, WE DO FIND VERY
SIGNIFICANTLY HIGH LEVELS OF
CIRCULATING CYTOKINES.
THAT IS SOMETHING THAT I'VE BEEN
ASKED ABOUT BEFORE.
SO INTERFERON GAMMA LEVELS ARE
ARETYPICALLY MUCH HIGHER THAN
PEOPLE IN OTHER AREAS.
IL12 AS YOU NOTICED IS
SIGNIFICANTLY HIGH.
WE DO NOT KNOW IF IT IS -- HOW
MUCH OF IT IS DETERMINED
GENETICALLY AND HOW MUCH OF IT
IS EXPOSURE TO THESE VARIETY OF
PATHOGENS THAT THE INDIAN
POPULATION UNDERGOES.
WHAT WE DO KNOW IS THAT THERE IS
THE LEVEL OF INFLAMMATORY
CYTOKINES, ESPECIALLY IN THE
CONTEXT OF TBS VERY, VERY HIGH.
TO ANSWER YOUR QUESTION ABOUT
WHETHER IL10 IS DOWN MODULATING
THE IL12 RESPONSES, I WOULD
EXPECT TO BE SO BECAUSE WHAT WE
DO FIND IN TB INFECTION, JUST TB
ALONE, IS THAT IL10 IS
SIGNIFICANTLY DOWN MODULATED
BOTH IN THE LEVEL OF T-CELL
PRODUCTION OR IF YOU LOOK AT
OTHER IL10 PRODUCERS OR IF YOU
LOOK AT CIRCULATORY LEVELS, SO I
THINK ONE OF THE REASONS WHY TB
DRIVES SUCH A PRO-INFLAMMATORY
RESPONSE, BY ITSELF I THINK IT
CAN DOWN MODULATE IL10.
>> OKAY, THANK YOU.
>> HI.
VERY IMPORTANT CLINICAL RESEARCH
AND DATA.
SO I'M KIND OF INTERESTED IN THE
LAST PART, THE INTERACTION
BETWEEN THE HELMINTH INK FEX
AND -- SO THERE ARE MICE
EXPERIMENT WHICH IS NOT QUITE
LIKE HUMANS THAT HAVE SHOWN THAT
IF YOU TAKE AWAY -- YOU SEE AN
INCREASE IN WEIGHT IN MICE --
IMPORTANT IN -- WEIGHT AND I WAS
JUST THINKING DO YOU HAVE ANY
DATA ON ILC2s IN THE CONTEXT
OF STRONG LLO STRONGYLOIDES INFS
THERE ANY EFFORT IN LOOKING AT
TISSUES, IS NATI ANY TISSUE SITE
AVAILABLE IN THESE PATIENTS BUT
CAN YOU COMMENT ON WHAT YOU
THINK --
>> SO YOU'RE TALKING ABOUT IL22?
>> GROUP 2 INNATE LYMPHOID
CELLS?
>> ILC2s.
>> SO WE HAVEN'T ACTUALLY LOOKED
AT ILC2s DIRECTLY, SO AS YOU
KNOW VERY WELL, ILC2s ARE
TYPICALLY INDUCED IN HELMINTH
INFECTIONS BOTH IN HUMANS AND IN
ANIMAL MODELS, AND AS YOU
RIGHTLY SAID, ANIMAL MODEL
EXPERIMENTS CLEARLY SHOW THAT
THE INDUCTION OF ILC2 HAS A
BENEFICIAL EFFECT AGAINST
METABOLIC DISORDERS, MAINLY
BECAUSE OF THE ABILITY OF
ILC2s TO GO INTO THE ADIPOSE
TISSUE AND BASICALLY, YOU KNOW,
CHANGE THE -- OF THE FAT,
INFLAMMATORY MILIEU, ET CETERA,
AND IN ADDITION, WITH
EOSINOPHILS AS WELL, SO -- WHICH
ALSO OCCUPY ADIPOSE TISSUE AND
CAUSE MODULATION OF THE
THERMOGENESIS OF -- METABOLISM.
WE UNFORTUNATELY HAVEN'T LOOKED
DIRECTLY AT ILC2 IN OUR
PATIENTS, BUT PEOPLE WHO ARE
LOOKING AT HELMINTH INFECTION IN
THE CONTEXT OF METABOLIC
DISORDERS DO SEE SIGNIFICANT
CONCENTRATION OF ILC2, THAT'S
KNOWN.
>> NICE TALK, SUBASH.
THANK
>> THANK YOU.
>> ANOTHER HALLMARK OF THE
STRONGY INFECTION ARE THOSE
EOSINOPHIL NUMBERS.
I WAS WONDERING DID IT LOOK --
EOSINOPHIL NUMBERS OF THOSE
STRONGY INFECTED PATIENTS --
COMPLETELY DETRIMENTAL OR
BENEFICIAL AND I WAS WONDERING
IF THERE WAS ANY CORRELATION
BETWEEN THE EOSINOPHIL LEVELS OF
THE STRONGY WITH THE CLINICAL
OUTCOMES IN THE TB OR IN THE
TYPE 2 DIABETES.
>> THAT'S A GREAT QUESTION.
SO I DON'T HAVE AN ANSWER TO
YOUR QUESTION BECAUSE WE
ACTUALLY NEVER FOCUSED IN ON
EOSINOPHIL -- WE SEE -- WE WERE
ONE OF THE FEW GROUPS THAT
ACTUALLY SAW THAT EOSINOPHIL
DERIVED PROTEINS ARE
SIGNIFICANTLY UPREGULATED IN
STRONGY, INCLUDING EBN AND THE
OTHER EOSINOPHIL MEDIATORS.
WHAT WE HAVEN'T LOOKED AT IS
WHETHER ANY OF THIS HAS AN
EFFECT ON ANY OF THE BYSTANDER
RESPONSES THAT WE'VE SEEN.
SO I DON'T HAVE AN ANSWER TO
YOUR QUESTION.
>> I THINK ANOTHER RELATED
QUESTION IS IF THE CHRONICITY OF
THE HELMINTH INFECTION MATTERS,
THEY ALWAYS GET THE
HYPERRESPONSIVENESS BUT THAT
DEPENDENT ON HOW CHRONIC THE
PATIENTS ARE MATTERS?
>> GOOD QUESTION.
HAVEN'T LOOKED AT THAT BUT WE
CAN CERTAINLY LOOK AT THAT.
[APPLAUSE] 1564 01:05:05,968 >> THANK YOU.