IT IS A TRUE PRIVILEGE AND HONOR
FOR ME TO INTRODUCE DR. ANNE
O'GARRA FOR WALS LECTURE, TRUE
PIONEER IN THE FIELD OF
IMMUNOLOGY AND SHE HAS MADE
NUMEROUS DISCOVERIES THAT HAVE
REALLY CHANGED OUR UNDERSTANDING
OF INFLAMMATION AND DISEASE
STATES.
SHE FIRST TRAINED IN THE U.K. IN
IMMUNOLOGY AT MRC IN LONDON.
SHE SUBSEQUENTLY MOVED TO A VERY
HISTORICAL LANDMARK OF
IMMUNOLOGY, FIRST AS A
POSTDOCTORAL FELLOW THEN P.I. IN
WHICH SHE DEFINED FUND NEN TALL
MECHANISM FOR CYTOKINE
RESPONSES.
REALLY TOGETHER HER WORK WAS THE
FIRST TO PROVIDE A MOLECULAR
BASIS FOR THE PROCESS OF
IMMUNOREG EU LAITION IN
CYTOKINES.
I'M GOING TO CITE A FEW THINGS,
SHE WAS THE FIRST TO SHOW THE
INABILITY OF MACROPHAGES TO
SUSTAIN RESPONSES, INFLAMMATORY
CYTOKINES AND THE FIRST TO SHOW
THAT MACROPHAGES THEMSELVES
COULD BE AN IMPORTANT SOURCE OF
THIS IMMUNOREGULATORY CYTOKINE.
A LANDMARK STUDY TOGETHER WITH
KEN MUR SEE, WAS THE FIRST TO
SHOW THAT A MICROBE CAN ACTUALLY
INSTRUCT APCs TO PRODUCE IL-12
AND IL-18 ALLOWING
TH1 RESPONSES.
SO TOGETHER THIS OBSERVATION
PARADIGM SHIFT REALLY OPENED THE
DOOR TO THE FUNDAMENTAL WORLD
THAT SHE CONDUCTED AS WELL AS
MANY OTHER IN THE WORLD IN THE
ROLE OF CYTOKINE AND IN
PARTICULAR IL-10 IN DISEASE.
THIS REALLY INCLUDED THE CENTRAL
ROLE IN IL-10 IN INFLAMMATORY
BOWEL DISEASE, PERSISTENCE,
REGULATORY TUMOR ENVIRONMENT AND
MANY MORE.
BECAUSE OF HER PIONEERING WORK
IN IMMUNOREGULATION, SHE WAS
REALLY ONE OF THE FIRST TO
PROPOSE THE IDEA OF A BREAK OF
IMMUNOREGULATION AS A WAY TO
UNLEASH IMMUNE RESPONSES,
SOMETHING THAT OF COURSE LED TO
THE EVENT OF IMMUNE CHECKPOINT
THERAPY RESPONSES AND THAT HAS
TRANSFORMED THE FIELD OF
IMMUNOTHERAPY.
UPON HER RETURN TO THE U.K.,
ANNE BECAME HEAD OF THE DIVISION
AT THE MRC BEFORE BECOMING THE
ASSOCIATE DIRECTOR OF THE
FRANCIS CRICK INSTITUTE IN
LONDON.
AND REALLY IN LINE WITH HER
RESEARCH, SHE DECIDED TO APPLY
HER UNIQUE SKILL TO AN
EXTRAORDINARY CHALLENGE THAT IS
MYCOBACTERIUM TUBERCULOSIS
INFECTION.
SHE POSITIONED HERSELF AS A
LEADER USING A SYSTEM BIOLOGY
APPROACH, THE UNIQUE TYPE
1 SIGNATURE IN THE BLOOD OF
PATIENT AND THIS REALLY ALLOWED
TO UNCOVER A ROLE UNKNOWN BEFORE
OF TYPE 1 AND SUSCEPTIBILITY
REGULATION OF BOTH IL-10 AND
IL-12, AND THIS ONCE AGAIN
CHANGED OUR UNDERSTANDING OF THE
DISEASE.
ANNE RECEIVED NUMEROUS AWARDS,
SHE'S A FELLOW OF THE ACADEMY OF
SCIENCE, AND MANY, MANY MORE.
IN ADDITION TO ALL THESE
ACHIEVEMENTS, I WOULD LIKE TO
SAY THAT ANNE IS ALSO AN
EXTRAORDINARY AND FORMIDABLE
ADVOCATE FOR SCIENCE IN GENERAL,
AN ADVOCATE FOR YOUNG
INVESTIGATORS AND FOR WOMEN IN
SCIENCE.
I HAVE TO SAY HUMBLY I WILL NOT
BE HERE PRESENTING HER IF IT WAS
NOT BECAUSE AT ONE POINT IN MY
LIFE, SHE ADOPTED ME AS A
MENTEE.
SO FOR ALL THESE REASONS, I
WOULD LIKE TO SAY THAT ANNE IS
REALLY A ROLE MODEL AND AN
INSPIRATION FOR ALL SCIENTISTS
AND IT'S A TRUE PRIVILEGE FOR ME
TO WELCOME HER TODAY FOR WALS
LECTURE.
[APPLAUSE]
>> GOOD AFTERNOON, EVERYBODY.
THANK YOU SO MUCH, YASMINE, FOR
THIS VERY GENEROUS INTRODUCTION.
AT THANK YOU FOR INVITING ME TO
GIVE THIS WALS TALK AT THE NIH,
WHICH IS A GREAT HONOR, AND ALSO
BRINGS ME THE PLEASURE OF
VISITING NIH AGAIN AND TALKING
WITH SO MANY EXCITING
SCIENTISTS, INCLUDING THE EARLY
CAREER POSTDOCS AND STUDENTS.
SO MY TITLE IS "CYTOKINE
INTERFERENCE AND IMMUNITY TO
INFECTION" BUT I'D JUST LIKE TO
JUST SHOW YOU A FEW SLIDES WHICH
ACTUALLY LED ME TO THIS.
AFTER FINISHING A POSTDOC AT THE
NATIONAL INSTITUTE FOR MEDICAL
RESEARCH IN LONDON, I WAS VERY
FORTUNATE TO OBTAIN A POSTDOC
POSITION AT THE DNAX RESEARCH
INSTITUTE IN CALIFORNIA.
ONE OF THE FANTASTIC ATTRACTIONS
THERE WAS THAT THEY HAD
DISCOVERED THAT CD-4 T-CELLS
COULD EXPLAIN THE HETEROGENEITY
OF MANY IMMUNE RESPONSES AND
THEY HAD DEFINED THE TH1 CELLS
PRODUCING INTERFERON GAMMA
IMPORTANT FOR MACROPHAGE
DEVELOPMENT AND THE TH2 CELLS
WHICH PRODUCED IL4 AND IL5 BND
MOST IMPORTANTLY TRIGGERING
EOSIN FILLS AND MAST CELLS.
AT THAT TIME THERE WAS TROASTLES
AND TIM AND BOB HAD OBTAINED
THESE FROM CHRONICALLY IMMUNIZED
MICE AS OTHERS, AND I USED TO
COME BACK TO MILL HILL AND BE
ASKED THE QUESTION, DO THESE
REALLY, TH1 AND TH2 CELLS REALLY
EXIST IN VIVO AND CAN THEY BE
DRIVEN?
SO THAT LED ME TO START A
PROGRAM WHICH I COLLABORATED AS
A VERY EARLY CAREER GROUP LEADER
WHERE I HAD TWO PEOPLE IN MY LAB
AND COLLABORATED WITH KEN MURPHY
TO BASICALLY IN SIMPLE SYSTEMS
SHOW THAT IF YOU TRIGGERED NAIVE
T-CELLS TO THE T-CELL RECEPTOR
AND PROVIDED THEM WITH INNATE
CELLS, MACROPHAGES AND DENDRITIC
CELLS AND BACTERIAL PATHOGENS,
THIS WOULD THEN ALLOW THE
T-CELLS IN VITRO TO
DIFFERENTIATE ALONG THE PATHWAY
TO TH1 CELLS PRODUCING GAMMA AND
ALLOW THIS TO ISOLATE THE
INTERLEUKIN 12 WAS AN IMPORTANT
FACTOR IN DRIVING THIS
TH1 RESPONSE.
NOW, AT THIS TIME, BILL PAUL AND
HIS LAB DEFINED THAT IL-4 WAS A
DRIVING FACTOR FOR THE
TH2 RESPONSE AND I'D LIKE TO
TAKE THIS OPPORTUNITY TO SAY
THAT I WILL DEDICATE THIS TALK
TO BILL PAUL BECAUSE IT ACTUALLY
IS HIS BIRTHDAY TODAY, AND IT
WAS THE FIRST TIME I VISITED
NIH, HE WAS MY HOST AND WAS
SINCE VERY KIND TO ME.
SUPPORTIVE OF MY CAREER.
SO AFTER WE FOUND IL-12 DRIVING
DEVELOPMENT, MANY PEOPLE STARTED
WORKING ON THIS AND THROUGH THE
YEARS IT WAS FOUND IT WAS VERY
IMPORTANT FOR PROTECTING AGAINST
SALMONELLA, ON THE OTHER HAND,
THE TH2 RESPONSE WAS
ANTI-HELMINTHS AS MANY OF YOU
HAVE SHOWN, HOWEVER, IF
UNCONTROLLED, BOTH OF THESE
PHENOTYPES COULD CAUSE
INFLAMMATORY PATHOLOGIES SUCH AS
COLITIS, ALLERGIC INFLAMMATION.
SO AT THAT TIME A CYTOKINE
CALLED INTERLEUKIN 10 WAS CLONED
AT DNEX AND WE FOUND THAT B
CELLS MADE INTERLEUKIN TEP SO 
10 SO WE
WERE VERY INTERESTED TO FIND
OUT -- THE B CELLS COULD
STIMULATE TH1 CELLS.
BRIEFLY WHAT WE SHOWED IS THAT
IL-10 WAS A DOMINANT FACTOR IN
INHIBITING MACROPHAGES FROM
PRODUCING IL-12 AND TNF,
DENDRITIC CELLS AT PRODUCING
PRODUCE IL12,
IN ADDITION OTHERS SHOWED THAT
IL-10 COULD INHIBIT THE KILLING
OF INTERCELLULAR PATHOGENS BY
INHIBITION OF VARIOUS FAK 
FACTORS.
SO THAT RESEARCH OR THE
MOLECULAR BASIS OF IT THEN TOOK
MANY, MANY YEARS AND I STAYED AT
DNEX FROM '87 TO 2001, AND I
RETURNED TO THE MRC NATIONAL
INSTITUTE FOR MEDICAL RESEARCH
AT MILL HILL IN 2001 TO START
THE DIVISION OF IMMUNOREGULATION
TO CONTINUE MY MOLECULAR
MECHANISMS OF CYTOKIE GENE
REGULATION BUT ALSO BY
DISCUSSION, IT FELT -- SINCE I
WAS GOING TO INTERFACE I EU
KNOLL AND INFECTION, I SHOULD
WORK ON A DISEASE DEVASTATED TO
MAN.
SO I EXPANDED MY MASS MODELS OF
INFECTION TO TUBERCULOSIS WHICH
FITTED WITH SOME OF MY PAST WORK
ON CYTOKINS AND BACTERIA WHICH
I DID MY PH.D. ON, AND THEN WENT
ON TO HUMAN STUDIES.
SO WHAT WAS KNOWN AT THE TIME,
THE EARLY 2000s, IN THE IMMUNE
RESPONSE TO TUBERCULOSIS IS MTB
INFECTS THE LUNG PRIMARILY, AND
BASICALLY CAN INFECT MACROPHAGES
AND AS CLIFF BARRY HAS MORE
RECENTLY SHOWNS -- WHAT I JUST
WANT TO POINT OUT IS THAT NAIVE
T-CELLS WILL THEN BE STIMULATED
IN THE LYMPH NODE BY DENDRITIC
CELLS CARRYING ANTIGENS AND IF
YOU GET A PROTECTIVE RESPONSE,
IL-12 AND INTERFERE ON GAMMA ARE
PROTECTIVE AS SHOWN IN BOTH
MOUSE MODELS AND HUMAN DISEASE
AS WELL AS TNF, WHERE BLOCKADE
IN THE HOUSE CAUSES EXPANDED
TUBERCULOSIS BUT ALSO IN HUMANS
TREATED WITH ANTITNF DRUGS WHERE
IF EXPOSED TO TB WILL REACTIVATE
TB.
THAT WAS WHAT WAS KNOWN.
BECAUSE OF WHAT WE FOUND WITH
IL-10 INHIBITING MACROPHAGES AND
DENDRITIC CELLS WE THOUGHT IT
MUST PLAY A ROLE IN THE RESPONSE
TO TB BUT AT THAT TIME IT WAS
RATHER TREEFS YAL, THERE WERE
TITLES SAYING IL-10 PLAYED NO
ROLE IN TUBERCULOSIS.
WE WENT TO INVESTIGATE THIS
BEARING IN MIND THAT IN
INFECTION, THERE HAD BEEN
VARIOUS ROLES SHOWN FOR IL-10,
SO IL-10 COULD SUPPRESS THE
RESPONSE TO STOP PATHOLOGY, FOR
EXAMPLE, IN MALARIA, WITH MAJOR
PATHOLOGY IN IL-10 KNOCKOUT, ON
THE OTHER HAND, THE IL-10 COULD
INHIBIT THE PATHOGEN TO LITTLE
TO OBSERVED PATHOLOGY IN VARIOUS
MODELS, FOR EXAMPLE, IN LCN
INFECTION.
SO SETTING UP THE AEROSOL MODEL
WHICH WAS NOT GOING THAT TIME AT
MILL HILL, WE FOUND THAT IL-10
WAS INDUCED PROTEIN LEVEL AND IN
THE RNA LEVEL UPON TB INFECTION
IN MICE AND THEN USING
KNOCKOUTS, WE FOUND INDEED THERE
WAS A DECREASE IN THE BACTERIAL
LOAD BOTH IN THE LUNG AND THE
SPLEEN IN IL-10 KNOCKOUT, BUT NO
CHANGE IN WEIGHT OR NO CHANGE IN
PATHOLOGY.
NOW THESE ARE RELATIVELY
RESISTANT MICE, AND THEREFORE
THE DECREASE COULD BE LOW BUT
THIS IS SOMEWHAT SIGNIFICANT FOR
MTB AND OTHERS HAVE SINCE SHOWN
IF YOU RAISE IL-10, THIS WILL
REALLY CAUSE CHRONIC INFECTION.
WHAT WE SHOWED, HOWEVER, IS THAT
THIS EARLY AND ENHANCED
TH1 RESPONSE WAS HAPPENING IN
THE LUNG, IN IL-10 KNOCKOUT YOU
GOT INCREASED INTERFERON -- THIS
WAS EARLY AND IT WANED AFTER
ABOUT 55 DAYS.
IN THE LUNG YOU COULD SEE THIS
INCREASE, IN THE KNOCKOUTS, AND
IN THE SERUM AND AS I SAID THIS
WANED, SHOWING IL-10 SUPPRESSED
THE IMMUNE RESPONSE EARLY AND
SUBSEQUENTLY HAD EFFECT ON THE
BACTERIAL LOAD.
WE SINCE SHOWED IN MY LAB ITS
IL-10'S PREDOMINANT ROLE FROM
T-CELLS BECAUSE TARGETED
KNOCKOUT OF IL-10 IN CD4 T-CELLS
AS DID THE WHOLE IL-10 KNOCKOUT.
NOW AT THIS TIME, I DID REALIZE
THESE ARE MOUSE MODELS OF TB,
THERE WAS A LOT CRITIQUE ABOUT
THESE AT THIS STAGE, HOWEVER,
MANY OF THE RESISTANCE FACTORS
HAD BEEN DEFINED IN THE MOUSE.
WE HAD NOW FOUND A FACTOR THAT
MAY BE CONTRIBUTING TO
SUPPRESSION OF THE IMMUNE
RESPONSE IN CHRONIC TB.
HOWEVER, TB IS A HUMAN DISEASE,
SO WE THOUGHT AT THAT STAGE, I
MUST WORK ON HUMAN TUBERCULOSIS.
SO THIS IS WHAT I UNDERSTOOD BY
A LOT OF STUDYING WITH THE
CLINICIANS, IS THAT ONE PERSON
CAN BE INFECTED WITH MTB AND YOU
CAN GET A LOT OF DEATHS STILL
PER YEAR, BUT A THIRD OF THE
WORLD REMAINS -- MAY BE INFECTED
OR EXPOSED BUT REMAINS
ASYMPTOMATIC.
THE CLINICIANS INFORMED ME THAT
DIAGNOSIS WAS PROBLEMATIC, DRUG
TREATMENT TOOK SIX MONTHS, AND
THE TREATMENT MONITORING WAS
PROBLEMATIC.
MANY OF YOU MAY NOT KNOW THAT
AFRICA AS WELL AS IN ASIA HAVING
A VERY HIGH BURDEN OF TB, WE
ALSO HAVE CASES OF TB IN THE
UNITED KINGDOM IN SOME POCKETS
OF ENGLAND BUT ALSO IN POCKETS
OF LONDON, WHERE IN 2010, LONDON
WAS CALLED THE TB CAPITOL OF
EUROPE.
SO WE STARTED OUR STUDIES IN
LONDON AND THEN VALIDATED THEM
IN AN INDEMIC COUNTRY IN AFRICA,
AND THE QUESTION WE WERE ASKING
IS, COULD WE REALLY SEE A
DIFFERENCE BETWEEN ACTIVE TB AND
LATENT TB, BY LOOKING AT THE
GLOBAL IMMUNE RESPONSE.
AND THE QUESTION WAS, WHY DO
CERTAIN INDIVIDUALS DEVELOP
ACTIVE TB WHILE OTHERS DON'T,
COULD A PARTICULAR TYPE OF
IMMUNE RESPONSE CONTRIBUTE TO
ACTIVE TB?
SO THE QUESTION IS WHAT WERE
FACTORS IN THE IMMUNE RESPONSE,
COULD WE SEE THOSE IN TB AND
WERE THEY MISSING IN LATENT, AND
AT THAT STAGE, HAVING SHOWN YOU
THOSE THREE SLIDES THAT WERE
LIKE 10 YEARS OR 20 YEARS OF
PEOPLE'S -- MANY PEOPLE'S WORK,
I THOUGHT I CAN'T DO IT MOLECULE
BY MOLECULE, COULD I DO THIS BY
LOOKING AT THE GLOBAL IMMUNE
RESPONSE.
AND THE QUESTION WAS, CAN HUMAN
BLOOD TRANSCRIPTIONAL SIGNATURES
DISTINGUISH INDIVIDUALS WITH
LATENT AND ACTIVE TB AND IF SO,
GIVE US SOME CLUES AS TO WHAT'S
GOING ON.
AND INDEED, I LED A STUDY WHERE
WE DEFINED AN
INTERFERON-INDUCIBLE
NEUTROPHIL-DRIVEN BLOOD
TRANSCRIPTIONAL SIGNATURE IN
HUMAN ACTIVE TUBERCULOSIS, WHICH
I'LL TELL YOU THE STORY ABOUT OF
HOW WE DID THE STUDY AND WHAT
RESULTS WE OBTAINED.
SO WE RECRUITED INDIVIDUALS WITH
ACTIVE TB, SUSPECTED ACTIVE TB
BEFORE THEY STARTED TREATMENT.
WE THOUGHT THAT WOULD BE
IMPORTANT BECAUSE WE'RE LOOKING
AT BLOOD SIGNATURE WHICH WOULD
RESPONSE.
WE ALSO TOOK LATENT INDIVIDUALS
THAT HAD TO BE POSITIVE FOR THE
INTERFERON GAMMA RELEASE ASSAY
FOR MTB-SPECIFIC ANTIGENS WHICH
SHOWS THAT THEY'VE BEEN EXPOSED
BUT DOESN'T SHOW WHETHER THEY'RE
GOING TO GO ON TO GET DISEASE,
AND THEN COMPARED TO CONTROL.
SO THE FIRST THING WE DID WAS
ISOLATE RNA FROM WHOLE BLOOD OF
ACTIVE TB AND THESE CONTROLS.
SO THE FIRST TEST TRAINING SET
THAT WE DID USING STATISTICS TO
GET RID OF ANY NOISE, WE REDUCED
THE SIGNATURE TO 393 TRANSCRIPT
OF WHOLE BLOOD THAT WE COULD SEE
IN A MAJORITY OF ACTIVE TB
PATIENTS.
I WILL TALK ABOUT THE OUTLIARS
LATER, BUT NOT SEEN IN THE
MAJORITY OF LATENT OR CONTROL
INDIVIDUALS.
NOW, EACH INDIVIDUAL IS A
VERTICAL AND EACH GENE IS THE
HORIZONTAL AND YOU CAN SEE
UPREGULATED AND DOWNREGULATED
GENES.
BUT BEFORE WE COULD GET EXCITED
ABOUT THESE, WE REALLY HAD TO
REPRODUCE THIS STUDY, VALIDATE
IT IN MAYBE ANOTHER LONDON SET
AND IN AFRICA.
SO WE VALIDATED THIS
393 SIGNATURE IN LONDON, WHERE
WE SAW THE MAJORITY OF
INDIVIDUALS WITH ACTIVE TB
HAVING THE SIGNATURE, AND THE
MAJORITY OF LATENT AND CONTROLS
NOT, AND THEN WE VALIDATED IT IN
AFRICA, WHERE ALL THE
INDIVIDUALS THAT WERE CONTROLS
WERE ALL LATENT BECAUSE THAT'S
WHAT MOST PEOPLE ARE IN SOUTH
AFRICA, BUT WE COULD SEE THAT
THE SAME GENE SIGNATURE WAS
APPARENT BOTH IN LONDON AND IN
COUNTRY OF HIGH INDEMIC BURDEN.
NOW, ONE THING THAT WE DID
NOTICE, AND YOU COULD SEE THESE
PEOPLE DIAGNOSE WITH ACTIVE TB
HERE IN THE CLINIC, BUT THEY
CLUSTERED WITH THE HEALTHY.
SO THE QUESTION AS I SAID TO THE
CLINICIANS, WHAT COULD BE GOING
ON?
YOU CAN SEE QUITE CLEARLY THAT
THESE INDIVIDUALS REALLY LOOK
HEALTHY AND NOT ACTIVE TB.
SO A VERY BRIGHT MEDICAL
CLINICIAN WHO WAS WORKING WITH
ME AT THE TIME THOUGHT TO LOOK
AT ALL THE X-RAYS FROM ALL THE
INDIVIDUALS THAT WE EXAMINED AND
HE AND THREE OTHER PHYSICIANS
SCORED THEM SEPARATELY AND
INDIVIDUALLY AND FOUND THAT
THOSE INDIVIDUALS WITH A HIGH
RADIOGRAPHIC SIGN OF DISEASE HAD
A STRONG SIGNATURE, WHEREAS
THOSE WITH KNOW SIGN OF DISEASE,
EVEN THOUGH THEY'VE BEEN
DETECTED IN THE CLINIC AS
POSSIBLY HAVING TB, BASICALLY
HAD NO SIGNATURE.
AND USING A SCORE FROM THE
X-RAYs AND THE MOLECUAR
DISTANCE, THE MOLECULAR DISTANCE
TO HEALTH, WE COULD SEE A
COMPLETE CORRELATION BETWEEN THE
LUNG RADIOGRAPHIC SIGN OF
DISEASE AND MOLECULAR DISTANCE
TO HEALTH.
WE THINK THIS IS THE FIRST TIME
WE COULD TELL A BLOOD SIGNATURE
TELLING US WHAT WAS HAPPENING IN
THE TISSUE.
NOW, WE WENT ON TO REALLY SHOW
THAT THIS SIGNATURE COULD BE
DIMINISHED ON SUCCESSFUL
TREATMENT, AND THEN WE VALIDATED
THIS IN ANOTHER STUDY WITH
ANOTHER PHYSICIAN, RECRUITED
MANY MORE PATIENTS IN LONDON,
SOUTH AFRICA, AND YOU CAN SEE
THE WHOLE SIGNATURE IS BEING
DIMINISHED AFTER TWO WEEKS, AND
THIS CHANGE IN DIFFERENT
INDIVIDUALS AT DIFFERENT RATES
AND YOU CAN SEE EACH INDIVIDUAL
HERE, THAT SOME HAVE A VERY
NARROW SLOPE, SOME HAVE A
DRAMATIC SLOPE, AND THEREFORE
THEY'RE RESPONDING TO TREATMENT
AT DIFFERENT STAGES, AND THIS
REALLY COULD ADVANCE THE
MONITORING OF TREATMENT FOR NEW
DRUGS AND WHERE THE PEOPLE
RESPONDING, AND SINCE CURRENTY
THE TEST IS SPUTUM CONVERSION
WHICH TAKES OVER TWO MONTHS AND
YOU CANNOT GET SPUTUM FROM OVER
50% OF PATIENTS OR MORE ONCE
THEY'VE BEEN TREATED AND
ACTUALLY AT THE BEGINNING, ONLY
FROM ABOUT 70%.
SO THIS COULD PROVIDE A VERY
QUANTITATIVE WAY FOR MEASURING
RESPONSE TO TREATMENT.
NOW, THIS 393 BLOOD SIGNATURE
WAS OF ACTIVE TB, BUT OF COURSE
THERE WAS A LOT OF CRITIQUE AS
TO WHETHER THIS WOULD ALSO BE
SEEN IN OTHER DISEASES, IT WAS
JUST AN INFLAMMATORY SIGNATURE
WAS ONE OF  WHAT ONE OF THE
REVIEWERS
SAID TO US AND WE ACTUALLY WERE
VERY FORTUNATE TO BE
COLLABORATING IN DALLAS, THE
BAYLOR INSTITUTE, WHEN DAMIEN
HAD COME UP WITH A SOLUTION FOR
A LOT OF GENES IN
TRANSCRIPTIONAL HEAT MAPS.
AND THIS WAS TRANSCRIPTION
MODULES, AND THE ADVANTAGE OF
THIS IS THAT MO DUDE IS
DATA-DRIVEN DOES NOT INVOLVE
MANUAL SELECTION, IT CONTAINS
MAGNITUDE AND COMPLEXITY OF DATA
BUT SIMPLIFIES THE PRESENTATION
SO YOU COULD EASILY COMPARE TO
OTHER DISEASES.
PRINCIPLE IS, IT'S BASED ON
CLUSTERING WHICH MANY OF THE
OTHER PROTOCOL ARE NOW BASED,
YOU COULD SEE GENES GOING UP OR
DOWN IN THE DIFFERENT DISEASES
BUT THE GENES CLUSTERED
TOGETHER, CLUSTER 2 WAS ANOTHER
CLUSTER, ET CETERA, ET CETERA,
AND THIS COULD BE CALLED MODULE
1, MODULE 2, THEN LOOKING AT THE
LITERATURE, YOU COULD ANNOTATE
THEM WITH PARTICULAR SETS OF
GENES ANNOTATED TOGETHER LIKE B
CELLS, T-CELLS, AND THEN WE
COULD NOW COMPARE THE TB SETS,
THE TRAINING AND VALIDATION
SUBSET, WHICH ALL OF YOU CAN SEE
ARE COMPLETELY SUPER IMPOSABLE,
WITH CONFOUNDING DISEASES.
YOU CAN SEE THAT THIS INTERFERON
SIGNATURE OF INTERFERON
INDUCIBLE GENES WAS THERE IN TB
BUT NOT IN STREP OR STAFF AT
LEAST WEEKLY, WHEREAS THEY IN
CONCERT HAD THESE PLASMA GENE
SIGNATURES IN THIS MODULE HERE,
WHICH WAS MISSING TO LOW IN THE
TB SET.
THEN ANOTHER AUTOIMMUNE DISEASE
SHARED THIS INTERFERON INDUCIBLE
SIGNATURE, WHICH I'LL COME BACK
TO, AND THIS WAS FROM VIRGINIA
PASS 
PASQUALE, ALTHOUGH THE TB WAS
SHARED, YOU COULD START TO
DISTINGUISH BETWEEN TB AND OTHER
DISEASES.
WE WENT ON TO ACTUALLY DEFINE
THE TRANSCRIPTION SIGNATURES
COULD NOT ONLY DISTINGUISH THOSE
DISEASES BUT ALSO PULMONARY SAR
COY 
SARCOIDOSIS, OTHER TBs, AND
LUNG CANCER WHICH BELIEVE IT OR
NOT THE CLINICIANS WILL TELL UL
CAN BE CONFOUNDING TO TB
DIAGNOSIS.
AT THAT STAGE, MORE RECENTLY, WE
REPRODUCED MODULAR
TRANSCRIPTIONAL ANALYSIS IN MANY
MORE -- IT WAS REPRODUCED BY
MANY IN THE FIELD AND SHOWN TO
BE PRETTY SIMILAR AND WE THEN
REPRODUCED IT BY RNA SEQ AS
BEEN DOING AND HERE WE HAVE THE
FIRST 2010 PAPER OF ACTIVE TB
VERSUS LATENT, LONDON, SOUTH
AFRICA, LESTER, WHICH IS OUR NEW
COHORT.
THIS IS A STUDY FROM AFRICA, AND
THIS IS A STUDY FROM THE
GATES -- OF ACTIVE TB.
YOU CAN SEE VERY CLEARLY THAT
MANY OF THESE INTERFERON
INDUCIBLE GENES NOW DEFINED BY A
NEW MODULAR APPROACH COULD BE
SEEN ACROSS ALL THE TB STUDIES
AND INDEED LOWERING OF T-CELL
SIGNATURE COULD ALSO BE SEEN AND
OTHER MODULAR SIGNATURES WERE
ALSO SHARED ACROSS ALL THE TB
STUDIES.
NOW AFTER WE PUBLISHED OUR
STUDY, THREE STUDIES CAME OUT
FROM THE LITERATURE WITHIN A
YEAR.
THE MTB WAS SHOWN TO TRIGGER THE
GHASTING PATHWAY AND SHOULD BE
TURNING INTERFERON SIMILAR TO
OTHER ORGANISMS, LIKE POSSIBLY
VIRUSES.
FURTHERMORE, SOME STRAINS OF MTB
TRIGGERING THROUGH TLR4 COULD
TRIGGER MORE INTERFERON.
SO THIS MADE US THINK, WELL,
WE'VE DISTINGUISHED FROM ALL
THESE DISEASES BUT EARLY VIRAL
INFECTIONS MAY REALLY ALSO
CONFOUND THE SIGNATURE.
HOW DOES THIS LOOK COMPARED TO
VIRAL INFECTION?
SO WE GOT VARIOUS VIRAL IP FEXES
INFECTIONS OUT OF THE LITERATURE
AND SINCE GOT MORE AND YOU CAN
SEE VERY CLEARLY INDEED AS WE
PREDICT TO THE TYPE I INTERFERON
SIGNATURE WAS THERE IN THE FLU
AND BOTH OF THESE MODULES WERE
THERE.
AND ACTUALLY A RECENT STUDY HAS
IDENTIFIED THAT A REDUCED GENE
SIGNATURE, WHICH YOU WILL NEED
FOR DIAGNOSIS, HOWEVER, WHEN
DONE WITH CLASSICAL MACHINE
ALGORITHMS, LEARNING ALGORITHMS,
ACTUALLY ALL THE GENES IN THAT
DIAGNOSTIC ARE IN THIS MODULE.
SO WE THOUGHT WE NEED TO BE A
BIT MORE CREATIVE IN THIS, AND
WE COULD SEE THAT THERE WERE
CERTAIN MODULES OF GENES LIKE
T-CELLS AND B CELLS THAT WERE
REDUCED IN THE TB BUT WERE NOT
AFFECTED IN FLU, THERE WAS HEMO
POIESIS TURNED ON IN FLU AND NOT
TURNED ON IN TB, SO ON AND SO
FORTH, SO WHAT WE COULD THEN DO
IS GO TO EACH MODULE AND SAY,
WHAT IS DIFFERENT BETWEEN TB AND
THE OTHER DISEASES, SELECT THE
NUMBER OF GENES THAT ARE
DIFFERENT, AND THEN APPLY THE
MACHINE LEARNING ALGORITHM TO
REDUCE THAT TO A NUMBER THAT
COULD BE USED IN THE CLINIC.
AND SO THIS SHOWS IN THE
CLASSICAL WAY.
ZACHATEL STUDY USING THE HEAT
MAP, CLASSIC MACHINE LEARNING
ALGORITHM TO DISTINGUISH ACTIVE
TB FROM LAY 10TB, IT DID
BUTTEICALLY AND THAT'S WHAT IT
WAS TESTED AGAINST.
BUT IT WASN'T TESTED AGAINST
OTHER DISEASES AND HERE YOU CAN
SEE IN INFLUENZA, ACTUALLY
CONTROL AND INFLUENZA CAN BE
DISTINGUISHED WITH THAT SAME
SIGNATURE.
WITH A SIGNATURE WE DERIVED WITH
THIS APPROACH COMPARING NOT ONLY
USING THE MODULAR BUT AGAINST
OTHER DISEASES, YOU COULD
DISTINGUISH ACTIVE TB FROM
LATENT AND HEALTHY BUT NOW YOU
DON'T TOUCH FLU.
AND USING -- AND WE HOPE TO BE
ABLE TO DEVELOP THIS AS A
DIAGNOSTIC IN THE CLINIC AND I
SHOULD DECLARE A CONFLICT WITH
RESPECT TO INTERACTION WITH --
WHO HAVE FUNDED US FOR THESE
STUDIES.
NOW, USING CLASSICAL ROCK CURVES
THAT MAYBE MANY OF YOU ARE VERY
WELL ASSOCIATED WITH TO SHOW THE
SPECIFICITY AND SENSITIVITY OF
OUR TEST, YOU COULD SEE IN THREE
DIFFERENT COHORTS, R20 GENE
SIGNATURE PICKS UP ACTIVE TB
FROM LATENT WITH HIGH
SENSITIVITY BUT IT REALLY HAS
POOR ABILITY TO PICK UP FLU,
WHEREAS ALL THE OTHER REDUCED
SIGNATURES HAVE BEEN DEFINED IN
THE LITERATURE, NOT ONLY PICK UP
TB BUT THEY ALSO PICK UP A VIRAL
INFECTION.
NOW PEOPLE SAY OH, FLU IS NOT
RELEVANT FOR TB, BUT IT'S JUST A
SURROGATE VIRAL INFECTION.
ALL VIRAL INFECTIONS TURN ON
TYPE 1 INTERFERON, EVEN THE
MILDEST ONES WHEN SOME OF US
HAVE WHEN WE GET A COLD AS WE
FOUND IN MANY OF OUR DONORS OF
HEALTHY CONTROLS.
SO WE'RE KEEN TO WORK ON THIS
SIGNATURE TO IMPROVE IT FURTHER,
BUT THAT WILL COME WITH TIME.
SO A BIG QUESTION THAT REALLY WE
ALSO ASKED IS, OKAY, SO TYPE
1 INTERFERON MAY CONTRIBUTE TO
ACTIVE TB, WE CAN NOW SEE A WAY
TO DISTINGUISH ACTIVE AND
LATENT, BUT COULD WE DETECT A
SIGNATURE IN EARLY LATENT
INDIVIDUALS OF WHICH THERE ARE A
HUGE NUMBER IN THE WORLD WHO ARE
ASYMPTOMATIC, SOME OF THEM MAY
BE SUBCLINICAL AND WILL PROGRESS
WITHIN MONTHS TO TWO YEARS POST
INFECTION.
AND WE'VE SHOWN IN OUR STUDY AND
RECENTLY REPORTED IN REVIEWS
THAT ACTUALLY ACTIVE -- PEOPLE
INFECTED WITH TB WERE
ACTUALLY -- WILL ACTUALLY GO ON
TO DEVELOP ACTIVE TB IF THEY
DON'T GET IT WITHIN THREE
MONTHS, SIX MONTHS, ONE YEAR,
AND THE MAX WE FOUND IS UP TO
TWO YEARS.
AFTER THAT, UNLESS I GET SEVERE
IMMUNOCOMPROMISE PRESENTATION,
THEY REMAIN HEALTHY.
SO WE WANTED TO LOOK AT THESE
LATENT INDIVIDUALS FURTHER, AND
JUST TO SHOW YOU THAT WE WERE
SUSPECTING THIS BECAUSE IN OUR
ORIGINAL HEAT MAP OF OUR 2010
PAPER, WE FOUND THAT CERTAIN OF
THESE LATENT INDIVIDUALS
ACTUALLY SHOW THE SIGNATURE VERY
CLOSE TO ACTIVE TB.
SO IF YOU LOOK AT THESE LATENT
INDIVIDUALS TOGETHER, YOU CAN
SEE THEY'RE HETEROGENEOUS WHICH
HAD BEEN PROPOSED BY CLIFF BARRY
AND DOUGLAS YOUNG A NUMBER OF
YEARS BEFORE, AND THIS REALLY
COMPLEMENTED THIS HETEROGENEITY
BUT THUS FAR THESE INDIVIDUALS
WERE ASYMPTOMATIC.
SIGNATURE AT LEAST USING THE
MODULES.
AGAIN, THE LATENT TB OUTLIERS WE
SEPARATED BOTH IN THE COMBINED
SETS AND ALSO IN OUR LESTER NEW
COHORTS.
AND YOU COULD SEE THAT THE
INTERFERON SIGNATURE A STARTING
TO COME UP IN THE LATENT
INDIVIDUALS, AND HERE, AND THESE
INTERFERON SIGNATURES ARE TWO
DIFFERENT MODULES.
THIS ONE CONSISTING OF BITF3,
BATF2 AND -- TO BE TURNED ON BY
TYPE I INTERFERON BUT ALSO
GENES, IF YOU LOOK AT THEM,
WHICH LOOK LIKE VIRAL INFECTION
BUT WE KNOW THIS IS TURNED ON BY
TB.
IN ADDITION TO THIS INTERFERON
INDUCIBLE SIGNATURE BEING THERE
IN THOSE OUTLIERS, WE COULD ALSO
SEE IN LESTER SOME OF THESE N, K
AND C MODULE WHICH WE NOW KNOW
IS INTERFERON GAMMA AND T BOX
21, WHICH SEEMS TO BE BEING DOWN
DIAGNOSE REGULATED, WE HAD
MISSED THAT USING THE MICRO RNA,
NOW WE CAN SEE IT.
THESE INDIVIDUALS WERE LATENT,
PEOPLE ASKED US IF WE COULD
FOLLOW THEM, OF COURSE WE DIDN'T
HAVE THE RESOURCES AT THAT TIME
TO DO THAT.
SO WE STARTED COLLABORATING WITH
LESTER COLLEAGUES AND OTHERS TO
REALLY CONTINUE THE STUDIES, AND
THIS WAS A STUDY THAT WE TOOK
ACTIVE TB PATIENTS AND THEY
RECRUITED THEM VERY FAST, THE
CONTACT TO THE CLINIC.
WE GOT 109 CONTACTS, 50 THAT
REMAINED NEGATIVE AND HEALTHY
AFTER TWO YEARS, 49 OF THE EE
GRA POSITIVE ACTUALLY REMAINED
POSITIVE OVER TWO YEARS, BUT
NINE OF THESE INDIVIDUALS WENT
ON TO DEVELOP TB.
YOU CAN SEE ACTUALLY FROM AFAR,
THIS OUTLIER OF IGRA NEGATIVITY
IS A VERY STRANGE PATIENT AND WE
KEEP ASKING THE CLINICIANS TO
KEEP FOLLOWING THEM BUT ALL THE
REST HAVE VERY, VERY LITTLE OF
THIS GENE SIGNATURE.
IN THE IGRE POSITIVE, WE SEE
THIS UPREGULATION AND DOWN
REGULATION WITHIN MONTHS, AND
THIS WAS THE MONTHS AFTER
RECRUITMENT, UP TO TWO YEARS, IN
THE BLOOD SIGNATURE, IN ABOUT
50% OF THEM, BUT THE SICT WENT
UP AND DOWN AND THEY REMAINED
HEALTHY OVER TWO YEARS.
BUT THESE INDIVIDUALS WITH A
PERSISTENT HIGH BLOOD SIGNATURE
IN 70% ARE THE ONES THAT WENT ON
TO GET TB, AND INTERESTINGLY,
TWO OF THESE PATIENTS WHO DIDN'T
SHOW A SIGNATURE WERE ON ACTUAL
ANTIBIOTICS CALLED MACRO LIGHTS
FOR PNEUMONIA, WHICH ARE KNOWN
TO SUPPRESS THE IMMUNE RESPONSE
SO WE NEED TO AVOID THIS IN THE
FUTURE IF WE'RE GOING TO USE
THIS TO MONITOR TREATMENT.
AND THIS 20 GENE SIGNATURE IS
WHAT WE'RE TRYING TO USE NOW TO
IMPROVE THE EARLY DIAGNOSIS OF
TB, AND I JUST WANT TO SAY THAT
WE'RE NOT STUCK WITH THIS 20
GENE SIGNATURE, WE'RE OPTIMIZING
THE REDUCED SIGNATURE OF TB AND
PROGRESSES OVER OTHER DISEASES
USING JEANS FROM ALL PUBLISH
REDUCED SIGNATURES WHEN MANY OF
THEM ARE NOT ACTUALLY COMMON,
AND TWO EXAMPLES WHERE THEY'VE
SHOWN THESE ARE CONTROLS, THESE
ARE LTBI AND THESE ARE THE LTBI
PROGRESSORS.
IN OUR OWN STUDY VERSUS THE
ACTIVE TB.
AND YOU CAN SEE THAT YOU'RE
STARTING TO PICK IT UP WITH ONE
OF THE GENES FROM ONE OF THE --
THREE OF THE OTHER STUDIES,
WHEREAS IT'S NOT SEEN IN
INFLUENZA, CANCER, SARCOID
INFECTIONS OR BACTERIA, AND THEN
THIS IS ANOTHER ONE FROM OUR OWN
STUDY WHICH CAN DISTINGUISH
BETWEEN ACTIVE TB AND OTHER
DISEASES AND AGAIN, YOU START TO
GET THIS DIAGNOSIS AND THE AIM
IS TO REALLY OPTIMIZE A
SIGNATURE THAT CAN BE BROUGHT
TOGETHER.
WE DON'T MIND WHAT -- IN ORDER
TO BEING ABLE TO HELP ERD TB AND
ERT TREATMENT.
BEFORE I GET TO THE IMOW
NON-PART OF THE TALK, INTERAKING
WITH CLINICIANS SEEING TB
PATIENTS MADE IT MY MISSION TO
HELP IN TRYING TO DEVELOP THIS
WITH DIAGNOSTIC, WE NEED A
REDUCED NUMBER GENES WITH HIGH
SPECIFICITY AND ALSO TO HELP
WITH TREATMENT MONITORING IF WE
CAN DETECT EARLY TB.
BY A CHEAP WAY, THAT COULD ALSO
PERHAPS HELP IN THE TREATMENT OF
THIS DEVASTATING DISEASE, AND
THIS LAST PART WAS FUNDED BY OUR
UNIVERSTY HOSPITALS, LESTER,
OUR MAJOR COLLABORATORS.
NOW IN THE MIDDLE, I STARTED
THESE STUDIES TO TRY AND
UNDERSTAND WHAT FACTORS GOING ON
TO PEOPLE GETTING TB AND I
ALLUDED TO THE FACT THAT UP WITH
OF THEM HAD A SIGNATURE, THEN IN
THE RNA SEQ WE FOUND THEY WERE
DOWN REGULATED, BUT FACTORS
INDUCED BY TYPE 1 INTERFERONS.
SO WE ASK THE QUESTION, AND WE
DEFINED THIS FURTHER, THEY
LOOKED AT IT IN MANY, MANY
DIFFERENT WAYS, THE MODULES,
ALSO GENES DOWNSTREAM, AND YOU
COULD SEE THAT THESE GENES
DOWNSTREAM WERE REALLY
UPREGULATED AND YOU COULD SEE
THEM UPREGULATED IN PURIFIED
NEUTROPHILS FROM THE BLOOD AND
MONOCYTES PORTION OF THE GENES
AS COMPARED TO THE WHOLE BLOOD
BUT NOT IN CD8 T-CELLS AND THIS
WAS LIKELY THAT THEY HAD BEEN
CIRCULATING AFTER STIMULATION IN
THE LUNG BUT OBVIOUSLY THAT CAN
ONLY BE PROVED IN EXPERIMENTAL
MODELS.
BUT WHAT SURPRISED US THE MOST
IS THAT TYPE I INTERFERENCE,
PROTECT AGAINST SOME CANCERS AND
CAN -- OTHER BASIC MODELS OF
INFECTION SHOWN TO EXACERBATE
BACTERIAL INFECTION, SO WHY
HADN'T IT CAUGHT ON IN THE MOUSE
MODELS?
AND SO WE WENT TO THE MOUSE
MODELS TO LOOK AT MECHANISMS,
AND ACTUALLY WE THEN FOUND TWO
STUDIES FROM KAPLAN IN 2001,
2005, WHERE INDEED SHE HAD SHOWN
THE HYPERVIRULENT STRAINS WILL
INDUCE HIGH LEVELS OF TYPE
1 WHICH DECREASE TH1 IMMUNITY
AND THAT THE INTERFERON --
HOWEVER NOT ONLY WAS IT A
DIFFERENT STRAIN OF BUG BUT IT
WAS A DIFFERENT STRAIN OF IN OUR
STUDIES.
THERE'S WORK SHOWING A POLYIC
TREATMENT IN MTB INFECTED MICE
CAUSED A TWOFOLD INCREASE AND
THIS WAS INTERFERON ALPHA
B2 DEPENDENT.
WE THOUGHT THERE MAY BE VIRUSES
OR REMOVING NEGATIVE SIGNALING
OF THE TPL2 PATHWAY MAY DO THE
SAME.
SO WE POSTULATED THAT EARLY TYPE
OF RESPONSE, IF -- GENETICS --
THIS MAY LEAD TO HIGH LEVELS OF
INTERFERON WHICH COULD IMPACT
TB.
AND IN THE MOUSE MODEL WITH
ANDREAS MARK AND ALSO ALLAN
SCHERR WE INDEED SHOWED MTB
INFECTION IN THE CONTEXT OF
INFLUENZA VIRUS INFECTION LED TO
INCREASED BACTERIAL LOAD AND
THIS WAS COMPLETELY ABRI GATED
IN THE KNOCKOUT AND THAT WAS
VIRAL INFECTION DOING IT.
ANOTHER WAY I SUGGESTED WAS
PERHAPS RELEASING THE BRAKES
THAT ARE THERE TO REGULATE THE
AMOUNTS OF TYPE 1 INTERFERON
DURING DISEASE, AND WE WASN'T TO
THIS PATHWAY DOWNSTREAM OF
PATENT RECOGNITION RECEPTORS OF
TPL2 AND MATT KINASE MEK ERK
WHICH WE TOGETHER WITH STEVE AT
THE TIME HAD SHOWN WOULD
ACTIVATE -- 10 BUT ALSO IF YOU
TOOK AWAY TPL2 IN BASIC MODELS,
WE COULD SEE ELEVATED TYPE
1 INTERFERON.
SO COULD IT BE THAT THIS COULD
EXACERBATE THE.
 MTB IN MOUSE
MODELS, AND IN FACT WE LOOK TO
MTB INFECTION AND LISTERIA
INFECTION, AND YOU CAN SEE IN
THE TPL2 KNOCKOUT, WE INDEED GET
A DECREASE IN LOAD, HOWEVER,
THIS INCREASE OF BACTERIAL LOAD
WAS COMPLETELY ABROGATED IN THE
ABSENCE OF TYPE 1 INTERFERON
SIGNALING.
HOWEVER, YOU DON'T SEE A
PHENOTYPE JUST WITH KNOCKOUTS ON
A B6 BACKGROUND.
SO IN LISTERIA, YOU DO SEE A
PHENOTYPE WITH THE KNOCKOUT BUT
AGAIN, WITH TPL2 KNOCKOUTS, YOU
SEE THIS WHICH IS TYPE
1 INTERFERON DEPENDENT.
SO THE MECHANISM WE COULD LOOK
AT IN LISTERIA MORE BECAUSE OF
THE AMOUNT OF CYTOKINE MADE IN
THE SERUM IS THAT IL-10 WAS
INDUCED IN THE SERUM OF THESE
MICE AND THIS IL-10 WAS
ABROGATED IN THE ABSENCE OF
INTERFERON ALPHA BEE TA
SIGNALING  BETA SIGNALING
AND YOU COULD SEE THIS HIGHLY
ELEVATED INTERLEUKIN 12
PRODUCTION OF HUGE AMOUNTS OF
THE IN THE SERUM OF THESE MICE.
SO IT LOOKS LIKE PUT IN PLACE IN
ORDER TO REGULATE THE AMOUNT OF
CYTOKINE YOU MAKE IN RESPONSE TO
A PATHOGEN IN ORDER TO GET A
TEMPERED RESPONSE THAT CAN CLEAR
THE PATHOGEN, HOWEVER, THIS
OBVIOUSLY COULD GO WRONG,
LEADING TO WROK INFECTION.
SO WE WANTED TO UNDERSTAND MORE
OF HOW TYPE 1 INTERFERON MAY
IMPEDE MTB CONTROL AND WE LOOK
TO THE MACROPHAGE AND FOUND THAT
MTB INFECTED MACROPHAGES WHEN
TYPE I INTERFERON SOMEBODY
RELATED TO THESE WILL INDUCE
IL-10 PRODUCTION IN VITRO, THIS
CAN BE REMOVED -- THIS CAN BE
SEEN AT THE MESSAGE LEVEL IN
BOTH CASES, AND ACTUALLY TYPE
1 INTERFERON ATTEMPTED TO
SUSTAIN -- TRANSCRIPTIONAL
CONTROL TO MAINTAIN IL-10
PRODUCTION.
IN FACT, IN ADDITION TO TYPE
1 INTERFERON ALSO INCREASED THE
STABILITY OF THE IL-10 MESSAGE
THAT GO TO THE DIE  THE DETAILS
OF THE
ASSAY, TURN OFF IL-10 AND
STABILIZE TRANSCRIPTION AND THE
MESSAGE.
SO TYPE 1 INTERFERON IN T.B.
APPEARS TO BE BAD NEWS, IT TURNS
ON IL-10, IT BLOCKS IL-12
PRODUCTION FROM DENDRITIC CELLS,
MACROPHAGES, BLOCKS
TH1 DIFFERENTIATION, AND FURTHER
WE'VE SHOWN IT WILL BLOCK -- I
HAVEN'T SHOWN ALL OF THAT FOR
LACK OF TIME, BUT THERE'S ALSO A
TYPE 1 INTERFERON PARADOX NPD IN
HUMANS.
THERE WAS ONE STUDY IN MOUSE
WHERE THE DIFFERENT STRAIN AT A
VERY LOW DOSE WHERE IT LOOKED
LIKE TYPE I INTERFERON SOMETIMES
CAN BE PROTECTED.
SO WE AND OTHERS HAVE SHOWN A
POSITIVE CORRELATION BETWEEN
TYPE 1 INTERFERON AND DISEASE IN
HUMAN.
WE'VE SHOWN THE ELEVATING TYPE 1
INTERFERO
N CAN LEAD TO
INCREASED BACTERIAL LOAD AND
DISEASE.
HOWEVER, THERE WAS SOME CLINICAL
STUDIES REPORTED WITH BOTH
BENEFICIAL AND DELETERIOUS
EFFECTS OF TYPE 1 INTERFERON
ADMINISTRATION DURING MAY CROW
BACTERIAL INFECTIONS.
SO PEOPLE HAD SHOWN THESE WERE
CASE REPORTS, BENEFIT TYPE OF --
WHEN COMBINED WITH ANTIMICRO
BACTERIAL THERAPY, THAT'S -- AND
THE BENEFICIAL IS WHEN THEY WERE
ALSO ADMINISTERED DRUGS, AND
DISEASE AK AS BAITION 
EXACERBATION IN AN
ACTIVE TB PATIENT WHO ACTUALLY
THOUGHT TO HAVE NOT HAD ACTIVE
TB BUT HEPATITIS SO THERE THE TB
WAS OBVIOUSLY PREDOM NAPT.
TO GO WHACK TO  BACK BACK TO THE
MOUSE JUS
T TO
REMIND YOU THERE'S NO PHENOTYPE
I THE MOUSE, ALTHOUGH -- YOU
CAN SEE VERY CLEARLY HERE, I
SHOWED YOU T-CELL IN IL-10 WAS
MOST IMPORTANT FOR INCREASING
THE 
THE BACTERIAL LOAD.
THE IL-10 KNOCKOUT HAVE A VERY
DRAMATIC IF HE KNOW TYPE.
THERE ARE SITUATIONS WHERE WE
CAN BRING THE KNOCKOUT TO
PHENOTYPE BUT THAT IS FOR
ANOTHER DAY.
BUT THE QUESTION WAS WHY WERE WE
MISSING THIS?
WHEN WE LOOKED IN VITRO, THE
MACROPHAGES, WHEN WE TRIGGERED
WITH LOW AMOUNTS OF MTB, EARLY
ON WE COULD SEE INDUCTION OF
IL-12, WHICH WAS BEGINNISHED IN
THE ABSENCE OF SIGNALING AND
THIS COULD ALSO BE SEEN AT THE
MESSAGE LEVEL, SO EARLY, AND
SOMETIMES WHEN YOU ADMINISTER
THE CYTOKINE BEFORE THE MTB
INFECTION, YOU COULD ACTUALLY --
COULD TURN ON IL-12 PRODUCTION.
SO THERE WAS THIS PARADOX.
AND SO THE QUESTION WAS, IF YOU
ADMINISTERED TYPE 1 INTERFERON
EARLY IN LOW AMOUNTS OF MTB OR
DRUG-DRIVEN TB, THIS MAY LEAD TO
IL-12 PRODUCTION, BUT THE
QUESTION WAS, WERE WE MISSING
THE EFFECT IN THE MOUSE MODELS
IN THIS SITUATION BECAUSE GAMMA
INTERFERON WAS SO DOMINANT THAT
IT WAS MASKING ANY EFFECTS OF
PROTECTION ON TYPE 1 INTERFERON.
SO THEY USED WILD TYPE, TYPE
1 INTERFERON RECEPTOR KNOCKOUT,
INTERFERON GAMMA RECEPTOR
KNOCKOUT WE KNOW IS SUSCEPTIBLE
IN THE DOUBLE KNOCKOUT POSSE THE
EFFECTS, USING THE KNOCKOUT
DIDN'T CHANGE, WHEN YOU TOOK
AWAY INTERFERON GAMMA RECEPTOR
SIGNAL, THE BUG LOAD WENT UP
DRAMATICALLY BUT NOW WHEN YOU
DIDN'T HAVE INTERFERON GAMMA,
YOU COULD SEE THIS INCREASE IN
THE BUG LOAD WITH TYPE
1 INTERFERON, THIS WAS
ACCOMPANIED BY INCREASE IN
LESIONS AND INFLAMMATORY
PATHOLOGY IN THE LUNG.
AND SO LUCIA LOOKED MORE AT THE
MECHANISM AND BASICALLY THIS
REALLY FIT WITH TYPE
1 INTERFERON ADMINISTRATION
SHOWING TO HAVE A PROTECTIVE
EFFECT AGAINST MYCOBACTERIAL --
WHEN THEY HAD BEEN ADMINISTERED
TOGETHER WITH AND MTB DRUGS, SO
THEREFORE THE BUG LOAD IS LOW,
AND SHE SHOWED THAT ACTUALLY IN
THESE SITUATIONS IN HER
EXPERIMENTAL MODEL, SHE GOT AN
INCREASE IN TN FSMGHT IN THE
TYPE I INTERFERON RECEPTOR
KNOCKOUT IN THE ABSENCE OF GAMMA
SIGNALING AND A DECREASE OF --
AND THEREFORE LEADING TO TYPE
1 INTERFERON CAUSING THE
PROTECTION AND EXPLAINING THIS
MECHANISM.
SO I JUST WOUND UP WITH THE
MODEL THAT I'LL LEAVE YOU WITH
AND WHAT WE'RE GOING TO BE
TESTING IN THE FUTURE YEARS,
BOTH IN HUMAN DISEASE AND IN
EXPERIMENTAL MODELS.
SO EARLY TYPE 1 INTERFERE ON
WILL PRIME IL-12 AND TNF
PRODUCTION PROVIDED THAT THE MTB
LOAD IS LOW OND IN -- MAYBE
THAT'S TONIC SIGNALING WE HAVE
TO TURN ON IL-12 AND TNF AT THE
BEGINNING.
HOWEVER, ONCE YOU GET A TYPE
1 SUSTAINED LATE HIGH DOSE TYPE
1 INTERFERON SIGNALING WHICH IS
REALLY MAINTAINED FOR QUITE A
LONG TIME, IT CAN DIRECTLY
INHIBIT IL-12 AND TNF, I DIDN'T
SHOW THAT, IT CAN TURN ON IL-10
TO STOP THIS PATHWAY, AND
FURTHERMORE, IT CAN BLOCK THE
ABILITY OF INTERFERON GAMMA TO
ACTIVATE MACROPHAGES AND
PROTECTION.
SO WE REALLY NEED TO UNDERSTAND
IN EXPERIMENTAL MODELS IN HUMAN
DISEASE IS HOW THE STRAIN OF
MTB, THE ACTUAL LOAD OF THE TB
AND THE ENVIRONMENT OR THE
GENETICS OF THE INDIVIDUAL
INFLUENCE WHETHER WE HAVE THIS
LOW LEVEL OF TYPE 1 INTERFERON
OR THIS HIGH SUSTAINED DOSE, AND
WHAT CAUSES THIS TIP OF BEING
ABLE TO PROGRESS TO ACTIVE TB.
AND SO I LEAVE YOU WITH THIS
VERY BASIC QUESTION WHICH WE
WILL BE ASKING BY LOOKING AT THE
AIRWAVES OF INDIVIDUALS WHO ARE
ACTIVE TB OR THEIR CONTACT THAT
I SHOWED YOU EARLIER VERSUS
EXPERIMENTAL MODELS THAT WE'VE
NOW DEVELOPED THAT LOOK MUCH
MORE LIKE THE HUMAN KEYS 
DISEASE
WHERE WE HAVE CHANGED THE
MYCOBACTERIAL INFECTION DOSE,
THE STRAIN OF THE MYCOBACTERIAL
STRAIN, AND THE STRAIN OF THE
MOUSE, AND ACTUALLY THERE START
TO GET A SIGNATURE THAT TOTALLY
RESEMBLES HUMAN DISEASE.
SO THAT IS THE FUTURE BUT IT'S
BEEN A LONG JOURNEY AND A LONG
JOURNEY THAT'S ONLY POSSIBLE
THROUGH GREAT PEOPLE IN THE LAB
AND GREAT COLLABORATION.
SO MATTHEW BARRY WAS THE FIRST
PHYSICIAN IN MY LAB THAT CAME
FOR -- HE HAD TO GO BACK TO
CLINIC, THEN WHO REALLY SET UP
STUDY.
THEN CHLOE BLOOM JOINED,
CHRISTINE GRAHAM WAS A LONG TERM
MEMBER OF THE LAB WHO HAS JUST
RETIRED WHO SUSTAINED ALL THE
LIBRARY PREP AND RNA PREP FROM
ALL THESE PATIENTS.
WHO'VE JOINED THE STUDY WHICH
ACTUALLY WE STARTED IN
COLLABORATION WITH JUDY PASQUALE
WHERE WE REALLY LEARNED TO
ANALYZE DATA, NOW WE DO IT
OURSELVES, AND WE HAVE STO THANK
THE PATIENTS AND THE CLINICIANS
THAT WE'VE COLLABORATED WITH IN
SOUTH AFRICA, IN LONDON, ROB
WILKINSON AND NOW MARK LITMAN
FOR SOME OF THE OTHER STUDIES,
ROLL FREE, AND NOW OUR
COLLABORATORS WHERE WE HAVE A
VERY LONG TERM COLLABORATION,
AND THE EXPERIMENTAL MOUSE
MODELS WERE INITIATED BY PAUL
REDFORD, THEN FIN MACH NAB, JOHN
YOU BANK, REALLY MAINTAINING
WHOLE SHOW OF TRAINING AND THIS
NICE DATA, POSTDOC IN MY LAB,
AND SHE MAY SUPPORT ALL THE
WORK.
 -- HERE AT THE NIH, AND JEREMY
SUZA AND MORTGAGE  -- VERY
HELPFUL WHEN WE
MOVED TO THE CRICK AND DIDN'T
HAVE THE MOUSE MODEL, THE ANIMAL
FACILITY FOR TB FOR TWO YEARS.
I JUST WANT TO MAKE AN IMPORTANT
POINT TO ESPECIALLY YOUNG PEOPLE
IN THE AUDIENCE, IS THAT I WENT
BACK TO THE MRC NATIONAL
INSTITUTE FOR MEDICAL RESEARCH
AND THIS IS ALSO IMPORTANT TO
NIH, WHERE I WAS DOING IL-10 AND
BASIC CYTOKINE.
I WANTED TO GET INTO
TUBERCULOSIS AND THE GRANT
FUNDERS HAD REVIEWS THAT SAID --
IS A MASSIVE IMMUNOLOGY, THERE'S
NO WAY SHE CAN DO HUMAN TB
RESEARCH.
SO I JUST SHIFTED MY CO-FUNDING
TO WORK ON THIS, THEN I WAS
FORTUNATE TO GET SOME MONEY FROM
THE DANA FOUNDATION.
IT WAS A VERY SMALL AMOUNT OF
MONEY FOR THE FIRST 2010 STUDY.
THAT LED TO THE ALLIANCE
SUPPORTING US, AND AT LAST NOW I
ACTUALLY GOT AN INVESTIGATOR
AWARD TO STUDY HUMAN TB SO IT'S
TAKEN A FEW YEARS BUT NOW PEOPLE
ACKNOWLEDGE THAT, YOU KNOW,
MOUSE PEOPLE CAN GO INTO HUMAN
STUDIES.
AND I'D JUST LIKE TO POINT OUT
BEAUTIFUL -- FOR MEDICAL
RESEARCH AT MILL HILL WHERE MUCH
OF THIS STU CAN  STUDY WAS DONE
AND WHERE
MANY OF YOU HAVE ACTUALLY
WORKED/TRAINED WHICH IS NOW ON A
FLAT PIECE OF LAND TO BE BUILT
INTO APARTMENTS, AND NOW THE
FRANCIS CRICK INSTITUTE WHICH IS
A VERY EXCITING INSTITUTE IN
LONDON WHERE WE'RE CONDUCTING
OUR WORK NOW CONDUCTING OUR
VISIT.
 THANK YOU VERY MUCH.
[APPLAUSE]
>> THE FLOOR IS OPEN FOR
QUESTIONS.
>> WERE MOST OF THE TUBERCULOSIS
CASES ARE LOCATED IN THE
DEVELOPING WORLD, THERE'S OFTEN
A COINFECTION --
>> CAN YOU PUT YOUR FACE CLOSER
TO THE MICROPHONE?
SORRY BECAUSE IT'S HARD TO HEAR.
>> OKAY.
WHERE MOST OF THE TUBERCULOSIS
CASES ARE LOCATED IN THE
DEVELOPING WORLD, THERE'S OFTEN
A COINFECTION WITH HIV, ET
CETERA.
AND THERE ARE OFTEN MANY OTHER
COMORBIDITIES THAT ARE NOT AS
WELL ADVERTISED LIKE
MALNUTRITION, ET CETERA.
ISN'T THAT GOING TO AFFECT YOUR
GENETIC SIGNATURE AND THE
EFFECTIVENESS OF IT BEING USED
IN ITS PRIMARY INDICATED AREA?
>> ABSOLUTELY.
AND INDEED WE ARE COLLABORATING
WITH ROB WILKINSON AND GRAHAM
MINGES IN SOUTH AFRICA, IN
CAPETOWN, WHERE INDEED THEY'RE
STARTING HIV TB AND WE'RE
LOOKING -- HELPING THEM LOOK,
TRAINING THEIR FELLOWS TO LOOK
AT THE EARLY EFFECTS IN HIV TB
TUBERCULOSIS AND INDEED ON OTHER
FACTORS THAT MAY BE AFFECTING
THEM.
BUT ONE CAN'T DO EVERYTHING, SO
THE IMPORTANT THING IS TO TRAIN
PEOPLE IN AFRICA IN ORDER TO BE
ABLE TO CONDUCT STUDIES OF THE
KIND THAT YOU'RE INDICATING AND
WE'RE ACTUALLY DOING THAT, WE
HAVE A CRICK AFRICA NETWORK FOR
TRAINING OF POSTDOCS AT THE&
CRICK TO THEN BE ABLE TO GO AS
GROUP LEADERS TO REALLY ASK
THESE SPECIFIC QUESTIONS.
THE SIGNATURES YOU COULD SEE,
LOOKING AT BROAD SET OF PEOPLE,
WAS RECAPITULATED AND THIS HAS
BEEN DONE BY AT LEAST 15 OTHER
STUDIES.
HOWEVER, ONE OF THE ADVANTAGES
OF DOING WHAT WE'RE DOING, WHICH
IS BASIC RESEARCH IN LESTER, IS
ACTUALLY TO TRY TO UNDERSTAND
THE IMMUNE RESPONSE WHICH IS
EARLY AND PROTECTING VERSUS
GOING ON TO PROGRESS TO TB
BECAUSE THEN YOU HAVE 10%
PROGRESSING, NIEP TI% NOD, AND
WE DON'T KNOW WHAT THE BASIS OF
THAT IS.
SWRANG OF THE ADVANTAGE OF DOING
IT IN
LESTER, IT'S STILL A DISEASE IN
LOW TO INTERMEDIATE BURDENED
COUNTRIES, IS THAT WE DON'T GE
REINFECTION IN LESTER.
SO WE CAN LOOK AT ONE INFECTION
AND SEE THE PROGRESS OF WHY SOME
PEOPLE PROGRESS AND SOME DO NOT.
IN AFRICA, ONE HAS TO GET THE
INDEX CASE AS WELL AS THE CASE
OF THE PEOPLE REACTIVATING.
SO WE CONSIDER ALL THESE THINGS,
WE CAN'T -- WE DO COLLABORATE
WITH PEOPLE IN AFRICA IN ORDER
TO ANSWER SOME OF THE QUESTIONS
YOU'RE REFERRING TO.
>> THANK YOU VERY MUCH.
>> BEAUTIFUL TALK.
IN FOLLOW-UP TO YOUR MOUSE
RESULTS ABOUT COINFECTION WITH
INFLUENZA, ARE THERE HUMAN
EPIDEMIOLOGIC DATA SUGGESTING
THAT CONVERSION FROM LATENT TO
ACTIVE TB IS OFTEN ASSOCIATED
WITH THE OCCURRENCE OF VIRAL
INFECTION SUCH AS INFLUENZA OR
OTHERS?
>> SO THIS IS A REALLY GOOD
QUESTION AND IT'S ONE WE HAD PUT
IN COLLABORATIVE AWARD TO THE
WELLCOME TRUST BUT IT DIDN'T
QUITE FLY, BUT WE'RE GOING TO DO
IT ANYWAY.
ALL THE THOUGH WITH ALTHOUGH
WITH OBVIOUSL
Y LOW
NUMBERS.
ONE WAS A SURROGATE, SO OUR
CLINICIANS IN LESTER DEFINITELY
GO IN AND TRY AND DICTATE --
DETECT WHETHER THEY HAVE
BACTERIAL PNEUMONIAS OR VIRAL
AND THIS DO THOSE DIAGNOSES.
THEY WILL DO THEIR BEST, BUT WE
KNOW AND THIS IS WORD FROM THE
CLINICIANS THAT TO PROVE THAT
SOMEBODY HAS A VIRAL INFECTION
OR BACTERIAL INFORMATION,
SOMETIMES WHEN IT'S CLEARED AND
THEN AFTERWARDS, YOU GET THE TB,
IT IS VERY DIFFICULT SO WE WILL
DO THE BEST AND THAT'S WHY I
BELIEVE THERE ARE NOT -- THIS IS
NOT GOING TO BE -- IT'S GOING TO
BE FLU, PARAFLU, RSV, WHATEVER
VIRAL CHALLENGE THAT PEOPLE MAY
GET.
SO IT'S AN IMPORTANT QUESTION
THAT WE TRY AND ADDRESS BUT THE
EPIDEMIOLOGY STUDIES ARE NOT
THERE.
>> THANKS.
>> BUT THAT'S THE POINT OF
LOOKING AT EARLY TB WITH GRAHAM
MINGES BECAUSE IN CERTAIN
INDIVIDUALS, BEFORE THE
CD4 COUNTS HAVE EVEN DROPPED,
ACTUALLY GET PEOPLE WHO HAVE
HIV, THEN GET TB AND THEY GO ON
TO DIE.
SO ONE WANTS TO KNOW BEFORE
THAT, WHAT ARE THE EVENTS THAT
ARE DETERMINING WHICH WAY THEY
GO, SO THAT WOULD BE ANOTHER WAY
OF ADDRESSING.
>> I MISSED THE FIRST PART OF
HIS QUESTION, BUT THIS IS
RELATED, I'M SURE.
AND YOU AND I HAVE TALKED ABOUT
THIS OFTEN BUT THE AUDIENCE
WOULD BE INTERESTED.
SO DO YOU THINK THAT THE
SIGNATURE IS REALLY SIMPLY
TELLING US THAT YOU HAVE
SUBCLINICAL TB PRESENT?
IT'S NOT REALLY AN IMMUNOLOGIC
SIGNATURE THAT'S TELLING YOU
THAT YOU'RE SUSCEPTIBLE TO TB.
>> SO IN THE LATENT INDIVIDUALS
WHERE WE HAD THOSE OUTLIERS, IT
REALLY LOOKED LIKE THEY MAY HAVE
SUBCLINICAL DISEASE.
NOW, IN THOSE TRANSIENT
RESPONSES IN OUR IGRA POSITIVE
INDIVIDUALS THAT WE FOLLOWED, WE
DIDN'T USE THE INTERFERON
RESPONSE BECAUSE THAT CONFOUNDED
WITH OTHER DISEASES.
WE HAD THIS 20-GENE SIGNATURE
THAT WENT UP AND DOWN, WHEREAS
IT WAS SUSTAINED IN THE OTHER
INDIVIDUALS.
SO SOMETHING PROBABLY IS
DIFFERENT, BUT I DON'T THINK
WE'RE GOING TO SEE IT IN THE
BLOOD AND THAT'S WHY WE NEED TO
GO IN THE AIRWAVES TO SEE WHAT
ARE THE EARLY EVENTS THAT
HAPPENED THAT MAY DETERMINE
WHETHER PEOPLE GET A LEVEL OF
TYPE 1 INTERFERON THAT REALLY
MAKES THEM GO ON TO EXACERBATE
TB WHEREAS GOING AND REALLY DOWN
REGULATING.
SO WE BELIEVE FROM OUR MOUSE
STUDIES OF LOOKING AT MOUSE LUNG
VERSUS BLOOD THAT WE WILL BE
ABLE TO GET A BETTER HANDLE ON
THIS AND THE AIM IS TO LOOK AT
THESE CONTACTS VERSUS THOSE THAT
PROGRESSOR THOSE THAT DON'T AT
THE DIFFERENT INNATE CELLS OR
CHANGES OF THEM THAT OCCUR VERY
EARLY IN THAT IMMUNE RESPONSE.
>> THERE'S ALSO ANOTHER PART OF
THIS STORY THAT'S KIND OF
EMERGING NOW IS THAT IT APPEARS
THAT THE IGRE-NEGATIVE AND
PBD-NEGATIVE PEOPLE CAN ACTUALLY
BE INFECTED, THAT THERE'S PEOPLE
THAT WE THOUGHT WERE ACTUALLY
PROTECTED AGAINST TB.
HAVE YOU SEEN SIGNATURES IN
PEOPLE WHO ARE INDEMIC NORMALS
THAT MIGHT BE THIS GROUP OF
PEOPLE?
>> SO THE IGRE-NEGATIVE, AS I
SAID WE HAD A VERY SMALL BLIP IN
THEM BUT YOU COULD SEE
SOMETHING.
HOWEVER, FOR THE AUDIENCE, THE
IGRE TEST, IT DETECTS
INTERFERON, IF YOU LOOK AT TNF
INSTEAD, YOU CAN ACTUALLY SEE A
RESPONSE TO THE MTP ANTIAGAINS
AND THERE'S ANOTHER GROUP WHO
ARE DOING -- IT'S LIKE A T-CELL
POLARIZATION, WHERE THEY'RE
ACTUALLY TAKING THE T-CELLS AND
GETTING TWO STEPS TO SEE IF --
IT COULD BE SENSITIVITY, BUT
CLEARLY THEY MAY HAVE RESPONDED.
WE DON'T KNOW WHAT PERCENTAGE OF
THOSE IGRE-NEGATIVE, BUT WE HAVE
GONE FOR THE IGRE-POSITIVE
BECAUSE THOSE WE HAD -- THE NINE
THAT PROGRESSED, EIGHT OUT OF
NINE WERE IGRE-POSITIVE SO WE
HAVE A BIGGER CHANCE WITH OUR
BIGGER NUMBERS TO REALLY GET
SOMETHING HAPPENING AND THEN THE
IGRE POSITIVE THAT DID NOT
PROGRESS, THEY HAD THAT
SIGNATURE IN THE BLOOD
SUGGESTING OKAY, WE'RE GOING TO
SEE A RESPONSE BUT STAYED
HEALTHY, BUT I THINK THE IGRE
NEGATIVE, THEY DON'T RESPOND TO
WHATEVER BUT I WONDER IF IT'S
JUST SENSITIVITY AND WHAT NOBODY
THINKS ABOUT, EVEN IN
IMMUNOLOGY, IS THE BURDEN OF THE
BUG LOAD AND HOW MUCH INSULT IS
THE INDIVIDUAL PERTURBED WITH.
>> WELL, YOU COVERED THE WHOLE
PROFILES OF TB IN DIFFERENT
PERSPECTIVES AND SORTED OUT AT
LEAST THE INTERFERON ROLE,
INTERLEUKIN 10 AND
INTERLEUKIN-12.
SO IS THERE A TISSUE
SPECIFICITY, IF I HAVE TB IN THE
LUNGS VERSUS IN THE BONE, IS
THERE ANY OTHER EFFECT THAT
MIGHT BE AUGMENTING OR
SUPPRESSING THIS TB RESPONSE?
>> I THINK THAT'S A FASCINATING
QUESTION AS TO WHAT ELSE IS
HAPPENING, YOU KNOW, IN SOME
INDIVIDUALS YOU GET
DISSEMINATION OR NOT.
IT'S VERY INTERESTING THE
ANTI TNF TREATMENT OF
INDIVIDUALS
WHO WERE LATENT ACTUALLY LEADS
TO EXTRA PULMONARY TB
INVARIABLY, AND ALSO HIV TB
OFTEN LEADS TO EXTRA PULMONARY
TB, AND SO WHAT IS CONTROLLING
THE DISSEMINATION AND ALL I CAN
SAY IS, WE'RE NOT WORKING ON
THAT, BUT BY CHANCE, LUCIA, MY
POSTDOC, MAY START BECAUSE WE
HAVE A KNOCKOUT WHERE THE
SPLEENS ARE THIS BIG, WHEN YOU
GIVE THEM MTB, AND SO THAT COULD
BE REALLY EXCITING, ESPECIALLY
THAT SHE COULD THEN, YOU KNOW,
USE THAT TO FOLLOW HER CAREER AS
WELL AS VERY EXCITING DATA.
>> I HAVE A TB -- SO I AM
FOLLOWING UP, SO I ASK -- AT
MASUR, I SEE THAT I HAVE THIS
WHEN IT WAS LEAVING MAYO CLINIC,
THE X-RAY THAT YOU HAVE THIS
PART, SO I WAS ASKING WHAT IS
THE CHANCE SHOULD I HAVE SIX
MONTH THERAPY.
HE SAID IF YOU DON'T GET IT BY
THIS TIME, IT'S NEVER GOING TO
HAPPEN.
>> WELL, I'VE HEARD PEOPLE WHO
HAD BACKACHE AND WERE AT THE GP
AND THEY WERE GIVEN PAINKILLERS
ALL THE TIME, AND ONE WEEKEND
THEY CAME IN TO ST. MARY'S
HOSPITAL WHERE THEY THINK ABOUT
IT. B AND IT HAD GONE ON FOR SO
LONG THAT THEY WENT TO DIAGNOSE
THEM AND FSKT IN THEY STOPPED
THE PAINKILLERS, GAVE THEM
ANTITB DRUGS AND THEY GOT
BETTER.
THAT WAS LONDON.
SO YOU KNOW, WE'RE OPEN TO ALL,
BUT ANYWAY, THANK YOU FOR YOUR
QUESTIONS.
>> THANK YOU.
>> I HAVE ONE SMALL QUESTION.
I WANTED TO ASK YOU, PEOPLE ARE
LOOKING AT THE MICROBIOME
RELATIONSHIP WITH TB BUT IT WILL
MAKE MORE SENSE TO LOOK AT THE
VIRAL INSTEAD OF THE BACTERIAL
IN TERMS OF SETTING THE TONE OF
THE TYPE 1 RESPONSES ISN'T IT?
>> YEAH, THAT COULD BE PRETTY
IMPORTANT TO SEE WHAT OTHER
INNATE FLORA ARE AFFECTING THEM
GOING THE WRONG WAY AND THE
VIRUSES COULD BE VERY IMPORTANT,
AND SO YOU AS A MICROBIOME
EXPERT, WE WERE DISCUSSING THIS
WITH ALLAN YESTERDAY AND HIS
POSTDOC, WE WERE DISCUSSING --
THEY STUDIED DESEES FECES AND I
WAS
TINKING I WOULD LIKE TO LOOK AT
THE LUNG AND THE SPUTUM.
WHAT WOULD YOU RECOMMEND?
PROBABLY ALL OF IT?
>> IF POSSIBLE, ALL OF IT.
I WOULD LIKE TO FIRST REMIND YOU
THERE WILL BE DRINKS AND
COOKIES, NON-ALCOHOLIC DRINKS
AND COOKIES AT THE LIBRARY, AND
THANKS ONCE AGAIN, ANNE, FOR
THIS FANTASTIC LECTURE.
THANK YOU VERY MUCH.
[APPLAUSE]
