>>> GOOD AFTERNOON, EVERYONE.
I WOULD LIKE TO WELCOME EVERYONE
WHO IS HERE AND WHO IS WATCHING
FROM ABROAD OR WHEREVER YOU ARE
WATCHING THE VIDEOCAST, TO THE
ROLA E. DYER LECTURE ESTABLISHED
IN 1950 IN HONOR OF THE FORMER
NIH DIRECTOR, ROLA DYER, THE
LECTURE FEATURES INTERNATIONALLY
RENOWN RESEARCHERS WHO HAVE
CONTRIBUTED TO INFECTIOUS
DISEASES.
MY NAME IS BRIAN KELTHAL, AND I
HAVE THE HONOR OF INTRODUCING
THIS SPEAKER HER BETTER
W. VERGER, IV, KNOWN AS SKIP.
HE'S THE PROFESSOR AND CHAIRMAN
AND DEPARTMENT OF PATHOLOGY AND
IMMUNOLOGY, PROFESSOR OF
MOLECULAR AND MICROBIOLOGY AND
PROFESSOR OF MEDICINE AS WELL AS
A DIRECTOR AND PRINCIPAL
INVESTIGATOR OF THE MIDWEST
REGIONAL CENTER OF EXCELLENCE IN
BIOMEDICAL AND EMERGING
INFECTIOUS DISEASE RESEARCH AT
THE WASHINGTON UNIVERSITY SCHOOL
OF MEDICINE.
SKIP GREW UP IN FLORIDA WHERE HE
ACTUALLY SAILED COMPETITIVELY
AND WHERE HIS FATHER AND HE WERE
IN MULTIPLE RACES TOGETHER AND
WHERE HE BECAME THE REAL SKIP,
WE FOUND OUT LAST NIGHT.
SKIP WAS AN UNDERGRADUATE AT
HARVARD, GRADUATED MAGNA
CUM LAUDE IN BIOLOGY, WENT TO
HARVARD MEDICAL SCHOOL, GOT HIS
Ph.D., DOING RESIDENCY AND
INTERNAL MEDICINE AT BRIGHAM
WOMEN'S HOSPITAL R WORKED WITH
BERNIE FIELD, ONE OF THE GIANTS,
AND DID A FELLOWSHIP IN
INFECTIOUS DISEASE AT WASHINGTON
UNIVERSITY IN 1990 AND HAS BEEN
THERE EVER SINCE.
HE'S HAD MULTIPLE ACADEMIC
APPOINTMENTS AND HAS RECENTLY
BECOME PROFESSOR OF PATHOLOGY
AND IMMUNOLOGY IN 2002 AND
BECAME THE PROFESSOR AND CHAIR
OF PROCEED PATHOLOGY AND
IMMUNOLOGY IN 2006 AND PROFESSOR
OF MEDICINE IN 2008.
DR. VIRGI IS A FIELD OF VIROLOGY
AND INFECTIOUS DISEASES HIS
LABORATORY CR STUDIES THE ARE
ARE PATHOGENESIS OF ACUTE AND
CHRONIC DISEASES, USING SEVERAL
EXPERIMENTAL MODELS OF INFECTION
WITH DNA AND RNA VIRUSES
INCLUDING HERPES SIMPLEX
VIRUS,  
A NUMBER OF STUDIES WITH GAMMA
HERPES VIRUS 68 AND NEURO VIRUS
TOGETHER WITH GENETIC STRUCTURAL
COMPUTATIONAL SEQUENCING METHODS
HIS LABORATORY REALLY DEFINED
THE MECHANISMS OF MANY VIRAL AND
HOST GENES AND VIRAL
PATHOGENESIS LATENCY,
ONCOGENESIS, RECENTLY
INFLAMMATORY BOWEL DISEASE.
IN ADDITION, THEY DISCOVERED THE
FIRST MIRIANURO VIRUS,
DISCOVERED THE FIRST CULTURE
SYSTEM FOR A NEUROVIRUS AND
SHOWED NEURO VIRUS INFECTION CAN
TRIGGER CR INTESTINE
INFLAMMATION IN MICE WHO HAVE A
HYPOMORPHIC MUTATION IN 1601 AND
THIS REALLY ESTABLISHED THE
CONCEPT THE COOPERATIVE ROLES
FOR VIRAL INFECTION AND GENETIC
SUSCEPTIBILITY THAT CAN RESULT
IN THE DEVELOPMENT OF
INFLAMMATORY DISEASES.
MORE RECENTLY, THEY HAVE
DEVELOPED NEXT GENERATION
SEQUENCING TECHNOLOGY TO DEFINE
THE INTESTINAL VIROME AND HAVE
BEEN PIONEERS IN IDENTIFYING
POTENTIAL ROLES FOR VIROME AND
DISEASES SUCH AS INFLAMMATORY
BOWEL DISEASE AND
HIVENTEROPATHY.
ADAPTIVE IMMUNITY, PATHOGEN
PERSISTENCE AND PROTEIN
SECRETION.
THEY WERE ONE OF THE FIRST
LABORATORIES TO IDENTIFY
NONCONICAL ROLES OF PROTEINS, IN
THIS CASE IMMUNITY, B CELL
DEVELOPMENT, PANOCELL
DEVELOPMENT AND CELLULAR
PATHOGENS.
THEY HAVE RECENTLY PROVIDED
FASCINATING EVIDENCE FOR
TRANSKINGDOM INTERACTIONS IN
REGULATING IMMUNITY.
HE'S RECENTLY PUBLISHED FIVE OR
SIX REALLY BRILLIANT MANUSCRIPTS
THAT REALLY HAVE DESCRIBED
MULTIPLE INTERACTIONS BETWEEN
ORGANISMS IN REGULATING IMMUNE
SYSTEMS, AND THIS HAS INCLUDED
THE DEMONSTRATION OF CHRONIC
HERPES VIRUS INFECTION CAN
ACTUALLY BE BENEFICIAL TO ITS
HOST AND STIMULATE INNATE
IMMUNITY AND TO PROVIDE INNATE
IMMUNITY TO OTHER INNER
INFECTIOUS AGENTS SUCH -- OTHER
INFECTIOUS AGENTS SUCH AS
BACTERIA.
THEY'VE DESTROYED THAT HELMUTH
INFECTION CAN ACTIVATE, FOR
SIGHT KIND ACTION ON VIRAL
REPLICATION.
GIVEN THE FACT WE ALL HARBOR A
VAST VIROME IN THE FORM OF LAY
TENT INFECTIONS AND
BACTERIOPHAGE POPULATIONS, I
THINK HIS STUDIES HAVE BROAD
IMPLICATIONS FOR UNDERSTANDING
THE ARE SUSCEPTIBILITY TO
CHRONIC INFLAMMATORY AND
INFECTIOUS DISEASES.
HE'S PUBLISHED OVER 200 PAPERS
AND CHAPTERS, HE'S WON NUMEROUS
AWARDS AND HONORS INCLUDING A
WELCOME YOUNG INVESTIGATOR AWARD
IN VIROLOGY, MELANCROFT SCHOLAR,
MEMBER OF THE AMERICAN
ASSOCIATES OF PHYSICIANS, MEMBER
OF THE AMERICAN ACADEMY OF
MICROBIOLOGY AND IT'S RECENTLY
INDUCTED INTO THE HENRY KUNKLE
SOCIETY.
HE ACTUALLY PERFORMS A NUMBER OF
ROLES BOTH AT WASHINGTON AND
ABROAD AND IN OTHER INSTITUTIONS
IN THE UNITED STATES.
HE HAS BEEN ON STEERING
COMMITTEES FOR THE POSTERE
INSTITUTE, FOR THE ROGAN
INSTITUTE, HARVARD AND MIT AND
HE'S ALSO BEEN ON THE STEERING
COMMITTEE OF THE NIH GENOME
CENTERS FOR INFECTIOUS DISEASES,
HE'S BEEN ADVISORY BOARD MEMBER
AT STANFORD IN IMMUNOLOGY
PROGRAM AS WELL AS OTHERS.
HE'S REALLY A VERY
WELL-RECOGNIZED EXPERT IN
VIROLOGY AND ITS INTERACTIONS
WITH THE IMMUNE SYSTEM.
FINALLY I SHOULD MENTION THAT IN
ADDITION TO SCIENCE HE'S VERY
COMMITTED TO EDUCATION AND
PERFORMS A NUMBER OF ROLES AT
WASHINGTON UNIVERSITY,
ADMINISTRATIVE ROLES, AS WELL AS
TEACHING AND MENTORING.
THIS IS EVIDENCED BY HIS AWARDS
FOR MENTORSHIP AND TEACHING AT
WASH U AS WELL AS HIS
CONTRIBUTIONS TO TRAINING
PROGRAMS.
AS YOU'LL FIND OUT, HE'S A VERY
ENGAGING, ENTHUSIASTIC PERSON
AND COLLEAGUE AND SPEAKER REALLY
IT'S A JOIL TO HAVE HIM VISIT
THE NIH AND TO PRESENT THE DYER
LECTURE TODAY.
SKIP?
[APPLAUSE]
>> YOU CAN HEAR ME?
I'M NOT 100% SURE WHO BRIAN JUST
INTRODUCED.
[LAUGHTER]
BUT IT IS INDEED A GREAT HONOR
TO BE HERE AND TO SPEAK IN THE
NAME OF DR. DYER.
AS YOU WILL FIND, I LOVE
INFECTIOUS DISEASES AND THIS IS
ONE OF THOSE THINGS THAT YOU ARE
GET TO DO, IT'S A PARTICULAR
HONOR TO BE AT THE NIH TO GIVE
THIS LECTURESHIP.
SO IT'S MUCH APPRECIATED.
PLUS IN EACH OF THE MEETINGS
TODAY, I HAVE LEARNED SOMETHING
NEW THAT I DID NOT KNOW BEFORE,
AND THAT'S WHY WE DO THIS.
RIGHT?
SO I'M GOING TO, TODAY, MAKE
WHAT'S REALLY A GENETIC
ARGUMENT, AND I'M GOING TO SAY
SOME THINGS THAT MAY BE
CONTROVERSIAL TO THOSE WHO THINK
THAT ALL THE GENES THAT MATTER
TO US ARE ON OUR OWN
CHROMOSOMES.
AND I'M GOING TO MAKE AN
ARGUMENT THAT YOU'VE HEARD
BEFORE IN TERMS OF THE BACTERIAL
MICROBUY OHM BUT I'M GOING TO
TRY TO ADD THE VIRUSES THAT LIVE
ON AND IN US AS GENETIC ELEMENTS
THAT CREATE THE COMPOSITE
ORGANISM THAT WE ARE AND MAKE
THE ARGUMENT THAT SOME OF THE
DARK MATTER OF INHERITANCE AND
THE FACT THAT WE DON'T ALWAYS
UNDERSTAND EVERYTHING WHEN WE
ANALYZE A CHROMOSOMAL GENE MIGHT
BE JUST BECAUSE YOU'RE IGNORING
SOME OF THE GENES IN YOU THAT
DON'T HAPPEN TO BE ON YOUR OWN
CHROME TION.
SO THAT'S THE ARG -- YOUR OWN
CHROMOSOMES, THAT'S THE ARGUMENT
I'LL MAKE HERE.
I'LL START BY HOW WE GOT THERE
AND SUMMARIZE TWO STUDIES THAT
GAVE U.S. THE IDEA THAT WE
SHOULD PURSUE AN AVENUE OF
RESEARCH TOWARDS UNDERSTANDING
HOW VIRUSES THAT ARE PRESENT IN
OR ON US MIGHT INFLUENCE OR
FUNDAMENTAL BIOLOGY AND IMMUNITY
AND THEN TELL YOU A SERIES OF
MORE RECENT STORIES THAT ARE
PUBLISHED AND THEN I WILL END
WITH A SET OF UNPUBLISHED DATA
WHICH I THINK IS INTERESTING IN
REGARDS TO HOW WE THINK ABOUT
SPECIES DIFFERENCES BETWEEN
IMMUNE RESPONSES.
THAT'S THE OUTLINE OF WHAT I
WILL TRY TO ACCOMPLISH TODAY.
SO EVERYTHING IS ABOUT THE
PEOPLE WHO WORK IN YOUR LAB, AND
WE HAVE GROUPS WORKING IN VIRAL
PERSISTENCE, THE VIROME WHICH
I'LL DEFINE AND INFLAMMATORY
BOWEL DISEASE, A NUMBER OF
DIFFERENT GENES AND I'LL REFER
TO THE WORK DONE BY THESE PEOPLE
BUT I WANT TO START BY TELLING
YOU THAT I HAVE THREE PEOPLE WHO
ARE ON THE JOB MARKET RIGHT NOW,
DONNA McDUFF WHO PUBLISHED
THIS E-LIFE PAPER SHOWING THAT
HERPES VIRUSES CAN COMPLEMENT
IMMUNODEFICIENCY, NORMAN WHO
SHOWED DISEASE IN DESCR BACTERIA
PHASES, TIM NICE WHO FOUND THERE
IS SUCH A THING AS STERILIZES
INNATE IMMUNITY.
I USED TO THINK THAT B CELLS AND
T CELLS WERE REQUIRED TO GET RID
OF VIRUSES, IT TURNS OUT AT
LEAST IN MY SET IT'S NOT TRUE.
THIS SMART MAN COVERED THAT.
MEGAN WILL COME OUT ON THE JOB
MARKET NEXT YEAR.
SHE'S FOUND THAT BACTERIA
CONTROL VIRUS PERSISTENCE IN THE
GUT AND ALSO THAT INHERITED
CHANGES IN THE RIN HETEROD
MICROBIOME CONTROL IN THE
PHENOTYPE OF THE HOST.
THESE ARE THE KIND OF YOUNG
PEOPLE WHO IF YOU CAN, YOU
SHOULD HIRE.
SO THE VIROME.
THIS IS FROM 2009.
AT THAT TIME THE NUMBER OF
PEOPLE ON EFORT, AT THAT TIME
ABOUT 7 AND 3/4 BILLION, THIS IS
A PROPORTION OF THE TOTAL PEOPLE
ON EFORT TO BE INFECTED WITH
THESE VIRUSES, AND YOU MEADELY
SEE THERE ARE A NUMBER OF
VIRUSES, AMONGST THEM HERPES
VIRUSES, THAT ARE PRESENT IN
EVERYONE AND IN FACT IN THIS
ROOM RIGHT NOW EACH OF YOU HAS
AROUND TEN OF THESE VIRUSES.
THEY ARE INSIDE YOUR BODY, YOU
WILL NEVER GET RID OF THEM.
THEY ARE THINGS LIKE EBV.
IF I WERE TO SWAB YOUR THROATS,
MOST OF YOU I WOULD BE ABLE TO
DETECT EBV DNA IN THE SWAB FROM
YOUR TON SINGLES.
IT'S OCCURRED TO US FROM THE TWO
STORIES I'LL START WITH THAT WE
HAVEN'T THOUGHT ENOUGH ABOUT
THIS BECAUSE WE KNOW THAT WHEN
YOU IMMUNOCOMPROMISE A PERSON,
FOR INSTANCE WITH A I DS, YOU
CAN GET CMV RETINITIS.
THE CMV IS IN EQUILIBRIUM WITH
THE IMMUNE SYSTEM, IN FACT ALL
THESE VIRAL INFECTIONS ARE IN
EQUILIBRIUM WITH THE IMMUNE
SYSTEM, BUT IF THAT'S TRUE, THEN
THIS IS A DYNAMIC INTERACTION.
THESE ELEMENTS ARE PERMANENT TO
US AND THEY'RE IN CONSTANT
MOTION STIMULATING THE IMMUNE
SYSTEM.
SINCE BEING RECOGNIZED BY THE
IMMUNE SYSTEM, AND SINCE
CYTOKINES MADE BY C CELLS AND T
CELLS AND OTHER INNATE CELLS,
DON'T JUST -- IT'S POSSIBLE
THERE ARE SUBSTANTIAL EFFECTS ON
THE HOST ITSELF AND THAT'S THE
CONCEPT WE HAVE COME TO AND THAT
I WILL BE TALKING TO YOU ABOUT.
THEN I WILL TALK TO YOU ABOUT
WHAT MIGHT BE REGULATING SOME OF
THESE THINGS.
IS IT ONLY OUR GENES?
OR IS IT ALSO GENES THAT WOULD
BE PRESENT IN OTHER ORGANISMS
THAT INHABIT US?
SO THIS IS THE CONCEPT, THAT
THERE IS A VIROME AND THAT THE
VIROME IS INDIVIDUAL TO
DIFFERENT PEOPLE AND IT'S
CONSTANTLY IN EXCHANGE WITH
OTHER MAMMALS, BIRDS, BATS, ET
CETERA, AND THAT IT EVOLVES VERY
QUICKLY.
THAT THEY'RE EUKARYOTIC VIRUSES,
ENDOGENOUS ELEMENTS SUCH AS
RETROVIRUS DERIVED ELEMENTS,
PROKARYOTIC AND ARKAO ORGANISMS
AND THAT THEY INTERACT WITH EACH
OTHER IN TRANSKINGDOM
INTERACTIONS AS A VIROLOGIST
FORGIVE ME, I'M GOING TO CALL
VIRUSES ALIVE FOR THE SAKE OF
THIS ARGUMENT, AND THAT THIS IN
TURN, THESE INTERACTIONS
INTERACT WITH GENETIC VARIATIONS
TO DEFINE OUR GENOTYPE/PHENOTYPE
RELATIONSHIP IN TERMS OF
SYSTEMIC INFLAMMATION, IMMUNEO
PHENOTYPE OF THE HOST, THE BASAL
IMMUNE SYSTEM, WE THINK OF HOW
THE ACTIVATION OF THE IMMUNE
SYSTEM WORKS, WHEN A NEW AGENT
COMES IN, THAT WOULD BE THE
IMMUNOPHENOTYPE OF THE
INDIVIDUAL AT THE TIME OF
CHALLENGE, DISEASE
SUSCEPTIBILITY I THINK SOME OF
THESE THINGS ARE CLEARLY GOOD
FOR YOU, THEY'RE MUTUALISTIC
SYMBIOSIS AND PERHAPS INDIVIDUAL
INTERVARIATION WOULD COME FROM
THE INTERACTION OF THESE VIERS
AND GENES AND OF COURSE
TRADITIONAL VIRAL PATHOGENS
WHICH CAUSE DISEASE IN THE
MAJORITY OF PEOPLE WHO ARE
INFECTED WITH THEM.
THAT'S THE CONCEPT WE'VE COME TO
TEST.
SO HOW DO WE GET THERE?
SO WE THOUGHT ABOUT THE VIROME,
CHANGING THE IMMUNOPHENOTYPE AND
CHANGING THE RELATIONSHIP OF THE
PHENOTYPE OF THE INDIVIDUAL AND
THE GENOTYPE BASED ON TWO
STUDIES THAT WERE PUBLISHED
ABOUT SEVEN OR EIGHT YEARS AGO.
ONE OF THEM, A VIRUS WE
DISCOVERED, A CHRONIC NOR OH
VIRUS INTERACTED WITH A GENE TO
CHANGE THE TRANSCRIPTIONAL
PATTERN OF EPITHELIAL CELLS AND
GENERATED PHENOTYPE TION IN MICE
THAT ACTUALLY LOOK JUST LIKE A
SUBSET OF PATIENTS WITH CROHN'S
DISEASE.
I WILL SHOW YOU A FEW SLIDES
FROM THE STUDY TO INTRODUCE IT.
AND IN ANOTHER, WE FOUND THAT
CHRONIC HERPES VIRUS INFECTION
COULD CHANGE GENE EXPRESSION IN
THE HOST AND ACTUALLY PROTECT
AGAINST BACTERIAL INFECTION AND
TUMORS.
SO IN EACH OF THESE CASES WE HAD
A CHRONIC VIRUS ALTERING
TRANSCRIPTION LEADING TO VERY
SUBSTANTIAL NEW PHENOTYPES THAT
DID NOT EXIST, JUST WITH THE
MUTATION OR JUST WITH THE
ORGANISM.
AND THAT'S WHAT'S MADE US THINK
ABOUT THIS IDEA THAT THERE'S
THIS INTERACTION WITH THE HOST
AND THE VIROME THAT CHANGES
BIOLOGY.
SO SOME PRELIMINARY SLIDES OF
THOSE DATA.
SO THIS IS THE STUDY HERE, IT'S
A VERY SIMPLE EXPERIMENT.
WE TOOK MICE AND LATENTLY
INFECTED THEM WITH A GAMMA
HERPES VIRUS SHOWN IN RED HERE
AND THEN CHALLENGED THEM WITH A
VERY HIGH DOSE OF LISTERIUM, AN
INTRACELLULAR BACTERIA, THIS
BACTERIA KILLED MICE EXCEPT WHEN
THEY WERE LATENTLY INFECTED.
THIS LASTED FOR MANY MONTHS, UP
TO SIX MONTHS IT'S BEEN OABLED
AND IN FACT -- IT'S BEEN
OBSERVED.
AND WE ENGINEERED VERSIONS OF
THIS VIRUS BY DELETING SOME
GENES SO WE COULD GET ACUTE
INFECTION AND NOT LATENT
INFECTION AND THIS EFFECT
DISAPPEARED.
THIS IS CHRONIC INFECTION
PROTECTING THE HOST.
THIS IS A CLASS OF VIRUSES WHICH
MOST OF YOU HAVE FOUR OR MAYBE
FIVE OF.
WE THINK IT'S REASONABLE TO
CONSIDER THE POSSIBILITY THAT
THAT CHRONIC INFECTION MIGHT
ALTER YOUR SUSCEPTIBILITY TO
BACTERIAL DISEASE, FOR EXAMPLE.
THE MECHANISM WAS PUBLISHED BUT
I'LL JUST OUTLINE IT, IT TURNS
OUT THAT THIS CHRONIC VIRAL
INFECTION SETS THE INNATE IMMUNE
SYSTEM BY STIMULATING INTERFERON
GAMMA SECRETION, ACTIVATING
MACROPHAGES, WE SHOW IN K CELLS
AND OTHER STUDIES, THOSE AK
VAITD MACROPHAGE TION --
ACTIVATED MACROPHAGES PROTECT
AGAINST INFECTION.
THEY PROTECT THE HOST.
IF YOU DO A VERY SIMPLE
EXPERIMENT AND TAKE AN ANIMAL
AND LATENTLY INFECT IT AND JUST
HARVEST THE ORGANS AND GENE
SHAPE THEM, LIVER, SPLEEN AND
BRAIN, THE FIRST THREE ARE FROM
THE VIRUS THAT CAN ESTABLISH
INFECTION, NEXT THREE THE MUTANT
THAT'S ONLY ACUTE, CHRONIC,
ACUTE, CHRONIC, ACUTE, AND LOOK
AT THE GENES, YOU CAN
IMMEDIATELY SEE THAT THE
LATENTLY INFECTED ANIMALS HAVE
SUBSTANTIAL CHANGES IN JUST
BASAL GENE EXPRESSION.
THIS IS DIFFERENT IN THE LIVER,
SPLEEN AND BRAIN.
IN FACT, IF YOU LOOK AT THESE
GENES, THERE'S SEVERAL GENES
WHICH HAVE BEEN LINKED IN
STUDIES TO SUSCEPTIBILITY TO
HUMAN DISEASES, CELIAC DISEASE,
CROHN'S DISEASE, MULTIPLE
SCLEROSIS, REGULATED BY THESE
CHRONIC INFECTIONS.
SO WHAT THIS SAYS IS THAT WE AS
TRANSCRIPTIONAL ENTITIES ARE NOT
THE SAME WHEN WE ARE CHRONICALLY
INFECTED AND YET WE ARE ALL
CHRONICALLY INFECTED BY MULTIPLE
VIRUSES.
SO THIS LEADS TO THE IDEA THAT
MAYBE THESE CHANGES IN GENE
EXPRESSION HAVE VERY IMPORTANT
PHENOTYPIC EFFECTS ON US.
SO THAT'S AN EXAMPLE OF THE
VIROME REGULATING THE
IMMUNOPHENOTYPE OF THE HOST.
SECOND STORY IS THIS CHRONIC
NOROVIRUS, WHICH ARE THE CAUSE
OF 85% OF THE CR GASTROENTERITIS
IN THE WORLD, NOT BEEN CULTURED,
WE DISCOVERED A CULTURE SYSTEM,
REVERSE GENETICS AND SUCH.
SO WE HAVE A NICE ANIMAL MODEL.
WE WERE STUDYING THE GENES AND
FOUND OUT THAT WE GOT THIS
INTERESTING CROHN'S DISEASE-LIKE
PHENOTYPE WHEN WE COMBINED THIS
VIRUS WITH THIS MUTATION.
SO THIS IS A VIRUS PLUS GENE
INTERACTION.
THIS IS A COMBINATRIAL CONCEPT,
THE IDEA YOU DON'T GET THE
PHENOTYPE WITH JUST THE GENE OR
VIRUS, IT'S ONLY THE TWO
TOGETHER.
MICE MU TAITD FOR THE GENE HAVE
NORMAL PENNET CELLS, THEY GET
COLITIS WHEN YOU GIVE THEM DSS
AND THEY HAVE NORMAL SMALL
INTESTINE, THIS IS THE ILEUM.
YOU TAKE THIS MUTANT ANIMAL AND
INFECT WITH THE VIRUS, YOU GET
ABNORMAL PENNAT CELLS, MUCH
CHANGED RESPONSE TO DSS
INCLUDING SOME PHENOTYPES THAT
LOOK MORE LIKE CROHN'S DISEASE,
NOW WE HAVE A COMPLETELY NEW
PHENOTYPE WHICH IS ILEAL
ATROPHY.
IF YOU WERE LOOKING FOR A
GENETIC EFFECT ON ILEAL ATROPHY,
YOU WOULD ONLY SEE IT IN THE
PRESENCE OF THIS CHRONIC VIRUS
INFECTION.
THAT PATHOLOGY, IF YOU NOW LOOK
IN HUMANS WITH CROHN'S DISEASE
WHO ARE WILD TYPE 3AT16, THESE
THESE NICE PENNAT CELLS, THE
HUMAN WITH THE MUTATION IN THE
GENE HAVE THE SAME PANOCELL
ABNORMALITY WE FOUND IN THE
MOUSE.
THINK ABOUT WHAT WE DID, WE TOOK
MOUSE WITH A GENE MUTATION,
NORMAL PANA CELLS, ADDED A
CHRONIC INFECTION, GOT A
PHENOTYPE WHICH IS DUPLICATED IN
HUMANS.
HERE IS SHOWN THE STAIN BEING
FOR THOSE PANOCELL GRANULES, YOU
CAN SEE THE AN ALTHOUGH INSIDE
IN
INSIDE -- THE ABNORMALITY INSIDE
THE CELL.
A SIMILAR MESSAGE IS IF YOU LOOK
AT TRANSCRIPTION IN THE PRESENCE
OF THE VIRUS IN WILD TYPE VERSUS
PRESENCE OF THE VIRUS IN THESE
MUTANT ANIMALS YOU GET
SUBSTANTIAL CHANGES IN
TRANSCRIPTION AND IT ISN'T JUST
QUANTITATIVE, THIS IS FOR SETS
OF GENES, FOR INSTANCE, PROTEIN
LOCALIZATION, YOU GET COMPLETE
INVERSION, THINGS GO UP INSTEAD
OF DOWN.
SO WHAT THAT MEANS IS THAT OUR
TRANSCRIPTIONAL IDENTITY CAN BE
INFLUENCED IN A COMMONATORIAL
FASHION BETWEEN A VIRUS AND A
GENE.
THAT'S AN EXAMPLE OF A VIROME
ENTER ACTING WITH A HOST
INTERACTION TO CAUSE PATHOLOGY.
I WANT TO RESPOND TO A QUESTION
I WAS ASKED AT A MEETING IN
ARGENTINA WHICH IS, DR. VIRGIN,
ISN'T THAT TERRIBLY COMPLICATED?
AND THE ANSWER IS YES.
BUT IT'S NOT MY FAULT.
OKAY?
THIS IS THE WAY BIOLOGY IS.
AND IF WE TRY TO LOOK IN SILOS
AT ONE PICTURE, WE'RE NOT GOING
TO GET THE WHOLE PICTURE.
SO I KNOW IT'S COMPLICATED, BUT
IT'S NOT MY FAULT.
SO WITH REGARD TO THE
IMMUNOPHENOTYPE F A VIRUS COULD
MAKE A WILD TYPE ANIMAL MORE
RESISTANT TO A BACTERIA, IT
OCCURRED TO US THAT A CHRONIC
VIRUS INFECTION MIGHT ACTUALLY
BE ABLE TO COMPLEMENT AN
IMMUNODEFICIENCY, AND SINCE
PEOPLE WITH IMMUNODEFICIENCIES
HAVE BROADLY VARIANT PHENOTYPES,
WE THOUGHT MAYBE THE PRESENCE OF
A VIRUS COULD ALTER SUCH A
PHENOTYPE.
SO WE COLLABORATED WITH
CASANOVA'S GROUP AND IDENTIFIED
THIS GENE CALLED HOYLE IN TWO
FAMILIES WHO HAD THREE CHILDREN
WHO DIED FROM DISEASE BOTH
IMMUNODEFICIENT AND
HYPERINFLAMMATORY, WE OBTAINED
THE MICE, AND I'LL SUMMARIZE,
THESE MICE ARE VERY
IMMUNODEFICIENT, THEY DIED WHEN
INFECTDZ WITH TOX OPLASMA AND
WITH LISTERIA, BUT THEY'RE THE
ONLY ANIMALS WE'VE STUDIED WHICH
HAVE A RATHER UNIQUE PHENOMENA
WHICH IS THAT THEY'RE RESISTANT
TO MICROBACTERIUM, AND CHRONIC
HERPES INFECTION LIMITING THE
ACTIVATION OF THIS VIRUS.
THIS GENE SEEMS TO CHROME THE
RELATIONSHIP BETWEEN
INFLAMMATION AND
IMMUNODEFICIENCY, BUT IT ALLOWED
US AN EXPERIMENTAL TOOL TO TEST
A HYPOTHESIS.
SO THIS ANIMAL DOESN'T DIE FROM
CHRONIC HERPES VIRUS INFECTION
SO WE COULD LOOK AT THE EFFECT
OF THIS ON THE GENETIC
SUSCEPTIBILITY.
SO THE MECHANISM OF THIS GENE IS
SHOWN HERE, IT'S RESPONSIBLE IN
THIS CASE AFTER BACTERIAL
INFECTION FOR GENERATING
CYTOKINES SUCH AS 6, 12,
KNOCKOUTS ARE IN RED, AT THE
TRANSCRIPTIONAL LEVEL, EACH OF
THESE GENES IS ESSENTIAL TO
RESISTANCE ARE IN A MOUSE.
BASICALLY IN THE ABSENCE OF
HOYLE, YOU DON'T MAKE THE
CYTOKINES THAT PROTECT YOU FROM
LISTERIA INFECTION.
THE REASON WE DID THIS
EXPERIMENT CAME HERE.
THE FIRST THREE PATIENTS THAT
WERE IDENTIFIED WITH HOYLE
DEFICIENCY HAD THIS DISEASE I
REFERRED YOU TO PLUS A MYOPATHY,
BUT THEN A NUMBER OF OTHER
PATIENTS WERE PUBLISHED WHO HAD
MUTATIONS, MANY OF WHICH LOOKED
LIKE NULL MUTATIONS BUT THEY
DIDN'T HAVE THE SAME PHENOTYPE.
THEY ALL, CLUCK THE MICE, HAVE
THE MY OP -- INCLUDING THE MICE,
HAVE THE MYOPATHY BUT DIDN'T
HAVE THE IMMUNODEFICIENCY AND
INFLAMMATION.
THERE ARE A LOT OF EXPLANATIONS,
MAYBE THE DATA ARE NOT CORRECT,
MAYBE THERE'S ANOTHER GENE
THATTED MONTH FIEZ THIS, BUT THE
OTHER POSSIBILITY IS THAT MAYBE
THESE PATIENTS AND THESE
PATIENTS HAVE A DIFFERENT
ENVIRONMENTAL EXPOSURE AND THESE
PATIENTS ARE LACKING SOMETHING
THAT THESE PATIENTS HAVE THAT
COMPLEMENT THE IMMUNODEFICIENCY.
SO WE DEVELOPED THE HYPOTHESIS
THAT CHRONIC HERPES VIRUS
INFECTION TO WHICH THESE MICE
ARE RESISTANT WILL COMPLEMENT
THAT SEVERE IMMUNODEFICIENCY,
AND GENERATE AUTOINFLAMMATION
THE SECOND PHENOTYPE.
SO WE DID A VERY SIMPLE
EXPERIMENT, WE TOOK THE KNOCKOUT
ANIMALS INFECTED WITH THE HERPES
VIRUS AND LOOKED FOR SIGHT KINDS
AND SURE -- CYTOKINES AND SURE
ENOUGH, THESE ANIMALS WHEN
CHRONICALLY INFECTDZ WITH THE
HERPES VIRUS ARE
HYPERINFLAMMATORY.
BUT THEY ARE NOT
HYPERINFLAMMATORY IN THE ABSENCE
OF THE VIRUS.
THEN WE DID THE KEY EXPERIMENT,
FROM OUR POINT OF VIEW, WE TOOK
A NUMBER OF DIFFERENT KNOCKOUT
ANIMALS AND WE ASKED CAN THE
VIRUS COMPLEMENT AND TRANSTHE
GENETIC IMMUNODWISHT -- GENETIC
IMMUNODEFICIENCY.
HERE IS DATA FOR THE HOYLE
KNOCKOUT.
HERE ARE THE ANIMALS THAT DIED,
THE HOYLE KNOCKOUT DIE, WILD
TYPE DIE.
IF YOU CHRONICALLY INFECT THE
HOYLE KNOCKOUT, YOU CAN
COMPLEMENT.
IF YOU DO THE SAME THING FOR
AISLE, IT COMPLEMENTS.
WE CAN MAKE AN ANIMAL RESISTANT
TO A VIRUS BY MANY ORDERS OF
MAGNITUDE TO A BACTERIAL
INFECTION BY CHRONIC VIRAL
INFECTION.
IT MAKES US WONDER WHETHER SOME
OF THE VARIATION IN CLINICAL
PRESENTATION OF GENETIC
IMMUNODEFICIENCY MIGHT BE DUE TO
ELEMENTS OF THE VIROME.
SO THAT'S AN EXAMPLE OF
PHENOTYPIC COMPLEMENTATION OF A
GENETIC IMMUNODEFICIENCY BY
CHRONIC HERPES VIRUS INFECTION
INFLUENCING THE
GENOTYPE/PHENOTYPE RELATIONSHIP
IN THAT ANIMAL MODEL.
NOW, I INTRODUCE #-D THE IDEA
AND BRIAN MENTIONED, WHAT
CROASMS THE VIROME -- WHAT
CONTROLS THE VIROME, IS IT JUST
OUR GENES AND THE IMMUNE SYSTEM
WHICH WE ALL KNOW AND LOVE?
OR ARE THERE OTHER ELEMENTS?
SO WE DEVELOPED A HYPOTHESIS
THAT TRANSKINGDOM INTERACTIONS,
CLUG ALL OF THE SEQUENCES IN AND
AROUND THE HOST WILL ALTER
PATHOGENESIS AND IMMUNITY AND WE
DID THAT BECAUSE THAT VIRUS PLUS
GENE PHENOMENA THAT I SHOWED YOU
THAT WAS THE ATG16 PLUS THE
NOROVIRUS, WE CAN ACTUALLY CURE
THAT WITH ANTIBIOTICS, SO
BACTERIA WERE REQUIRED FOR A
VIRUS PHENOTYPE THAT ONLY
OCCURRED IN THE PRESENCE OF A
HOST GENE MUTATION THAT REALLY
SUGGESTED TO US THAT BACTERIA
WERE INTERACTING WITH VIRUSES IN
A MANNER CONTROLLED BY THE HOST
IMMUNE SYSTEM.
SO IN EACH OF THESE STORIES, IT
TURNS OUT THAT EXPLORING THIS
CONCEPT HAS LED US TO SOME
INTERESTING DISCOVERIES.
SO WITH REGARD TO THE
INTERACTION BETWEEN A VIRUS AND
AN OTOPHAGY GENE, IT TURNS OUT
THAT THE BACTERIAL MICROBIOME
ACTUALLY CONTROLS VIRAL
PERSISTENCE, THAT'S A MECHANISM
BY WHICH ANTIBIOTICS CAN CHANGE
CHRONIC VIRUS INFECTION.
I'LL SHOW YOU THOSE DATA.
WE FOUND THAT HELMAN INFECTION
SUBSTANTIALLY ALTERED CHRONIC
HERPES VIRUS INFECTION INCLUDING
I'LL SHOW YOU SOME HUMAN VIRAL
DATA, AND IT'S THREW A SIGHT
KIND.
SO SINCE -- THROUGH A CYTOKINE.
SO IT'S POTENTIALLY IMPORTANT
THAT THERE WOULD BE AN
EVOLUTIONARILY CONSERVED GENETIC
INTERACTION BETWEEN THE INDUCER
OF AISLE4 AND 13 AND A VIRAL
PROMOTER AND THAT'S WHAT I'LL
TELL YOU.
THE CONCEPT HERE IS THAT THE
VIRUS IS CONTROLLED BY THE WORM
THROUGH SOMETHING WE CALL
CYTOKINE COMPETITION AT A VIRAL
PROMOTER, AND I'LL EXPLAIN THAT.
I WANT TO PRESTAINING THE
ARGUMENT -- PRESTAGE THE
ARGUMENT THAT THE PREANCESTRAL
HERPES VIRUS IS SHARED BETWEEN
BIRDS, ANIMALS AND ANIMALS, THE
HERPES VIRUS HAS BEEN STUDYING
YOU FAR LONGER THAN YOU'VE BEEN
STUDYING THE HERPES VIRUS.
THERE'S BEEN CO-EVOLUTION WITH
EACH SPECIES FROM THE TIME THE
SPECIES SEPARATED.
SO WHEN MAMMALS SPECIATE, THEIR
HERPES VIRUSES COME ALONG WITH
THEM AND CO-EVOLVE.
SO I WILL SHOW YOU THAT THAT
GIVES THE CHANCE FOR THE VIRUS
TO DO SOME PRETTY REMARKABLE
STUFF.
SO WE DID A VERY SIMPLE
EXPERIMENT.
WE TOOK A VIRUS WHICH WAS
ENGINEERED WHEN IT WAS LATENT IN
A HOST, IF YOU REACTIVATED IT,
IT WOULD EXPRESS LUCIFERASE AND
WE COULD MEASURE THE AMOUNT OF
REACTIVATION BY IMAGING THE
AMOUNT OF LIGHT THAT CAME OUT OF
THE MOUSE AND INFECTED WITH THE
HELMITH AND LOOKED TO SEE WHAT
HAPPENED.
THE HELMITH INFECTION
REACTIVATED THE VIRUS.
THIS IS 7 DAYS AFTER THE
INFECTION, THERE'S SIGNIFICANTLY
MORE LIGHT COMING FROM THE
ANIMALS THAT HAVE THIS VIRUS SO
THIS IS REACTIVATION OF THE
VIRUS.
WE SHOWED IT BY OTHER METHODS AS
WELL.
SO THE WORM IS REACTIVATING THE
VIRUS FROM LATENCY.
SO OUR HYPOTHESIS WAS THAT
THERE'S SOMETHING ABOUT THE
IMMUNE RESPONSE FROM THE WORM
THAT ACTUALLY TRIGGERED THE
VIRUS AND THAT THEREFORE AISLE4
WHICH IS INDUCED BY HELMUTH
INFECTION AS A RESULT OF TH2
RESPONSE, MIGHT INCREASE
REPLICATION, I WON'T SHOW YOU
ALL THE DATA, BUT TESTING THE
HYPOTHESIS LED TO THE DISCOVERY
THAT AISLE4 AND 13 MAKE THE
VIRUS GROW FASTER, REQUIRE THE 6
WHICH IS DOWNSTREAM FROM THE
RECEPTOR FROM THESE, AND VERY
INTERESTINGLY, THIS IS BECAUSE
THE VIRAL GENE 50 WHICH IS
ESSENTIAL FOR GROWTH AND
REACTIVATION, IT'S A SWITCH GENE
BASICALLY, WHEN THE VIRUS IS
LATENT, THIS GENE IS OFF.
WHEN THE GENE TURNS ORK THE
VIRUS EMERGES FROM LATENCY AND
MAKES INFECTIOUS VIRUS, IT TURNS
OUT THESE CYTOKINES TURN ON THAT
GENE.
OKAY?
THAT'S THE MECHANISM WE BELIEVE
BY WHICH THE CYTOKINES
REACTIVATE THE VIRUS.
THAT'S SHOWN HERE.
THIS IS JUST EXPRESSION OF GENE
50 FROM THE VIRUS, AND IF YOU
TREAT, THIS IS THE EXPRESSION OF
THE GENE WITHOUT CYTOKINES, IF
YOU PUT INTERFERON GAMMA WHICH
BLOCKS REACTIVATION, YOU CAN
INHIBIT THE EXPRESSION OF THE
GENE BUT AISLE 4 ADDED HERE
COUNTERS.
SO THIS GENE SOMEHOW IS SENSING
BOTH HOST CYTOKINE THAT TURNS IT
OFF AND A HOST CYTOKINE THAT
TURNS IT ON.
SO HOW DOES THAT WORK?
IT TURNS OUT THAT THERE ARE FIVE
DIFFERENT PROMOTERS IN THE VIRUS
FOR THIS GENE, GENE 50, AND ONE
OF THEM IS DIRECTLY RESPONSIVE
TO AISLE 46789 THIS IS NOT THE
IMMUNE SYSTEM CONTROLLING THE
VIRUS, THIS IS THE VIRUS ACTING
AS A SENSOR BY HAVING ITS OWN
PROMOTERS ACTUALLY RESPOND TO
HOST CYTOKINES AND WE SHOWED
THAT THIS IS THROUGH STAT 6
BINDING USING CHIP ASSAYS.
IF THIS IS A TRUE GENERAL
PHENOMENON NARKS WE SHOULD BE
ABLE TO REACTIVATE A HUMAN
HERPES VIRUS WITH AISLE 4 AND WE
SHOULD BE ABLE TO USE IN MICE
BOTH CYTOKINES AND GET A GREATER
EFFECT.
WHAT I MEAN BY THAT IS WE SHOULD
BE ABLE TO, IF WE INHIBIT
REACTIVATION WITH INTERFERON
GAMMA, WERBLED SEE LIMITED
REACTIVATION.
IF WE TREAT THE ANIMALS WITH
AISLE 4,  LIMITED, BUT IF YOU DO
BOTH, YOU GET HUGE AMOUNTS OF
REACTIVATION, THIS IS A LOGGED
SCALE.
SO IT MEANS THAT THE VIRUS IS
ACTUALLY A TWO-SIGNAL MODEL.
IT'S USING A PROMOTER TO SENSE
ONE THING TO TURN IT OFF, ONE
THING TO TURN IT ON, SO IT'S
ACTUALLY LEARNED HOW TO SENSE
THE IMMUNOLOGIC MILIEU OF THE
HOST.
WITH REGARD TO THE HUMAN VIRUS,
IF WE ADD AISLE 4 TO CULTURED
CELLS WITH CAP AT THAT C HERPES
VIRUS, WE INDUCE THE EXPRESSION
OF SIMILAR GENES AND
REACTIVATION OF THE VIRUS, THAT
WAS DONE AT THE UNIVERSITY OF
FLORIDA.
SO THIS IS AN EVOLUTIONARILY
CONSERVED MECHANISM BY WHICH
PART OF OUR VIROME, HERPES
VIRUS, ACTUALLY SENSES THE
IMMUNOLOGIC MILIEU OF THE HOST.
HELMUTH CO-INFECTION REACTIVATES
TWEERN A TRANSKINGDOM
INTERACTION BETWEEN THE WORM AND
VIRUS AND THE SAME VIRUS CROAMS
THE IMMUNOPHENOTYPE OF THE HOST
AND RESISTANCE TO BACTERIAL
INFECTION.
WE ALSO AT THE SAME TIME WORKING
WITH DAVID ARTISS FOUND THAT
THIS HELMUTH INFECTION, SAME
INFECTION ACTUALLY INHIBITED THE
CD8 TC RESPONSE TO ANOTHER
CHRONIC VIRUS, SO THESE
INTERACTIONS ARE VERY
COMPLICATED.
THE SAME WORM REACTIVATED A
HERPES VIRUS AND INHIBITED THE
CD8 RESPONSE TO OUR NOROVIRUS.
ALL RIGHT.
THE SECOND TRANSKINGDOM
INTERACTION STORY.
THE BACTERIAL MICROBIOME
CONTROLS CHRONIC NOROVIRUS
INFECTION.
THERE ARE TWO EFFECTS.
ONE IS THAT THE BACTERIA ARE
ACTUALLY REQUIRED FOR THIS VIRUS
TO ESTABLISH CHRONIC INFECTION
AND THE OTHER IS THAT A SPECIFIC
CYTOKINE AND CYTOKINE RECEPTOR
ARE INVOLVED IN THAT AND WE CAN
LEF RANG THAT TO CURE --
LEVERAGE THAT TO CURE CHRONIC
VIRUS INFECTION.
THIS STORY STARTS WITH OUR
DISCOVERY OF THE MARY NOROVIRUS.
IT TURNS OUT HUMAN NOROVIRUS, A
CERTAIN PROPORTION OF PEOPLE
CHRONICALLY SHED THESE VIRUSES
FOR LONG PERIODS OF TIME,
EXPLAINING HOWMP THE VIRUS CAN
CAUSE EPIDEMICS EVEN THOUGH
THERE'S NO ANIMAL RESERVOIR.
SOME PROPORTION OF YOU IN THE
AUDIENCE OR WHEREVER YOU'RE
WATCHING THIS LECTURE ARE
PROBABLY SHEDDING CHRONIC
NOROVIRUS INFECTION, AND
OCCASIONALLY SOMEONE SHEDDING
THE VIRUS MAKES FOOD FOR A
PICNIC AND YOU GENERATE AN
EPIDEMIC FOR CAM NATHANING THE
FOOD OR A CRUISE SHIP OR
MILITARY BASE, ALL OF THEM ARE
SUSCEPTIBLE TO HE DIX OF THIS
VIRUS.
IT'S -- EPIDEMICS OF THIS VIRUS.
IT'S.
WHEN WE DISCOVERED THE MYRIAD
VIRUS, WE DISCOVERED SOME
VIRUSES IN ORANGE HERE WHICH CAN
CONSISTENTLY BE SHED IN THE
STOOL AND OTHER VIRUSES WHICH
CANNOT.
THIS VIRUS, THE BLUE VIRUS HERE,
IT'S NOT ATTENUATED VIRUS, IT
ACTUALLY SPREADS SYSTEMICALLY,
GOES THROUGH THE SPLEEN AND
LYMPH NODES.
THIS ONE DOESN'T.
THIS VIRUS IS ADAPTED TO THE
INTESTINE, GRIFG US A MODEL FOR
UNDERSTANDING THE PERSISTENT
CEARNG OF THE NOROVIRUS.
THAT'S WHERE THE STORY BEGINS.
WE DID A SIMPLE EXPERIMENT, WE
TREATED WITH INTOCTSZ FOR 14
DAYS -- WITH ANTIBIOTICS FOR 14
DAYS AND THEN INFECTED WITH THE
VIRUS.
DURING THE RECEPTION AFTERWARDS,
YOU CAN ASK ME WHY WE WOULD EVER
DO THIS EXPERIMENT.
THERE WAS A GOOD REASON.
IT WASN'T JUST LUCK, I DON'T
THINK.
WHAT HAPPENED WAS WHEN WE
TREATED WITH ANTIBIOTICS, THE
VIRUS WHICH WOULD NORMALLY
BECOME PERSISTENT WAS ACTUALLY
CLEARED, AND HERE IS SHOWN
ACROSS MANY EXPERIMENTS MANY OF
THE ANIMALS ARE CURED, THEY
DON'T GET THIS PERSISTENT
INFECTION, EVEN THOUGH THEY
CLEARLY HAVE THE VIRUS EARLY,
THEY DON'T GET THE INFECTION.
SO SOMETHING ABOUT THE
ANTIBIOTICS IS PREVENTING THE
VIRUS FROM ESTABLISHING A
CHRONIC INFECTION.
THAT'S A TRANSKINGDOM
INTERACTION, BACTERIA, THE
VIRUS.
IS IT THE BACTERIA?
WELL, WE JUST DID A SIMPLE
EXPERIMENT AGAIN, WE STOPPED THE
ANTIBIOTICS AND WE FED FECAL
PELLETS, DID A FECAL
TRANSPLANTATION AND WE RESTORED,
THIS IS UNTREATED, ANTIBIOTICS,
FECAL FEEDBACK, RESTORES THE
VIRUS AND COLON, LYMPH NODE AND
SHEDDING IN THE STOOLS, IT'S
REALLY SOMETHING IN THE FECAL
MATERIAL THAT THE ANTIBIOTICS
ARE REMOVING, AND TO UNDERSTAND
THE MECHANISM, WE DECIDED WE
WOULD ASSESS THE REQUIREMENT FOR
HOST GENES IN THIS EFFECT.
WE TOOK A BROAD RANGE OF
KNOCKOUT MICE AND DID THE SAME
EXPERIMENT, AND THESE ARE ALL
GENES WHICH ARE NOT REQUIRED FOR
THE ANTIBIOTICS TO WORK.
THIS IS NOT PROJECTING.
THAT'S THE INTERFERON ALPHA-BETA
RECEPTOR, GAMMA RECEPTOR, BOTH
THE INTERFERON ALPHA AND GAMMA
RECEPTOR, ARE POLL LIKE
RECEPTORS, SENSORS FOR THE, THE
ANTIBIOTICS ARE FINE.
THERE ARE THREE GENES,
INTERFERON LAMBDA RECEPTOR, THE
ANTIBIOTICS THAT DID NOT WORK.
SO WHAT THIS MEANS IS THAT THE
IMMUNE SYSTEM IS SOMEHOW
INVOLVED IN THIS TRANSKINGDOM
INTERACTION.
THAT LED US TO DO THE FOLLOWING
EXPERIMENT.
INTERFERON LAMBDA IS WHAT IS
ALSO CALLED TYPE 3 INTERFERON.
IT'S LESS WELL STUDIED, IT'S
BEEN USED TO TREAT HEPATITIS C
IN HUMANS, IT'S LESS WELL
STUDIED THAN TYPE 1 AND TYPE 2
INTERFERONS, INTERFERON
ALPHA-BETA AND GAMMA AND THE
OTHER.
IT'S STAT 1, ANOTHER ONE OF THE
GENES REQUIRED FOR OUR
EXPERIMENT, WE TOOK TYPE 3
INTERFERON SUPPLIED BY
BRISTOL-MYERS SQUIBB AND TREATED
BEFORE FERKZ AND THE ANIMALS --
BEFORE INFECTION AND THE ANIMALS
DO NOT BECOME PERSISTENTLY
INFECT.
YOU CAN PRETREAT WITH INTERFERON
LAMBDA AND THE INFECTION DOES
NOT OCCUR.
WE DID WHAT I CAWSM THE KEY
EXPERIMENT, WE WAITED FOR THE
PERSISTENCE TO BE ESTABLISHED,
THIS IS DAY 21, AND THE VIRUS IS
SHEDDING, THIS IS A WILD TYPE
ANIMAL AND WE TREATED WITH
INTERFERON LAMBDA AND WE COULD
CURE THE PERSISTENT INFECTION.
IN AN ANIMAL LACK BEING THE TYPE
 -- LACKING THE TYPE 1
INTERFERON RECEPTOR, IT STILL
WORKS, BUT IN AN ANIMAL LACK
BEING THE INTERFERON RECEPTOR,
THERE'S NO EFFECT.
INTERFERON LAMBDA CAN CURE A
PERSISTENT VIRUS INFECTION WITH
THIS NOROVIRUS.
NOW, I WAS ALWAYS TAUGHT THAT
THE INNATE IMMUNE SYSTEM
CONTROLS INFECTION UNTIL T CELLS
AND B CELLS CAN COME INTO THE
FRAY AND CLEAR AN INFECTION OUT
AND IT'S STERILIZING IMMUNITY IS
DUE TO THE EFFECT OF T AND B
CELLS.
BUT ONE OF THE MICE THAT WE HAD
STUDIED IN THE ANTIBIOTIC
TREATMENT WAS A RAG KNOCKOUT,
WHICH SUGGESTED THE INNATE
IMMUNE SYSTEM ACTUALLY CAN DO
WHATEVER IT IS THAT WE'RE
STUDYING HERE, SO WE DID THE
FOLLOWING EXPERIMENT.
THIS IS TIM NICE'S KEY LAST
EXPERIMENT IN HIS PAPER.
WE TOOK PERSISTENTLY INFECTED
RAG KNOCKOUTS AND TREATED THEM
WITH INTERFERON LAMBDA AND CURED
THEM.
THIS IS BY PCR BUT WE ALSO TOOK
THE FECAL MATERIAL HERE AND PUT
IT BACK INTO STAT KNOCKOUT AND
RAG KNOCKOUT MICE SO WE THINK
THAT IS AN ACTUAL CURE OF A
VIRUS INFECTION IN THE ABSENCE
OF T AND B CELLS AND THAT THAT
SUGGESTS TO US THAT THERE IS
STERILIZING INNATE IMMUNITY,
WHICH SUGGESTS IN TURN THAT WE
MIGHT BE ABLE TO INDUCE THIS
KIND OF IMMUNITY TO ELIMINATE
VIRUS INFECTION EVEN WHEN T AND
B CELLS ARE COMPROMISED.
IT'S AN INTERESTING CONCEPT TO
US.
SO THESE ARE EXAMPLES OF
TRANSKINGDOM INTERACTIONS WHERE
COMMENSAL MY EXPROABZ A HOST
MOLECULE INTERFERON LAMBDA ARE
RESPONSIBLE FOR CONTROLLING
NOROVIRUS INFECTION AND WHERE WE
CAN DISCOVER SOMETHING NEW ABOUT
THE IMMUNE SYSTEM BY LEVERAGING
THE INITIAL STUDIES OF THE
TRANSKINGDOM INTERACTIONS TO
IDENTIFY WHAT PARTS OF THE
IMMUNE SYSTEM MIGHT THEN IN TURN
BE INVOLVED IN CONTROLLING VIRUS
INFECTION IN THE INTESTINE.
NOW, WE SHOULD BE ABLE TO
DEMONSTRATE CHANGES IN THE
VIROME IN DISEASE STATES.
SO WE BEGAN TO LOOK AT THAT IN
HUMAN STUDIES AND WE PERFORMED A
STUDY TOGETHER WITH MILES PARKS
IN THE UNITED KINGDOM, RON
XAVIER AND ALI AT RUSH WHERE WE
LOOKED AT THE ENTERIC VIROME IN
PATIENTS WITH INFLAMMATORY BOWEL
DISEETZ.
THIS COHORT IS NOTABLE.
BECAUSE THEY HAVE A REMARKABLE
CLINICAL SCENARIO THERE, SETTING
THERE, THEY COULD GET US
HOUSEHOLD CONTROLS AND THE DATA
IS MUCH MORE POWERFUL WHEN YOU
DO SHOTGUN SEQUENCING OR
METAGENOMIC COMPARISONS OF
PATIENTS, A NUMBER OF STUDIES
HAVE SHOWN THAT OUR MICROBIOMES
ARE RELATED TO THE PEOPLE WE
LIVE WITH.
THIS WAS A PARTICULARLY POWERFUL
COHORT.
IT HAS BEEN LONG PUBLISHED THAT
PATIENTS WITH INFLAMMATORY BOWEL
DISEASE HAVE ABNORMALITIES IN
THEIR BACTERIAL MICROBIOME.
IN FACT, THESE PATIENTS HAVE
DECREASED SPECIES DIVERSITY AND
SPECIES RICHNESS COMPARED TO
CONTROLS.
SO THERE'S SOMETHING NOT
COMPLICATED, DECREASED
COMPLEXITY OF THEIR BACTERIA, SO
THE FIRST THING WE DID IN OUR
CAMBRIDGE, CHICAGO AND BOSTON
COHORTS IS LOOK AT THE NUMBER OF
SPECIES AND THE DIVERSITY AND WE
SHOWED THAT BOTH FOR CROHN'S
DISEASE AND ULCERATIVE COLITIS,
PURPLE AND RED HERE, WE GOT
EXACTLY WHAT EVERYONE ELSE HAD
PUBLISHED.
SO THIS IS BACTERIAL 16S DATA
AND THESE PATIENTS HAVE AN
ABNORMALITY OF THE BACTERIAL
MICROBIOME, THEIR BACTERIA ARE
LESS COMPLEX.
SO THEN WE PURIFIED VIRUS PARDON
MES FROM THE FECAL MATERIAL --
PARDON MES FROM THE FECAL
MATERIAL FROM THESE TR PATIENTS,
WE DESEQUENCED THEM.
WHAT WE FOUND WAS THE FOLLOWING,
THAT THESE ARE HOUSEHOLD
CONTROLS, THESE ARE ULCERATIVE
COLITIS PATIENTS AND THESE ARE
CROHN'S DISEASE PATIENTS, AND
THIS IS THE NUMBER OF DIFFERENT
SPECIES OF BACTERIA, SO THE
BACTERIA PHAGES ARE BECOMING
MORE DIVERSE AND RICHER, THERE
ARE MORE VIRUSES EVEN WHEN THERE
ARE LESS BACTERIA.
WE BELIEVE THAT IT IS A STRETCH
THAT THIS DECREASE IN BACTERIAL
DIVERSITY COULD EXPLAIN THE
PRESENCE OF GREATER NUMBERS OF
DIFFERENT BACTERIA YA PHAGES.
THIS SIGNATURE IS DISEASE
SPECIFIC IN THAT THE VIRUSES IN
ULCERATIVE COLITIS ARE DIFFERENT
THAN THE VIRUSES IN CROHN'S.
THIS REPEATED TO A GREATER OR
LESSER DEGREE IN ALL OF OUR
COHORTS.
SO ACROCHES THE OCEAN AND
ACROSS -- ACROSS THE OCEAN AND
ACROSS THREE DIFFERENT COHORTS.
SO THE BACTERIA WHICH ARE
CHANGING IN A DOWNWARD DIRECTION
AND VIRUSES WHICH ARE NOW
GREATER IN NUMBER.
IS THERE A RELATIONSHIP?
SO WE DEVELOPED AN APPROACH TO
TAKE THE DISCRIMINATE BACTERIA,
BACTERIA IN THE UK COHORT WHICH
CORRELATE WITH DISEASE AND PUT
THEM STATISTICALLY AGAINST THE
TOP 30 OR SO VIRUSES AND A RED
DOT MEANS THERE'S A NEGATIVE
CORRELATION, THAT MEANS WHEN
THERE'S MORE OF THIS PHAGE,
THERE'S LESS OF THAT BACTERIA,
SO ON, A BLUE IS A POSITIVE
RELATIONSHIP.
THESE ARE THE HOUSEHOLD
CONTROLS.
THEN WE DID CROHN'S DISEASE.
WHAT'S REALLY STRIKING IS THAT
THE PATTERN OF RELATIONSHIPS
HERE AND HERE ARE COMPLETELY
DIFFERENT.
SO THERE IS IN FACT A SIGNATURE
OF THE RELATIONSHIP BETWEEN
THESE BACTERIORPHAGES AND THE
BACTERIA WHICH IS IN CROHN'S
DISEASE COMPARED TO CONTROLS AND
IN TURN ULCERATIVE COLITIS IS
DIFFERENT THAN EITHER.
SO THESE DATA DEMONSTRATE THAT
THERE IS A CORRELATION BETWEEN
THE ENTERIC VIROME AND A HUMAN
DISEETZ.
THE WAY WE ARE THINKING OF THIS
IS SHOWN IN THIS PICTURE.
THIS IS A PICTURE OF A VIRUS.
HERE IS ANOTHER VIRUS.
THIS IS A BACTERIA.
AND ANOTHER BACTERIA.
WE THINK THERE COULD BE A
PREDATOR/PREY RELATIONSHIP
BETWEEN THE BACTERIA -- BETWEEN
THE VIRUSES AND THE BACTERIA
SUCH THAT MAYBE INFLAMMATORY
BOWEL DISEASE IS ACTUALLY A
VIRAL DISEASE IN SOME SENSES,
THAT BACTERIORPHAGES EITHER
EMERGE OR ARE INTRODUCED, THAT
THAT CHANGES THE BACTERIAL
MICROBIOME INTO A NEW
EQUILIBRIUM STATE AND THAT THAT
MAY, IN FACT, BE HOW HAVE THE
VIRUSES MIGHT TRIGGER
INFLAMMATORY BOWEL DISEASE.
THIS IS PURELY HYPOTHETICAL AND
WE'RE IN THE PROCESS OF SETTING
UP ANIMAL MODELS TO TRY TO
UNDERSTAND THIS.
NOW, THAT'S AN EXAMPLE OF A
TRANSKINGDOM INTERACTION BETWEEN
A VIRUS AND A BACTERIA.
SO WE'VE SEEN WORMS INTERACTING
WITH VIRUSES, WE'VE SEEN
BACTERIA INTERACTING WITH
VIRUSES IN A POSITIVE SENSE
WHERE BACTERIA WERE REQUIRED FOR
PERSISTENT VIRUS, AND THIS IS A
NEGATIVE RELATIONSHIP, WE THINK,
BETWEEN A VIRUS AND A PARTICULAR
GROUP OF BACTERIA.
SO THAT WE THINK IS THE FIRST
EXAMPLE OF A RELATIONSHIP
BETWEEN THE VIROME, IN THIS CASE
BACTERIORPHAGES AND THE HUMAN
DISEASE.
WHAT DO WE THINK ARE THE
IMPLICATIONS?
WE WONDER WHETHER THIS IS
RELEVANT TO OTHER DISEASES WHERE
THE BACTERIAL MICROBIOME HAS
BEEN 50EU6D TO BE A RISK FACTOR,
TYPE 1 DIABETES, CARDIOVASCULAR
DISEASE, NUTRITIONAL
DEFICIENCIES, THERE'S BEEN
EXTENSIVE TYPE 1 AND TYPE 2
DIABETES, THERE'S EXTENSIVE DATA
RELATING THE BACTERIAL
MICROBIOME TO SHE'S DISEASES BUT
NO ONE HAS LOOKED AT THE VIRUSES
YET.
SO WE WONDER WHETHER THAT'S A
GOOD IDEA.
WE ALSO THINK THAT PROBIOTIC
THERAPIES ADDED INTO THE
INTESTINE MIGHT FALL PREY TO THE
SAME BACTERIORPHAGES WHICH WE
IDENTIFIED AND SPECULATIVE BUT I
WONDER WHETHER ONE COULD MAKE
PROBIOTICS, THAT WOULD BE
ANTIBIOTICS WHICH YOU COULD PUT
INTO THE HOST TO MANIPULATE THE
BACTERIA IN A WAY THAT WAS
USEFUL FOR THE HEALTH OF THE
HOST.
MAYBE THAT COULD CORRECT SOME OF
THE ABNORMALITY TION IN BACTERIA
THAT WE SEE IN DIFFERENT
DISEASES.
SO AGAIN, WE'RE TRYING TO
DEVELOP ANIMAL MODELS TO LOOK AT
THESE IDEAS.
SO COMING BACK TO THE
IMMUNOPHENOTYPE, I'VE MADE AN
ARGUMENT THAT CHRONIC INFECTIONS
CAN ALTER THE FUNDAMENTAL NATURE
OF THE IMMUNE SYSTEM.
NOW, I'M GOING TO SHOW YOU SOME
UNPUBLISHED DATA.
THIS IS ONE OF THE EXPERIMENTS
WHERE I'VE ALWAYS WANTED TO DO
THIS EXPERIMENT AND IT WAS
MERELY A MATTER OF ME FINDING
SOMEONE I COULD CONVINCE TO DO
IT BECAUSE I TRIED TO CONVINCE A
NUMBER OF PEOPLE TO DO THIS
EXPERIMENT AND NO ONE WAS BRAVE
ENOUGH EXCEPT FOR TIFFANY REESE
WHO PUBLISHED THAT WORM PAPER
AND WHO IS NOW A NEW FACULTY
MEMBER AT UT WESTERN ON THE
TENURE TRACK AND SHE DESERVES
CREDIT FOR THIS EXPERIMENT.
THRMS A BIAS THAT MICE ARE NOT
HUMANS AND I COMPLETELY
UNDERSTAND THAT MICE LOOK VERY
DIFFERENT THAN HUMANS.
BUT THERE'S ALSO A BIAS THAT THE
MOUSE IMMUNE SYSTEM IS NOT
REFLECTIVE OF THE HUMAN IMMUNE
SYSTEM AND THEREFORE HUMAN
IMMUNOLOGISTS AT TIMES LOOK DOWN
ON THE MOUSE MODEL BECAUSE THEY
SAY THE MOUSE MODEL IS NOT
REFLECTIVE OF HUMAN IMMUNE
RESPONSES.
I CANNOT GET A PREDICTION FROM A
MOUSE MODEL THAT IS RELEVANT FOR
MY HUMAN VACCINE STUDY.
SO I UNDERSTAND THAT CONCERN.
BUT WHAT IF THERE WAS A WAY TO
LOOK MICE LOOK MORE LIKE HUMANS
INSTEAD OF TRANSPLANTING HUMAN
TISSUES INTO THEM, ALTERING
THEIR ENVIRONMENT?
SO NOW THINK ABOUT WHAT WE'VE
DONE WITH EXPERIMENTAL MICE.
WE PUT THEM IN EVER-CLEANER
ENVIRONMENTS AND THEN WE HAVE
MADE THE DATA FROM THEM VERY
REPRODUCIBLE, THE SAME THING
HAPPENS EVERY TIME MORE OR LESS.
BUT AT THE SAME TIME WE'VE
REMOVED THEM FROM ALL OF THEIR
ENVIRONMENTAL TRIGGERS.
BUT ALL OF US ARE SEQUENTIALLY
INFECTED BY HERPES VIRUSES AND
WORMS AND OTHER THINGS, SO IS IT
POSSIBLE THAT THE REASON THAT
THE IMMUNE SYSTEM IN A MOUSE IS
DIFFERENT THAN THE IMMUNE SYSTEM
IN HUMAN IS IN PART NOT JUST THE
CHROMOSOMAL ABNORMALITIES BUT
SOMETHING ABOUT THE ENVIRONMENT
OF THE MOUSE?
SO THAT'S THE HYPOTHESIS.
THE IDEA IS THAT SERIAL
CO-FERKZS THAT LIMB --
CO-INFECTIONS THAT MIMIC THE
EARLY LIFE EXPOSURE TO HUMANS
MIGHT ALTER THE IMIZATION.
WE DID A TRULY MASSIVE
EXPERIMENT WITH A LOT OF MICE
AND FOUR DIFFERENT REPLICATES
AND WE LEFT SOME MICE UNINFECTED
AND THEN JUST SEQUENTIALLY
INFECTED MICE WITH DIFFERENT
PATHOGENS, GAMMA HERPES VIRUS,
BETA HERPES VIRUS, THEN A WORM,
WE WAITED VARIOUS PERIODS OF
TIME, THEN WE GAVE YELLOW FEVER
VACCINE, BLED THE MICE AT DAY 0
AND BLED THEM 3, 7, 21 AND 34
DAYS AFTER VACCINATION, WE
PICKED THIS VACCINATION FOR A
REASON THAT WILL BE CLEAR IN A
MOMENT.
WE ASKED FIRST THE QUESTION IS
THE IMMUNE SYSTEM DIFFERENT WHEN
THE MOUSE HAS HAD A HISTORY OF
BEING INFECTED WITH SOME OF
THESE CHRONIC VIRUSES AND OTHER
PATHOGENS?
FIRSTLY, IF YOU TAKE THE
ANIMALS, THIS IS MOCK OR CO
MEANS CO-INFECTED, THESE ARE THE
ANIMALS SEQUENTIALLY INFECTED,
THEY ALL MAKE A NICE IMMUNE
RESPONSE, EARLY, BUT THE
CO-INFECTED ANIMALS LOSE THEIR
ANTIBODY RESPONSES OVER TIME.
SO WE JUST LOOKED AT WHAT GENES
ARE EXPRESSED IN RESPONSE TO
VACCINATION.
THIS IS THE MOCK, SO IF YOU WERE
TO DO THIS WITH MICE FROM A
CLEAN MOUSE FACILITY, GIVE THEM
17D YELLOW FEVER ON DAY 3, 318
GENES WOULD BE UP, 142 DOWN, ET
CETERA.
THIS IS WHAT A NON-- A CONTROL
MOUSE WOULD LOOK LIKE.
IF YOU TAKE THE CO-INFECTED
MICE, GENES ARE CHANGED, BUT
THERE IS NEGLIGIBLE OVERLAP.
SO WHAT THIS FIGURE SHOWS IS
THAT THE IMMUNE RESPONSE OF THE
MOUSE IS COMPLETELY DIFFERENT IF
IT HAD THOSE ENVIRONMENTAL
INFECTIONS IS HE QUECIALGLY WHEN
IT WAS -- SEQUENTIALLY WHEN IT
WAS GROWING UP.
OKAY?
NOW, IS THIS MORE LIKE A HUMAN
IMMUNE RESPONSE?
IT COULD BE THAT THOSE SERIAL
INFECTIONS WOULD ALTER THE MOUSE
IMMUNE RESPONSE SO THAT IT
LOOKED MORE HUMAN.
SO THAT'S THE SECOND HYPOTHESIS.
CO-INFECTION INDUCED CHANGES
WILL INCLUDE THE EXPRESSION OF
GENES RELATED TO HUMAN VACCINE
RESPONSES.
SO IF WE LOOKED AT THE GENES IN
THE CO-INFECTED MICE VERSUS THE
NONCO-INFECTED MICE, WE WOULD
FIND THE RESEMBLANCE BETWEEN
HUMANS IN THE CO-INFECTED MICE
THAT WAS NOT SEEN IN THE MOCK
INFECTED MICE.
SO LET ME INTRODUCE YOU TO THIS
KIND OF A FIGURE.
THIS IS A FIGURE LOOKING AT THE
GENES WHICH ARE -- LET ME COME
BACK TO THE COHORT.
I'M SO EXCITED ABOUT THIS, I
JUMPED AHEAD.
THIS IS A COLLABORATION BETWEEN
PO, ARE YELLOW FEVER ARE VIRUS,
ONE IS IN SWITZERLAND AND IN
EACH THEY DID EXACTLY THE SAME
EXPERIMENT THAT I SHOWED YOU IN
THAT THEY BLED THE PATIENTS AT
DAY 0 AND THEN DAY 3, DAY 7 AND
THEN SEQUENTIALLY AFTERWARDS AND
DID ARRAY ANALYSIS TO LOOK AT
THE GENE EXPRESSION PATTERNS.
SO WE HAD THE MOUSE DATA AND NOW
WE HAVE HUMAN DATA FROM TWO
DIFFERENT COHORTS.
WE'RE GOING TO ASK IS THERE A
RELATIONSHIP?
SO THIS IS IN TEBBY DAY 3 SUB
SUBTRACTING OUT BASELINE ON DAY
0 WE'RE LOOKING AT THE GENES
CO-INFECTION REGULATED ON DAY 3
IN THE MOUSE AND THE GRAPHS WILL
ALL BE THE SAME.
THESE ARE GENES THAT ARE UP IN
BOTH COHORTS, DOWN IN BOTH
COHORTS, AND ARE INVERTED, AND
YOU CAN SEE A VERY SIGNIFICANT
OVERLAP BETWEEN THE CO-INFECTED
REGULATED GENES AND THE GENES
EXPRESSED IN PATIENTS IN UGANDA
AFTER VACCINATION.
IF YOU LOOK AT THE DAY 0 DATA,
THIS IS CORRECTED FOR DAY 0, THE
GENES EXPRESSED IN LASIN ON DAY
0 ARE HIGHLY RELATED TO THE
CO-INFECTED GENES, LASIN ON DAY
3, AND IF YOU NOW LOOK AT THIS
SET OF GENES IN A NETWORK
ANALYSIS, YOU DISCOVER THAT THE
GENES WHICH ARE HERE ARE THINGS
LIKE STOUT 1, TRAFTS,
CHEMOKINES, THIS IS ACTUALLY THE
MOUSE IMMUNE RESPONSE BEING MADE
TO OVERLAP WITH THE HUMAN IMMUNE
RESPONSE.
SIMILARLY IF YOU LOOK AT IN TADI
ON DAY 7 AND DAY 3 AND YOU LOOK
AT THE NETWORK, AGAIN YOU FIND
STAT 1-RBGS STAT -- STAT 1-RBGS
STAT 2, HLA MOLECULES, SO WHAT
WE'RE SEEING HERE IS THAT THE
IMMUNE RESPONSE OF THE MOUSE WAS
MADE TO BE MORE SIMILAR IN
RESPONSE TO A VACCINE TO THE
IMMUNE RESPONSE IN A HUMAN BY
SERIAL CO-INFECTION.
SO THAT IS AN EXAMPLE WE THINK
THAT THE GENOTYPE/PHENOTYPE
RELATIONSHIP IN THIS CASE
MEASURED BY A VACCINE RESPONSE
MAY BE ALTERED BY CO-INFECTIONS.
SO TODAY WHAT I'VE SHOWN YOU OR
I'VE TRIED TO ARGUE TO YOU IS A
GENETIC ARGUMENT, THAT WHEN WE
LOOK AT OUR OWN
GENOTYPE/PHENOTYPE RELATIONSHIP,
THAT WE NEED TO ACCOUNT FOR THE
VIROME, THAT IN FACT THERE ARE
ADDITIONAL INTERACTIONS IN THE
METAGENOME BETWEEN BACTERIA AND
VIRUSES, BETWEEN WORMS AND
VIRUSES, BETWEEN VIRUSES AND
BACTERIA WHICH CAN INFLUENCE OR
BE RELATED TO INFLAMMATION OR
HUMAN DISEASES.
THAT HOST GENETIC VARIATION
PLAYS A ROLE.
WHEN WE'RE MUTATED IN A GENE, IT
COULD BE THAT THE EXPRESSION OF
THAT MUTATION IS NOT SOLELY
DEFINED BY ITS PRESENCE ON OUR
CHROMOSOMES AND HOMOZYGOUS OR
HETEROZYGOUS STATE, THAT IT MAY
TAKE A TRIGGER OR AN ELEMENT
FROM THE VIROME IN ORDER TO HAVE
THAT HOST GENETIC VARIANT
ACTUALLY GENERATE A PHENOTYPE.
I'VE GIVEN YOU MULTIPLE EXAMPLES
OF HOW FAR THE
GENOTYPE/PHENOTYPE RELATIONSHIP
CAN BE CHANGED.
WE CAN COMPLEMENT
IMMUNODEFICIENCY, WE CAN CREATE
NEW PATHOLOGIES THAT MIMIC HUMAN
PATHOLOGIES, I'VE ARGUED FOR
EACH OF THESE, SYSTEMIC
INFLAMMATION CHANGES THE
IMMUNOPHENOTYPE A RELATION TO
DISEASE SUSCEPTIBILITY,
SYMBIOSIS OF VIRUSES, IT'S NOT
ALL BAD NEWS.
ENTER INDIVIDUAL PHENOTYPIC
VARIATION AND PROFOUND CHANGES
IN THE TRANSCRIPTIONAL MILIEU
WHEN YOU HAVE A CHRONIC VIRUS OR
YOU DON'T IN MULTIPLE ORGANS,
THE BRAIN, SPLEEN, LIVER.
AND I'VE SHOWN YOU THAT MULTIPLE
DIFFERENT ELEMENTS OF THE VIROME
CAN PLAY A ROLE AND I THINK
WE'RE IN THE VERY INFANCY OF
THIS FIELD.
THE NUMBER OF SEQUENCES WE CAN
ACTUALLY ANNOTATE WITH CURRENT
DATABASES IS VERY LIMITED, SO I
THINK THERE'S A HUGE OPPORTUNITY
TO DEFINE THE VIROME AND ITS
RELATIONSHIP TO THESE IMPORTANT
PIECES OF BIOLOGY IN THE FUTURE.
AND I'M GOING TO END BY TELLING
YOU THAT MEGAN B -- BALDRIDGE
WAS INVOLVED INNED STUDIES
CONTROLLING CHRONIC INFECTION.
SIMON PARK WAS INVOLVED WITH
DONNA McDUFF.
TIM NICE FOUND STERILIZING
INNATE IMMUNITY.
JASON NORMAN AND SCOTT HANDLY
WITH ABLE ASSISTANCE FROM A
NUMBER OF OTHERS WERE THE
AUTHORS AND THE DISCOVERERS OF
THE RELATIONSHIP BETWEEN THE
ENTERIC VIROME AND INFLAMMATORY
BOWEL DISEASE.
THIS IS WHY I LOVE THIS JOB,
THESE ARE SMART PEOPLE, THEY
CHALLENGE YOU EVERY DAY, THEY
DON'T BELIEVE WHAT YOU SAY, AND
THEY TRY TO DISPROVE YOU AND IN
SO DOING YOU DISCOVER SOMETIMES
EXCITING THINGS.
SO I AM VERY INDEBTED TO THEM.
AND WITH THAT, I'LL STOP AND BE
HAPPY TO TAKE ANY QUESTIONS.
[APPLAUSE]
>> THANK YOU VERY MUCH.
WE HAVE TIME FOR A COUPLE OF
QUESTIONS AND THEN I WANT TO
MAKE SURE EVERYONE KNOWS THERE
IS A RECEPTION IN THE LIBRARY
AFTERWARDS IF YOU WOULD LIKE TO
TALK MORE WITH SKIP.
JULIE?
>> SO SKIP, REALLY NICE TALK.
YOU TALK ABOUT IT LIKE THERE'S
TWO WORLDS, THERE'S THE VIERGSES
THAT -- THE VIRUSES THAT INFECT
BACTERIA AND THERE'S THE VIRUSES
THAT INFECT THE MAMMALIAN CELLS
AND I WONDER IF YOU'RE THINKING
THAT THERE'S GOING TO BE SOME
COMMUNITY, SOME ASSEMBLY AND
SOME WAY THAT THEY SENSE EACH
OTHER, OR IS IT REALLY THROUGH
WHO THEY INTERACT WITH RATHER
THAN THEIR RECOGNITION OF EACH
OTHER?
>> SKIP:  SO I DON'T HAVE ANY
DATA WITH WHICH TO ANSWER THAT,
SO THAT GIVES ME PERMISSION TO
EXPLAIN MY BIAS.
I THINK THAT THESE THINGS ARE
ALL GOING TO INTERACT WITH ONE
ANOTHER.
IT'S IMPOSSIBLE FOR ME TO
BELIEVE THAT VIERS THAT
CHANGE -- VIRUSES THAT CHANGE
THE INFLAMMATORY MILIEU OF THE
HOST DO NOT THEN IN TURN CHANGE
BACTERIA AND THAT THAT DOESN'T
IN TURN INTERACT WITH OTHER.
SO I THINK THERE WILL BE A VERY
COMPLEX AND NOT GRATED MATRIX,
AND I BELIEVE THAT THIS IS AN
EVOLVED PROCESS.
THESE VIRUSES HAVE EVOLVED WITH
US, AS HAS THE BACTERIA.
SO IT WOULD BE VERY SURPRISING
IF CERTAIN INTERACTIONS HADN'T
DEVELOPED GENETICALLY WHICH
ALLOW THOSE COMMUNITY
INTERACTIONS THAT YOU'RE TALKING
ABOUT.
A SIMPLE ANSWER IS THAT WE
HAVEN'T PUBLISHED THIS BUT THERE
ARE A FEW PAPERS IN THE
LITERATURE THAT SHOW THAT HOST
CELLS, EUKARYOTIC CELLS, CAN
ACTUALLY SENSE BACTERIORPHAGES,
SO YOU COULD ALSO ARGUE THAT THE
BACTERIORPHAGE COULD INTERACT
WITH THE BACTERIA BUT IT COULD
ALSO BE INTERACTING WITH THE
HOST AND IT WAS ACTUALLY SHOWN I
BELIEVE HERE IN THE 1960S THAT
BACTERIORPHAGES CAN BE
IMMUNOGENERAL NICK, STUDIES OF
FY X.
I THINK THERE'S A LOT YET TO BE
DISCOVERED BUT MY BIAS IS THAT
THERE'S GOING TO BE THE NETWORK
THAT YOU DESCRIBED.
>> YES.
WITH RESPECT TO ASTHMA AND THE
HYGIENE HYPOTHESIS, I'VE SEEN
THAT THERE ARE CONTRASTING
POINTS OF VIEW IN TERMS OF
EXPOSURE.
SOME PEOPLE SAY THAT LEADS TO
IT, SOME SAY IT'S THE OTHER.
THEY TALK ABOUT TH1 AND TH2.
DOES YOUR WORK IN ANY WAY RELATE
TO THIS?
I KNOW YOU'VE TALKED ABOUT INNER
INFLAMMATORY BOWEL DISEASE, HAVE
PEOPLE TALKED ABOUT THAT AND THE
MICROBIOME, ET CETERA, SO I
GUESS I'M TRYING TO SAY, COULD
YOU SHED SOME LIGHT ON HOW THIS
RELATES TO ASTHMA AND THE
HYGIENE HYPOTHESIS?
>> SKIP:  SO I THINK THIS IS THE
HYGIENE HYPOTHESIS EXCEPT WHAT
I'M SAYING IS THAT IN ADDITION
TO THE THINGS THAT ONE WOULD
NORMALLY PERHAPS HAVE THOUGHT
ABOUT WHEN THE HYGIENE
HYPOTHESIS WAS ORIGINATED, THAT
THE VIRUSES WHICH LIVE IN US
PERMANENTLY AND ON US ARE A PART
OF THAT INTERACTION BETWEEN
ORGANISMS THAT SETS UP OUR
IMMUNE SYSTEM, CHMTION THE HEART
OF THE HIGH -- WHICH IS THE
HEART OF THE HYGIENE HYPOTHESIS.
IF WE CHANGE THAT IS CORRECT WE
COULD CHANGE OUR IMMUNE
RESPONSES, THAT COULD LEAVE TO
INFLAMMATORY DISEETZ.
WE HAVE NO DIRECT DATA TO
SUPPORT THAT HYPOTHESIS.
ITFOR VIRUSES.
IT IS A VERY ATTRACTIVE
HYPOTHESIS.
THERE ARE CLEAR CHANGES IN THE
EPIDEMIOLOGY OF THESE CHRONIC
VIRUSES THAT OCCUR IF YOU
COMPARE WHAT WE THINK OF AS
WESTERNIZED COUNTRIES TO
NONWESTERNIZED COUNTRIES.
WHEN YOU COMPARE ENVIRONMENTS IN
WHICH ONE IS MORE EXPOSED TO THE
NATURAL WORLD VERSUS MORE
STERILE FROM THE NATURAL WORLD.
ALL OF THOSE THINGS DO IN FACT
CHANGE VIRUS INFECTION.
SO I THINK IT'S THE SAME GENERAL
IDEA AND I'M SAYING THAT YOU
SHOULD THINK ABOUT VIRUSES BUT I
DON'T HAVE ANY DATA WHICH WOULD
SPECIFICALLY SAY THAT A CERTAIN
VIRAL INFECTION OCCURRED EARLY
VERSUS LATE WOULD PREDISPOSE OR
NOT PREDISPOSE TO ASTHMA.
>> THANK YOU.
>> IT LOOKS LIKE YOU COVERED ALL
THE GENOMES.
AND ALSO YOU SHOWED THE
BENEFICIAL EFFECT AND ALSO
ADVERSE EFFECTS OF THIS
COMBINATION.
SO WHEN DO YOU THINK YOU WILL
MAKE SOME COCKTAILS FOR PEOPLE
WHO WANT TO TAKE A --
>> THE QUESTION IS, IF I MAY
PARAPHRASE, IF IT'S THAT
COMPLICATE, HOW IS IT POSSIBLE
THAT YOU'LL GET A SPECIFIC
CHANGE IN THE HOST WITH ONE
PARTICULAR APPROACH TO ALTERING
THE VIRUSES?
I THINK THAT'S A REAL CHALLENGE.
I THINK THAT PROBABLY THE
BACTERIAL MICROBIOME IS THE BEST
EARLY TARGET FOR DOING THIS.
BUT I WOULD POINT OUT THAT EVEN
IN PRIMATE STUDIES THERE ARE
MAGNIFICENT DATA SHOWING THAT
CERTAIN VIRAL VECTORS, CMV, CAN
INDUCE VERY VALUABLE IMMUNE
RESPONSES WHEN OTHER VIRAL
VECTORS DO NOT.
AND THAT SOME OF THOSE VIRAL
VECTORS, CMV, THE WORK OF LUF
WIS PICKER AND OTHERS -- LOUIS
PICKER AND OTHERS, ARE ACTUALLY
CHRONIC VIRUSES AND SO I'M I
DON'T THINK THAT WE COULD TODAY
DESIGN A COCKTAIL OF VIRUSES
WHICH WOULD GET RID OF ASTHMA OR
CHANGE YOUR SUSCEPTIBILITY TO
IBD, BUT NEITHER DO I THINK THAT
THERE'S NO HOPE THAT SPECIFIC
RESULTS COULD OCCUR IF ONE COULD
JUST UNDERSTAND THE FUNDAMENTAL
RELATIONSHIP BETWEEN THE VIRUS,
ITS HOST CELL AND THEN THE
TISSUE FOR WHICH IT HAS TROUBLE.
>> WHEN DO WE THINK WE WILL HAVE
FECAL TESTS FOR PATIENTS WITH
INFLAMMATORY BOWEL DISEASE AND
CROHN'S DISEASE?
>> THIS IS NOT AN AREA THAT I
WORK IN.
I CAN TELL YOU THAT I'VE JUST
COME FROM A KEYSTONE MICROBIOME
MEETING AND THERE WAS A LOT OF
INTEREST INTERESTING DATA IN
FECAL TRANSPLANTATION.
I THINK YOU'RE PROBABLY AWARE OF
THE DATA OF HUMAN FECAL
TRANSPLANTATION, IN C COLITIS IS
NOTHING SHORT OF STUNNING.
THERE HAVE BEEN SOME TRIALS OF
FEEK AL TRANSLATION IN IBD WHICH
HAS BEEN LESS THAN IMPRESSIVE,
IT'S ALSO POSSIBLE THAT'S
EVOLVING AND SOME PEOPLE BELIEVE
THEY HAVE POSITIVE DATA.
IT'S INTERESTING.
I DON'T THINK THERE'S ANYTHING
PUBLISHED THAT SAYS THAT WE
SHOULD DROP EVERYTHING, STOP
IMMUNOMODULATORY DRUG THERAPIES
AND FECALLY TRANSPLANT PEOPLE,  
BUT IT COULD HAVE A ROLE.
>> GOOD LUCK.
>> I WAS WONDERING ABOUT THE
DEMOGRAPHICS OF THE
BACTERIORPHAGES AND HAVE YOU
LOOKED AT COHORTS OF FAMILY
MEMBERS AND WHETHER OR NOT THEY
HAVE SIMILAR PROFILES, OR DO
THEY DIFFER, OR TAKING IT
FURTHER, IF I GO TO AFRICA, I
IMAGINE I WOULD HAVE ONE PROFILE
AND IF I COME TO THE UNITED
STATES I WOULD HAVE ANOTHER, IF
I GO TO INDIA, ANOTHER.
I'M JUST CURIOUS TO KNOW.
>> THIS IS A REALLY GREAT
QUESTION, AND THE ANSWER IS THAT
THERE ARE PROFOUND DIFFERENCES
IN THE DATA IF YOU COMPARE
CHICAGO, BOSTON AND THE UNITED
KINGDOM.
NOW, THE CAVEAT TO THAT
STATEMENT THAT I JUST MADE IS
THAT AT THE CURRENT LEVEL OF
CAPACITY TO ANNOTATE VIRUSES,
GIVEN THE WEAKNESS OF CURRENT
DATABASES, OKAY, IT COULD BE
THAT SOME OF THAT APPARENT
VARIATION IS DUE TO FAILURE TO
FULLY ANNOTATE THE SEQUENCES,
AND THERE IS NO QUESTION THAT
THE BACTERIAL METAGENOMIC WORLD
IS LEAGUES AHEAD OF THE VIRAL
METAGENOMIC WORLD AND IN MY
VIEW, GIVEN DATA LIKE THIS AND
DATA FROM OTHERS, THAT
DIFFERENCE NEEDS TO BE FIXED.
WE NEED TO BE ABLE TO ANNOTATE
THESE THINGS AS WELL AS WE CAN
ANNOTATE BACTERIA TODAY.
NOW, THE MOST INTERESTING
DIFFERENCE IS BETWEEN BOSTON AND
THE OTHER TWO SITES AND THERE
ARE MORE BACTERIORPHAGES IN
PEOPLE IN BOSTON.
NOW, I HAVE A NUMBER OF
COLLEAGUES IN BOSTON, AND AS A
VIROLOGIST, WE OCCASIONALLY GET
THE PERMISSION TO NAME A VIRUS
AND I'M STRONGLY CONSIDERING
NAMING THE EXTRA VIRUSES IN
BOSTON CHOUDAVIRUSS FOR THE FACT
THAT THESE ARE PEOPLE WHO EAT
CLAM CHOWDER AND MAYBE THEY HAVE
CHOWDERVIRUSES.
IT'S STRIKING.
IF YOU LOOK AT THE CONTROLS
THERE.
I DON'T HAVE AN EXPLANATION FOR
WHY THAT MIGHT BE.
BUT THERE WILL DEFINITELY BE
GEOGRAPHIC VARIATIONS.
>> HOW ABOUT FAMILY MEMBERS?
>> THAT'S BEEN DONE IN SOME
RECENTLY STUDIED WORK AND IT IS
CLEAR AND WE HAVE SOME OTHER
DATA THAT'S UNPUBLISHED TION IT
IS CLEAR THAT WE SHARE NOT ONLY
OUR BACTERIA WITH OUR FAMILY
MEMBERS BUT ALSO OUR VIRUSES
WITH OUR FAMILY MEMBERS.
AND YOU KNOW THAT BECAUSE
CHILDREN GET CMV OR CHICKENPOX
FROM, YOU KNOW, GRANDPARENTS
WITH ZOSTER SO YOU KNOW THERE IS
THIS KIND OF TRANSFER BUT THAT
CLEARLY HAPPENS WITH
BACTERIOPHAGES AS WELL AND WITH
THE ENVIRONMENT.
IF YOU GO INTO A HOUSEHOLD AND
YOU SEQUENCE THE ENVIRONMENT,
DOORJAMBS, YOU WILL FIND THAT
THE FAMILY MICROBIOME AND VERY
LIKELY VIROME ARE SIGNIFICANTLY
CONTROLLED BY THE IMMEDIATE
FAMILY ENVIRONMENT.
>> THANK YOU.
>> I HAVE A RELATED QUESTION TO
IBD BECAUSE OF THE DIVERSITY OF
BACTERIOPHAGES WITH IBD, HAVE
YOU LOOKED AT -- IF YOU LOOK AT
FAMILY MEMBERS, IS THAT A SOURCE
OF THE DIVERSITY THAT PRECEDES
THE DISEASE OR IS THIS SOMETHING
THAT DEVELOPS AS YOU'RE
DEVELOPING IT?
>> BRIAN ASKS A VERY GOOD
QUESTION.
IN THE COHORT WHERE WE HAVE MORE
VIRUSES AND WE HAVE HOUSEHOLD
CONTROLS, WHAT IS THE OVERLAP
BETWEEN THE VIRUSES IN THE TWO?
OUR DATA IS IT'S A REALLY GREAT
QUESTION, OUR DATA IS NOT ROBUST
ENOUGH TO ANSWER THAT QUESTION
BECAUSE WHAT WE ANNOTATE IS NOT
THE FULL GENOMES OF VIRUSES.
WHAT WE ANNOTATE ARE SECTIONS OF
THE VIRUS.
SO IN ORDER TO REALLY KNOW
WHETHER I SHARE A VIRUS WITH MY
DAUGHTER OR MY WIFE, WE WOULD
ACTUALLY HAVE TO SEQUENCE THE
VIRUS AND SHOW THAT UNIQUE
SEQUENCE VARIATIONS WITHIN THE
OVERALL SEQUENCE OF THAT VIRUS
ARE SHARED BETWEEN THE TWO OF
US, AND OUR DATA IS JUST NOT
ROBUST ENOUGH TO DO THAT AT THE
CURRENT TIME.
AS WE GET BIGGER AND BIGGER
DATASETS, THIS IS A KEY
QUESTION.
>> BECAUSE IF YOUR HYPOTHESIS IS
REALLY THAT THE DIVERSITY OR
PREDATOR/PREY RELATIONSHIP IS
SOMETHING THAT RELATES TO THAT
DIVERSITY WHICH RELATES TO THE
PREY, SO WHAT IS IT THAT CREATES
THAT INITIAL DIVERSITY IF IT'S
NOT FOR SOME OTHER DIVERSITY
WITHIN THE BACTERIUM?
>> FIRST OF ALL, THERE'S CLEARLY
A GENETIC ELEMENT TO THE RISK
FOR CROHN'S DISEASE, FOR
EXAMPLE, SO ONE COULD ARGUE THAT
ALL THE PEOPLE IN THE HOUSEHOLD
WERE EXPOSED TO THE SAME VIRAL
MILIEU BUT THE GENETIC
SUSCEPTIBILITY SELECTED OUT
CERTAIN PATTERNS WITHIN THE
PATIENT WHO WAS PREDISPOSED TO
THE DISEASE.
BUT IT'S ALSO POSSIBLE THAT ONE
PERSON ATE AT A SALAD BAR THAT
THE OTHER PERSON DIDN'T EAT AT
AND GOT DIFFERENT VIRUSES
INTRODUCED INTO THEM.
OUR DATA CAN'T ADDRESS THOSE TWO
VARIANT HYPOTHESES AT THE
CURRENT TIME.
>> THANK YOU FOR THE EXCELLENT
PRESENTATION.
ARE A QUESTION ABOUT BACTERIA IN
THE GUT CAN TRANSLOCATE INTO THE
BLOOD AND WHICH WOULD BE
ASSOCIATED WITH INFLAMMATION,
WITH AGING AND OTHER THINGS.
I WONDER, LIKE VIRUSES IN THE
GUT, COULD THIS SAME THING BE
HAPPENING WITH VIRUSES OR NOT?
>> FIRST OF ALL, THE NIH IS THE
SOURCE OF THIS HYPOTHESIS, DANNY
DUEX'S GROUP WAS THE FIRST TO
PUBLISH THAT, THAT'S A PAPER WE
PAID A LOT OF ATTENTION TO.
WE'VE FUNDAMENTALLY CONFIRM
THOSE SAME FINDINGS IN PRIMATES
WITH HIV INFECTION ADVANCING TO
AIDS.
WE'VE FOUND WITH REGARD TO THE
VIROME THERE ARE MANY HYPOTHESES
BY WHICH YOU WOULD GET
TRANSLOCATION INTO THE SYSTEMIC
CIRCULATION AND THAT WOULD DRIVE
INFLAMMATION.
YOU COULD CHANGE THE NATURE OF
THE IMMUNE RESPONSE TO BACTERIAS
THAT'S ONE GOOD HYPOTHESIS.
WHAT WE FOUND WHEN WE DEEP
SEQUENCED THE PRIMATES, AND THIS
WAS PUBLISHED A COUPLE YEARS
AGO, IS 21 NOVEL VIRUSES IN THE
PRIMATES THAT WERE ADVANCING TO
AIDS AND THEY WERE NEVER
DISCOVERED BEFORE, YOU WOULDN'T
FIND THEM BY PCR NECESSARILY,
AND THEY WERE FROM GROUPS OF
VIERGSES WHICH ARE KNOWN -- OF
VIRUSES WHICH ARE KNOWN
PATHOGENS.
SOME OF THE VIRUSES WE
DISCOVERED COULD ACTUALLY BE
SEEN IN LESIONS IN THE GUT WHERE
THERE WAS AN ABNORMALITY AND A
BREAK IN THE EPITHELIUM AND WE
COULD STAIN AND SHOW THAT A
NOVEL HAD NO VIRUS WAS ACTUALLY
PRESENT IN THE LESION.
SO OUR HYPOTHESIS WOULD BE THAT
SOME TRANSLOCATION IS DUE TO THE
PRESENCE OF AS YET DIAGNOSED
VIRUSES THAT ARE PRESENT, WHICH
ACTUALLY MAY BE ACTING IN A MORE
CLASSICAL FASHION.
THEY HAVE A TROPISM FOR CELLS IN
THE INTESTINE, CAUSE
INFLAMMATION, CAUSE BREAK DOWN
OF THE BARRIER AND SOME OF THE
TRANSLOCATION YOU EVER GET COULD
BE DUE TO THE PRESENCE OF
VIRUSES.
VIRAL DIAGNOSTICS IN HUMANS ARE
WONDERFUL THINGS BUT THEY'RE
VERY TARGETED TO SEQUENCES THAT
ARE IN DESCRIBED VIRUSES.
IF YOU DO METAGENOMICS IN THOSE
SETTINGS YOU FREQUENTLY FIND THE
PRESENCE OF VIRUSES THAT WOULD
BE MISSED BY STANDARD PCR-BASED
DIAGNOSTICS.
SO YOU REALLY CAN'T, IN MY VIEW,
FULLY DIAGNOSE, IF YOU WILL, THE
ENTERIC VIROME WITH CURRENT
DIAGNOSTIC TOOLS SO I THINK
METAGEE MOW MIX -- METAGENOMICS,
SHOTGUN SEQUENCING, IS A GOOD
WAY TO KNOW WHETHER THERE'S
ACTUALLY A VIRUS THERE.
STANDARD DIAGNOSTIC, YOU DO THE
DIAGNOSTICS, YOU DON'T FIND A
VIRUS, YOU SAY THERE'S NO VIRUS,
I DON'T THINK THAT'S ACCURATE.
>> DO YOU HAVE NONRESPONSIVE
DATA LINKING CANCER
SUSCEPTIBILITY AND THE VIROMES,
FOR INSTANCE, CANCER DUE TO
ONCOGENIC VIRUSES OR OTHER TYPE
OF CANCER?
>> THE QUESTION IS WHETHER
THERE'S A LINKAGE BETWEEN THE
VIRUS TION AND CANCER.
WE'VE NOT DONE THOSE STUDIES AND
SO IT'S AN ATTRACTIVE
HYPOTHESIS.
WE'LL BE HAPPY TO SEND PEOPLE
THE METHODS FOR HOW TO DO THIS
STUFF.
>> WE'LL TAKE ONE MORE QUESTION,
THEN I THINK WE'LL MOVE TO THE
RECEPTION.
>> YOU'VE MENTIONED THIS
DIFFERENCE BETWEEN THE ABILITY
TO ANNOTATE ARE BACTERIA VERSUS
VIRUSES.
IT'S GOT TO BE PARTLY DUE TO THE
LACK OF MARKER GENE IN VIRUSES
LIKE 16S.
SO HOW DO YOU CURRENTLY DO
SOMETHING WHERE YOU WANT TO
GIVEN A DATASET IDENTIFY ALL THE
VIRUS TION?
>> SO THERE ARE TWO PARTS TO
THIS QUESTION AND IT'S ONE WE
THINK ABOUT A LOT.
SO IS THE REASON THAT IT'S
DIFFICULT TO ANNOTATE VIRUSES
BECAUSE VIRUSES DO NOT SHARE A
COMMON GENE THAT CAN BE TARGETED
BY CONSERVED PCR AS IS DONE FOR
18 BACTERIAL 16S?
THE ANSWER TO THAT IS IN PART
YES BUT IT IS MUCH MORE THAN
THAT.
BACTERIA, WHICH DIFFER BY 5% AT
THE NUCLEOTIDE LEVEL OR 10% AT
THE NUCLEOTIDE LEVEL ARE VERY
DIFFERENT FROM EACH OTHER.
VIRUSES WHICH VARY BY 5% WITHIN
A QUASI-SPECIES ARE THE SAME
VIRUS.
SO THE REAL PROBLEM IS THAT THE
DATABASES DON'T HAVE ENOUGH
VIRAL SEQUENCES TO FULLY
ANNOTATE.
YOU CANNOT DO VIRAL METAGENOMICS
BY NUCLEIC ACID HOMOLOGY.
IT CANNOT BE DONE.
YOU CAN IDENTIFY KNOWN VIRUSES
THAT WAY.
BUT VIRUSES VARY SO MUCH FROM
EACH OTHER, EVEN WITHIN A SINGLE
INDIVIDUAL, THAT YOU CAN'T USE
STRICT CONSERVATION OF NUCLEIC
ACID, AND THAT MEANS YOU HAVE TO
DO PROTEIN BASED SEARCHES AND
THAT'S A LOT OF WHAT WE DO.
OKAY?
SO NOT ENOUGH VIRUSES, NO COMMON
GENE AS AN ELEMENT, YOU NEED TO
DO PROTEIN, AND THE LAST THING
IS, WITH DUE RESPECT TO MY
BACTERIAL COLLEAGUES, THE
BACTERIAL GENOMES WHICH GO INTO
THE DATABASES, ANNOTATED AS
BACTERIA, CONTAIN PROPHAGES.
OKAY?
SO IF YOU TAKE A PROPHAGE, IF I
MAKE PURIFIED VIRUS PS FROM THE
GUT, I GET EUKARYOTIC VIRUSES, I
GET SOME PROKARYOTIC VIRUSES, IF
I SEARCH THE PROKARYOTIC VIRAL
SEQUENCES, THE DATABASE SAYS
THEY'RE BACTERIA.
THEY'RE NOT BACTERIA.
THEY'RE PHAGES.
THEY'RE JUST MATCHING PHAGES IN
THE BACTERIAL DATABASE SO THERE
IS A PROBLEM WITH THE ANNOTATION
OF THE DATABASE ITSELF BECAUSE
THEY ARE SOMETIMES NOT
COMPLETELY ANNOTATED FOR
VIRUSES.
WE'RE WORKING HARD TO SOLVE
THESE PROBLEMS.
THE LAST THING, AND I THINK IT'S
A REALLY IMPORTANT POINT, AND
IT'S A GOOD ONE TO END ON, NOT
ALL LIFE IS ENCODED BY DNA.
OKAY?
NOT ALL LIFE IS ENCODED BY DNA.
THERE ARE RNA ORGANISMS.
WHEN YOU SEE -- I STUDIED, I
DEFINE THE MICROBIOME WITH DNA
SEQUENCING, YOU NEED TO READ I
DID NOT DEFINE THE MICROBIOME BY
DOING ONLY DNA SEQUENCING.
ALL OF THE MAJOR VIRAL
PATHOGENS, MOST OF THE -- THE
MAJOR VIRAL PATHOGENLESS IN THE
GUT OF HUMAN -- PATHOGENS IN THE
GUT OF HUMANS ARE NOROVIRUSS,
ROTOVIRUSS, ASTRO VIRUSES AND
ADENOVIRUSES, SO THERE'S A DNA
VIRUS DOWN THERE.
SO WE REALLY HAVE TO GET AWAY
FROM THIS IDEA THAT SEQUENCING
DNA IS THE WAY TO GET AT THE
METAGENOME BECAUSE THERE ARE RNA
PHAGES, RNA VIRUSES, AND THE
METHODS ARE THERE.
I THINK THAT IT'S JUST EASIER TO
MAKE DNA THAN IT IS DNA AND RNA
AND I THINK THAT'S A MAJOR FLAW
IN MANY CURRENT STUDIES OF THE
VIROME AND THE METAGENOME
ITSELF.
>> THANKS.
>> SO THANK YOU FOR YOUR
ATTENTION.
01:13:48.333,00:00:00.000
[APPLAUSE]
