Herbert "Skip" Virgin - Animal Models and Microbiome Research

Animal Models and Microbiome Research:
A Trans-Kingdom Perspective
Skip Virgin
Pathology and Immunology
Washington University
School of Medicine
Saint Louis, Missouri USA
NIH, NIH Center for Excellence in Translational Research, NIH Primate Infectious Disease Resource,
Crohns and Colitis Foundation, Juvenile Diabetes Research Foundation
Virgin Lab 12-2016

Viral Persistence, Latency, Symbiosis
Craig Wilen
Robert Orchard
Sanghyun Lee
Xin Zhang
IFNs, autophagy and inflammation in immunity and disease

Qun Lu
Anthony Orvedahl
Taylor Feehley
Michael McAllaster
Yating Wang
Cathy Liu
Annie Mayer
Dale Balce
The virome in IBD, T1D and AIDS
Chandni Desai
Lindsay Droit
Scott Handley
Guoyan Zhao
Tiffany Reese
UTSW
Megan Baldridge
WUSM
Tim Nice
OHSU
Microbiome: all of the organisms that live in or

on the host: virome, bacterial microbiome,
archaeal microbiome, mycobyome, meiofauna, others?
Metagenome: The sum of all of the genes
in or on the host: host genes plus
genes in the microbiome.
Outline
Virome- concept
Virome- substantial physiologic effects
Transkingdom interactions- components
of the microbiome cannot be considered in isolation
Potential transkingdom interactions in humans?
Can we improve mouse models
with this knowledge?
The virome: A permanent and dynamic

contributor to our metagenome
Total > 60 billion, ca. 10/person, some make 1012 particles per day
Virgin, Wherry, Ahmed, 2009 Cell 138:30
The virome has important effects on physiology,

inflammation, immunity and disease
Virgin, 2014 Cell 157:142
Resistance
to infection
and tumors
IFN
Chronic
Herpesvirus
Barton 2007 Nature 447:326

White 2010 Blood, 115:4377
Canny 2013 J. Virol. 88:730
Virome
Immunophenotype
GenotypePhenotype
Relationship
Virgin, Wherry, Ahmed, Cell 2009 138:30
Atg16L1
Chronic
Norovirus
Susceptibility
to genetic
disease
Cadwell 2008 Nature 456:259
Cadwell 2010 Cell 141:1135
Resistance
to infection
and tumors
IFN
Chronic
Herpesvirus

White 2010 Blood, 115:4377
Virome
Immunophenotype
GenotypePhenotype
Relationship
A latent herpesvirus can be a mutualistic symbiont
Latent HV68 Infection: 3 months pi
100
80
n=15
60
40
20
0
n=15
0
5
10
15
20
Day Post Listeria Challenge
Mock
Percent survival
Percent survival
Latent HV68 Infection: 1 month pi
100
80
60
n=10
40
n=10
20
0
10
20
Day Post Listeria Challenge
Latent HV68
Chronic herpesvirus infection defines the basal set point

of the innate immune system through IFN secretion
in response to viral reactivation from latency.
Barton et al. 2007 Nature 447:326

Herpesvirus latency confers

symbiotic protection from
bacterial infection
Barton et al., 2007. Nature 447:326
Virgin 2014 Cell 157:142
Hypothesis: Phenotypic characteristics of

mammalian hosts will be substantially altered
by components of the microbiome, including the virome.

Can viral infection alter a genetically determined immunodeficiency?
Boisson et al. 11/2012
Hoil-1 controls the balance between

immunodeficiency and hyper-inflammation
Severe Immunodeficency
Hoil-1-/-
Hoil-1-/-
Toxoplasma
gondii
Highlysusceptible
Listeria
monocytogenes
Highlysusceptible
MacDuff et al., 2015 eLIFE 4:e04494
Hoil-1-/-
Mycobacterium
tuberculosis
Resistant
Hoil-1-/-
MHV68
Resistant
Latent herpesvirus infection phenotypically

complements genetic immunodeficiency
Hoil-1-/IL-6-/Caspase 1/11-/-
MHV68
Day 28
Challenge with L.
monocytogenes

Phenotypic complementation of genetic

immunodeficiency by chronic herpesvirus infection
MacDuff et al. 2015 eLIFE 4:e04494
Resistance
to infection
and tumors
IFN
Chronic
Herpesvirus

White 2010 Blood, 115:4377
Virome
Immunophenotype
GenotypePhenotype
Relationship
Atg16L1
Chronic
Norovirus
Susceptibility
to genetic
disease
Pathogenic consequences of virus + gene

interactions
No Trigger
Barrier Raised
Atg16L1
Mutant mouse
Normal Paneth cell
Standard DSSinduced colitis
No DSS-induced
villus blunting
MNV
Trigger
Abnormal Paneth cell
Cadwell et al., 2010 Cell 141:1135
Increased DSSinduced colitis
DSS-induced
villus blunting
Autophagy gene mutations affecting Paneth cells

predict patient outcomes and a new disease subtype
VanDussen et al. 2013. Gastroenterology

Virus-plus-susceptibility gene interaction

determines Crohns diseases gene
Atg16L1 phenotypes in intestine
Outline
Virome- concept
Perhaps humans are not the

center of the metagenomic solar system
The Earth must be at

the center of the solar system
What makes sense when all of the

interactions between components of
the solar system are accepted
Importance of specific design considerations

for control of metagenomic effects in experiments
2016 Nature 354:191
2016 Science. 351(6270): aad5872
IL4
Resistance
to infection
and tumors
IFN
IL13
H. polygyrus
Reese 2014 Science 6196:573
Chronic
Herpesvirus

White 2010 Blood, 115:4377
Virome
Immunophenotype
GenotypePhenotype
Relationship
HOIL-1
IFN-
Bacterial
microbiome
STAT-1
IRF3
Baldridge 2015 Science 347:266

MacDuff 2015 eLIFE 4:e04494
Nice 2015 Science 347:269
Atg16L1
Chronic
Norovirus
Susceptibility
to genetic
disease
Trans-kingdom interactions between helminth infection

and herpesvirus infection
IL4
IFN
IL13
H. polygyrus
Reese 2014 Science 6196:573
Chronic
Herpesvirus
Resistance
to infection
and tumors
White 2010 Blood, 115:4377
Helminth infection induces herpesvirus reactivation from latency
PBS
H. polygyrus
Reese et al., 2014 Science 6196:573
Day 7
Day 7
IL4 and IL13 activate the viral gene 50 promoter that is responsible
for triggering reactivation from latency
Transcription of gene 50
n.d.
n.d.
Cytokine regulation of gene 50 promoter
Efficient herpesvirus reactivation in vivo requires that the virus

sense two different immune signals
D0
D48
Treat
D5
Image
Light emission secondary to viral reactivation

PIP
antiIFN
IL-4c +
IL-4c anti-IFN
6.0
5.0
2.0
1.0
3.0
x10
4.0

Virus-helminth co-infection reveals a

microbiota-independent mechanism of
immunomodulation
Helminth co-infection reactivates

gammaherpesvirus infection through viral
promoter-targeted cytokine competition
Osborne et al., 2014 Science 6196:578
Transkingdom interactions between bacteria and persistent

enteric viral infection
HOIL-1
IFN-
Bacterial
microbiome
STAT-1
IRF3
Baldridge 2015 Science 347:266

MacDuff 2015 eLIFE 4:e04494
Nice 2015 Science 347:269
Atg16L1
Chronic
Norovirus
Susceptibility
to genetic
disease
Human and murine noroviruses persistently

infect the intestine and are shed in feces
Viral genomes are shed for weeks/months after resolution of symptoms
Prevalence of asymptomatic human norovirus shedding ranges from 3-17%
(Karst et al. Advances in Norovirus Biology. 2014. Cell Host and Microbe. 15:668)
CR6
Persistent
CW3
Non-persistent
Nice et al., 2013 J. Virol. 87:327
Antibiotic treatment inhibits the establishment of persistent

intestinal norovirus infection
Abx
-14
CR6
0
Day
Analysis
14
(Ampicillin, Vancomycin, Neomycin,

and Metronidazole)
Baldridge et al., 2015 Science 347:266
Fecal transplantation reverses antibiotic-mediated

inhibition of persistent intestinal norovirus infection
Stop Abx
Fecal Transplant
Abx
-17
CR6
-3 -2 -1 0
Day
Analysis
7
IFN responses are required for antibiotic-mediated

inhibition of persistent norovirus infection
Abx
Knockout
Mice
-14
CR6
Analysis
0
Day
(Ampicillin, Vancomycin, Neomycin,

and Metronidazole)
14
Treatment with IFN (also called IL-28) prevents establishment

of persistent intestinal norovirus infection
Nice et al., 2015 Science 347:269
IFN cures persistent intestinal norovirus infection

through sterilizing innate immunity
Nice et al., 2015 Science 347:269

Interferon- cures persistent murine

norovirus infection in the absence
of adaptive immunity
Commensal microbes and interferon-

determine persistence of enteric murine
norovirus infection
Nice et al., 2015 Science 347:269.
Baldridge et al. 2015 Science 347:266
Outline
Virome- concept
Enteric virome in IBD
Norman et al., 2015 Cell 160:447
In contrast to the bacterial microbiome, the enteric virome

becomes more complex in IBD
250
250
200
200
200
150
100
Household controls
Ulcerative colitis
Crohn's disease
50
0
0
10
20
30
# of Samples
Ulcerative
colitisUC
N=36
78
42
8
114
40
Crohn's
disease
CD
N=16
64
8
150
100
Healthy controls
Ulcerative colitis
Crohn's disease
10 15 20 25 30
# of Samples
50
0
0
Ulcerative
colitisUC
N=18
29
13
31
107
Crohn's
disease
CD
N=7
71
29
Caudovirales
richness
250
Caudovirales
richness
Caudovirales
richness
Boston USA
Chicago USA
Cambridge UK
150
100
Healthy controls
Ulcerative colitis
Crohn's disease
10 15 20 25 30
# of Samples
50
0
0
Ulcerative
colitisUC
N=11
30
23
35
132
22
38
HHC
Household
controls
N=21
HHC
Healthy
controls
N=23
HHC
Healthy
controls
N=20
Crohn's
disease
CD
N=14
44
19
Disease-specific relationships between disease-associated

bacterial taxa and bacteriophages in IBD
The virome has important effects on mammalian

biology, inflammation, immunity and diseases
Disease-specific alteration
in the enteric virome in
inflammatory bowel disease
Diseases currently under study- Virginlab 12-2016

Category
Clinical Outcome
1o
Collaborator
Country
Publication
Funding
Partner
IBD
Disease and
exacerbation
Parkes,
Handley
US, UK
Norman, 2015 Cell 160:447
CCFA
HIV/SIV
Enteropathy
Kwon
Uganda,
Botswana
Handley 2012 Cell. 151:253

Monaco, 2016 Cell Host & Microbe.
19:311
NIH
Acquisition risk,
vaginal inflammation
Kwon
South
Africa
Anahtar, 2015 Immunity 42:965

Gosmann, 2017 Immunity In press
NIH
HIV/SIV
Barouch
Thailand,
Africa, US
Barouch, 2015 Science 349:320

Handley, 2016 Cell Host and Microbe
19:323
PND NIH
Rotavirus
Harris
Ghana
--
Gates
T1D
Risk for development
Xavier
Finland
--
JDRF
Host genes
controlling
metagenome
Autophagy genes in
mice
Zhao
US
Baldridge, 2015 Science 347:266

Nice, 2015. Science 347:269
NIH
Diagnostics
Enteric disease in
monkeys
Lackner
US
Handley 2012 Cell. 151:253

Handley, 2016. Cell Host & Microbe
19:323
NIH
Vaccine
Response
Outline
Virome- concept

Virgin, Cell 2014 157:142
Does a history of infection, mimicking the early-life human exposure to

chronic infections, alter the normal immune system and change the
immune response to vaccination?
Test the hypothesis

that sequential infections
fundamentally alter
vaccine immune responses
50
49
169 B6
mice
30
40
Reese et al., 2016 Cell Host and Microbe 19:1
Co-infections define the transcriptional response

to Yellow Fever Virus vaccination
Day
21 21
IFN response
IFN response
IL-1 expression
Memory CD8 response
Platelet formation
Coagulation/hemostasis
Wound healing
Tregs/Teffectors
ERK1/ERK2
Inflammation
Macrophage activation
Erythrocyte differentiation
Healthy vs. RSV
infected infant
Healthy vs St. aureus
infected infant
Neutrophil response to F. tularensis

Macrophage response to dsRNA
Memory CD4 response
Partial humanization of the mouse transcriptome

by co-infection
Day
21 21

Sequential infection with common pathogens

promotes human-like immune gene expression and
altered vaccine response
Outline
Virome- concept
Potential transkingdom interactions in humans
Some Needs Based on These Studies

Careful Clinical and Animal Studies
Consensus Methods, Proper Controls,

Databases, Full Reporting
Bioinformatics for the other omes
Modular, Crowd Friendly, Accessible
Genome Databases
Massive Improvements in Scope and

Annotation Quality a Must
Biological Hypotheses
Integration of Bioinformatic Platforms

With Studies of Model Organisms
Animal Models
Primate, Mouse, Pig, Model Organisms
Molecular Manipulation of the Omes
New Technologies Essential
Mechanism
Of Course
Translation
CLIA Sequencing Now
Companion Diagnostics
Clinical Grade Databases
Training
Training Grants, PhD, MD/PhD,

Accelerated Junior Faculty
Virgin Lab 12-2016

Viral Persistence, Latency, Symbiosis
Craig Wilen
Robert Orchard
Sanghyun Lee
Xin Zhang
IFNs, autophagy and inflammation in immunity and disease

Qun Lu
Anthony Orvedahl
Taylor Feehley
Michael McAllaster
Yating Wang
Cathy Liu
Annie Mayer
Dale Balce
The virome in IBD, T1D and AIDS
Chandni Desai
Lindsay Droit
Scott Handley
Guoyan Zhao
Tiffany Reese
UTSW
Megan Baldridge
WUSM
Tim Nice
OHSU
Key needs for a viromics computational platform

Technology not yet democratized
Bioinformaticsbacteria
DNA
Bioinformaticsvirus
DNA + RNA
Viromics platform can be used for bacteria etc.
Modular virome analysis software application work flow
Vertically and horizontally transmitted

regulation of Immunity by the microbiome
http://www.nature.com/nature/journal/v
534/n7606/images_article/nature18285f2.jpg
Moon, Baldridge et al. 2015. Nature. 521:90
Controlling for
microbiome in
experiments
Additional
possible
tests

Transformative opportunities to understand biology

The metagenome
Easy to sequence all of the genes
in the metagenome (RNA + DNA).
The metagenome really matters: It
may explains a lot of the WHY and
HOW of disease.
A major challenge is bioinformatic
analysis of the sequences and
validation of computational results.
Once hypotheses are formed, it
can be hard to evaluate them in a
reductionist manner.
The virome is a major actor in
controlling the phenotype of
mammals.
Transkingdom interactions occur
within the microbiome.

Computational
challenges for defining
the virome
Virgin, 2014 Cell 157:142
Expansion of the enteric virome in SIV-infected macaques
Sequences
Viruses
PCR
Confirmation
Handley et. al., 2012 Cell 151:253
Role of the enteric virome in SIV/AIDS
Key Findings:
Expansion of enteric virome
Many novel viruses
Confirmed by PCR
Adenovirus-induced epithelial
pathology
Enteric parvoviruses in
circulation
What is the Role of the Virome?
AIDs enteropathy?
Barrier breakdown?
PAMPS/antigens into tissue?
Systemic immune activation?
Progression to AIDS?
Handley et. al., 2012 Cell 151:253

Altered Virome and Bacterial

Microbiome in HIV-Associated AIDS
Monaco, et al 2016. Cell Host and
Microbe. 19:311
Pathogenic SIV infection is

associated with significant
expansion of the enteric virome
Handley et al., 2012. Cell.
151:253
Helminth-induced IL-4 increases herpesvirus replication and

expression of a key viral reactivation gene
IL-4 and IL-13 (but not IL-5) stimulate herpesvirus growth in
macrophages.
IL-4 stimulation of herpesvirus replication requires STAT-6.
IL-4 stimulates the transcription of herpesvirus gene 50 which
is essential for viral replication and reactivation from
latency.
IL-4 stimulates reactivation through STAT-6 binding to ciselements in the viral promoter for gene 50.
IL-4 stimulates gene expression in human Kaposis sarcoma
herpesvirus.
HV68/MHV68
Gammaherpesvirus
Genome/genes related to KSHV and EBV
Acute infection cleared by 12-14 days
Latency in B cells, macrophages, dendritic cells
Latency regulated by IFN and IL-4
LPD/Lymphoma
T and B cell
Immunity
Vasculitis
Latent infection has broad effects

on host gene expression
MHV68
28
Days
Spleen, liver, brain

gene expression
Canny et al. 2013 J. Virol. 88:730
Celiac
Crohns
MS
Virus + gene interactions define transcription in

epithelial Paneth cells
WT
WT
vs
WT + MNV
16HM
WT
16HM
Atg16L1HM
vs
Atg16L1HM + MNV
The effects of IL4 on viral reactivation are evolutionarily conserved

between murine and human herpesviruses
Variation in mouse models

Phenotypic variation in mouse models between
investigators and institutions is a common issue
Usually attributed to genetic drift or microbiota
differences between facilities, but often not carefully
explored
Many investigators compare KOs vs WT strains that are
maintained in separate breeding schemes, or use WT
mice ordered from separate facilities
A specific example of variation caused by the

microbiome, in genetically identical mice
Immunoglobulin A (IgA)
IgA dimer
and secretory
component
Produced by plasma cells in

the lamina propria
Some roles in protection
against mucosal viruses
Epithelial cell
poly-Ig
receptor
(Pigr)
Prevents bacterial
translocation
IgA
Protective in dextran
sodium sulfate (DSS)
challenge
Murthy et al. J. Gastroenterol. Hepatol. 2006.
Reikvam et al. Eur. J. Immunol. 2012.
Wild-type C57BL/6J mice exhibited a

binary fecal IgA phenotype
high
low
Moon, Baldridge, et al. Nature. 2015.
IgA levels are vertically transmissible

high
high
high
low
low
low
IgA levels are horizontally

transmissible, and IgA-low is dominant
high
low
+
Cohouse
14 days
low
low
IgA-low element(s) is horizontally

transmissible, and removed by
filtration
low
Fecal
Transplant (FT)
high
Filtration
low
high
IgA-low element is susceptible to

antibiotic treatment
Antibiotics
14 days
low
low
FT
high
low
Antibiotics = Vancomycin, Neomycin,

Ampicillin, Metronidazole
IgA status confers differential

susceptibility to dextran sodium
sulfate
Antibiotics
14 days
WT
WT
FT
high
low
IgA status confers differential

susceptibility to dextran sodium
sulfate
Antibiotics
14 days
Pigr-/-
Pigr-/-
FT
high
low
DSS effects appear to depend on IgA status and not the microbes themselves.
Enteric Virome and Bacterial Microbiome

in SIV/AIDS
Handley et al., 2012 Cell 151:253

Handley et al., 2016 Cell Host and Microbe 19:323
Novel viruses associated with AIDS enteropathy

Animal
#
# of
Adenovirus
readsa
WUHARV
Adenovir
usa
PCR
screena,b
Adenovirus
Enteritisc
SI
Adenoviru
s IHCc
LI
Adenovirus
IHCc
Other GI Pathologiesc
23
889
1,
othersd
Pos
Yes
Pos
Neg
Cytomegalovirus enteritis
25
26
27
0
0
n/a
n/a
Neg
Neg
No
No
Neg
Neg
Neg
Neg
653
5,
othersd
Pos
Yes
Pos
Neg
No
No
Balantidium typhlitis
14
1
0
52
4
0
0
othersd
othersd
n/a
othersd
othersd
n/a
n/a
Neg
Neg
Neg
Neg
Neg
Neg
Neg
No
No
No
No
No
No
No
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
640
othersd
Pos
Yes
Pos
Pos
29
30
31
32
33
37
38
41
B:Histologyfromanimal23
Handley et. al. Cell 2012
No
No
Balantidium sp. colitis
No
No
No
Balantidium sp. colitis
Balantidium sp.
typhlocolitis
C:Histologyfromanimal27
SIV vaccine cohort study of the enteric virome and

bacterial microbiome
Progressive SIV-associated immunodeficiency is associated with

changes in the enteric virome and bacterial microbiome
Analysis of Total Sequences in Fecal Samples From SIV Vaccine Cohoort
Expansion of the enteric virome during progression of

SIV infection to AIDS
Week 5
Week 32
or necropsy
Week 5
Week 32
or necropsy
Association between changes in the virome

and gastrointestinal disease
Axis2[11.4%]
Meta-analysis of vaccination and the enteric virome in SIV/AIDS
Axis1[19.6%]
Emergence of discriminant bacterial taxa during

SIV infection progression to AIDS
Enteric Virome and Bacterial Microbiome

in HIV/AIDS
Monaco et al., 2016 Cell Host and Microbe 19:311
Cohort for the study of the enteric DNA virome and

bacterial microbiome in HIV/AIDS
The enteric DNA virome and the bacterial microbiome

change in in HIV/AIDS
Expansion in the enteric DNA virome in HIV/AIDS
Emergence of discriminant bacterial taxa during

HIV infection progression to AIDS
Hoil-1 controls the balance between

immunodeficiency and hyper-inflammation
Severe Immunodeficency
Hoil-1-/-
Hoil-1-/-
Toxoplasma
gondii
Highlysusceptible
Listeria
monocytogenes
Highlysusceptible
Hoil-1-/-
Mycobacterium
tuberculosis
Resistant
Hoil-1-/-
MHV68
Resistant
Hypothesis: Chronic herpesvirus infection,

to which Hoil-1-/- mice are resistant, will
complement the severe immunodeficiency
observed in barrier raised Hoil-1-/- mice
and generate auto-inflammation.
Hoil-1 mutant mice exhibit hyper-inflammatory phenotype

during chronic herpesvirus infection
Hoil-1-/-
Day 28
Harvest serum
for quantitation
of cytokines
MHV68
p<0.01
p<0.01
p<0.01

Hypothesis: Transkingdom metagenomic interactions

will alter viral pathogenesis and viral immunity.
Multi-Center study of the enteric virome and bacterial

microbiome in inflammatory bowel disease
Addenbrookes
Cambridge UK
Miles Parkes
34 Subjects
17 Household controls
11 UC, 6 CD
73 Samples,
Many longitudinal
MGH, Boston
Ramnik Xavier
Dirk Gevers
45 Subjects
20 Controls
11 UC, 14 CD
45 Samples
None longitudinal
Rush, Chicago
Ali Keshvarzian
Ece Mutlu
42 Subjects
23 Controls
18 UC, 7 CD
48 samples
Few longitudinal

UC-Boston
CD-Boston
Healthy-Boston
UC-Chicago
CD-Chicago
Healthy-Chicago
UC-Cambridge
CD-Cambridge
HHC-Cambridge
UC-Boston
CD-Boston
Healthy-Boston
UC-Chicago
CD-Chicago
Healthy-Chicago
UC-Cambridge
CD-Cambridge
HHC-Cambridge
Observed Species
Alpha diversity (PD)
Clinical cohorts of IBD patients

exhibit bacterial dysbiosis as expected

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Herbert &quot;Skip&quot; Virgin - Animal Models and Microbiome Research

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Animal Models and Microbiome Research:

Virgin Lab 12-2016

IFNs, autophagy and inflammation in immunity and disease

The virome in IBD, T1D and AIDS

Microbiome: all of the organisms that live in or

The virome: A permanent and dynamic

Virgin, Wherry, Ahmed, 2009 Cell 138:30

The virome has important effects on physiology,

Virgin, 2014 Cell 157:142

Barton 2007 Nature 447:326

Virgin, Wherry, Ahmed, Cell 2009 138:30

Barton 2007 Nature 447:326

Virgin, Wherry, Ahmed, Cell 2009 138:30

A latent herpesvirus can be a mutualistic symbiont

Latent HV68 Infection: 3 months pi

Latent HV68 Infection: 1 month pi

Chronic herpesvirus infection defines the basal set point

The virome has important effects on physiology,

Herpesvirus latency confers

Hypothesis: Phenotypic characteristics of

The virome has important effects on physiology,

Can viral infection alter a genetically determined immunodeficiency?

Virgin 2014 Cell 157:142

Boisson et al. 11/2012

Hoil-1 controls the balance between

MacDuff et al., 2015 eLIFE 4:e04494

Latent herpesvirus infection phenotypically

MacDuff et al., 2015 eLIFE 4:e04494

The virome has important effects on physiology,

Phenotypic complementation of genetic

Virgin 2014 Cell 157:142

Barton 2007 Nature 447:326

Virgin, Wherry, Ahmed, Cell 2009 138:30

Pathogenic consequences of virus + gene

Standard DSSinduced colitis

Abnormal Paneth cell

Cadwell et al., 2010 Cell 141:1135

Increased DSSinduced colitis

Autophagy gene mutations affecting Paneth cells

VanDussen et al. 2013. Gastroenterology

The virome has important effects on physiology,

Virus-plus-susceptibility gene interaction

Virgin 2014 Cell 157:142

Perhaps humans are not the

The Earth must be at

What makes sense when all of the

Importance of specific design considerations

2016 Science. 351(6270): aad5872

Barton 2007 Nature 447:326

Virgin, Wherry, Ahmed, Cell 2009 138:30

Baldridge 2015 Science 347:266

Trans-kingdom interactions between helminth infection

Helminth infection induces herpesvirus reactivation from latency

Reese et al., 2014 Science 6196:573

Reese et al., 2014 Science 6196:573

Cytokine regulation of gene 50 promoter

Efficient herpesvirus reactivation in vivo requires that the virus

Light emission secondary to viral reactivation

Reese et al., 2014 Science 6196:573

The virome has important effects on physiology,

Virus-helminth co-infection reveals a

Helminth co-infection reactivates

Osborne et al., 2014 Science 6196:578

Reese et al., 2014 Science 6196:573

Virgin 2014 Cell 157:142

Transkingdom interactions between bacteria and persistent

Baldridge 2015 Science 347:266

Herbert "Skip" Virgin - Animal Models and Microbiome Research

Herbert "Skip" Virgin - Animal Models and Microbiome Research