VIRGIN, Skip, VIROME, WUSTL, May 27, 2015
<p class="MsoNormal" >VIRGIN, Skip, VIROME, WUSTL, May 27, 2015</p>
<p>
This is a memorial lecture at Stanford in Munzer Aud.
He is an MD, PhD from Harvard.</p>
<p>
This is Skip Virgin in Dept of Pathology and Immunology at
Wash Univ Med School in St Louis. = WUSTL.</p>
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he has many funding agencies; huge lab;</p>
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(this is an outstanding lecture and much of it is online in a YouTube video. See it!)</p>
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Viral mechanisms of viral persistence. huge lab... shows his students.</p>
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Virome in IBD, T1D and AIDS.</p>
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slide 1: The virome as part of our metagenome that contributes to our phenotype.</p>
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including bacteriophages and eukaryotic viruses interact with our own genome.</p>
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he shows 20 viruses or so that all of us have...</p>
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abt 10 of these per person...</p>
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some of us have 8 different herpes viruses eg.</p>
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see Virgin, wherry, ahmed Cell in 2009 138</p>
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these viruses drive cytokines chronically!</p>
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lots are in and on us.</p>
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divide into eukaryotic and
endog viral elements and prokaryotic viromes</p>
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and they interact with trans-kingdom creatures.</p>
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they control</p>
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systemic inflammation...
immunophenotype
disease susceptibilities
mutualistic symbiosis</p>
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all these viruses (see 2009 article above)</p>
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when new pathogen comes in... what is the state of immune system that sees it.</p>
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eg we cultured chronic norovirus.</p>
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combinatorial effect when it interacts with Atg16L1.</p>
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chronic herpesviruses interact with IFN... to produce resistance to infection/ tumros.</p>
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Latent herpesvirus infection' protects against lethal Listeria infeciton... huge effect.
it IS the CHRONIC infeciton that does it.</p>
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controls set point of IFN (interferon) gamma secretion.
which affects macrophages and killer cells.</p>
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chronic herpesvirus causes massive changes in gene expression in liver, spleen and brain.</p>
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and may cause suscept to Celiac, Crohns and MS (multiple sclerosis).</p>
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virus + gene in mouse causes abnormal paneth cells (secretory cells in gut)</p>
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that leads to DSS-induced villus blunting.</p>
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Barrier raised Atg16L1 mutant mouse.</p>
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(describes the facility at WUSTL where the mice are kept... v v clean a lot of autoclaving)</p>
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effect of virus on paneth cells.
chronic virus... the whole genome expression shifts...</p>
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so, virome has important effects on immunity, etc.</p>
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also interactions btwn virus, gene, and bacteria...
(in gut, eg... can rx virus induced gut infection with antibiotic)</p>
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Boisson 2012.. immunodeficient people (and mice)</p>
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Hoil-1 controls the balance btwn immunodefic and hyper-inflammation...</p>
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mechanism: Hoil1 is required for cytokine production by macrophages
afer L monocytogenes infection...</p>
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but also see MacDuff 2015 in eLIFE...</p>
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16 pts with immunodefic.</p>
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so, hypothesis: chronic Herpes infec to which Hoil1 KO mice are resistant
will complement the immunod defic to exhibit hyper-inflammatory
(during chronic Herpes infection)</p>
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presence of chronic virus can make up for immunodeficiency.</p>
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*</p>
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another story:</p>
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(trans-kingdom interactions)</p>
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co-infeciton with a helminth induces Herpes reactivaiton from latency.</p>
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get reactivaiton of the virus at day 7 after infeciton with helminth.</p>
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hypothesis: helminth induced IL4 increase MHV68 replication and reactivaiton.</p>
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this requires STAT6 (a switch gene is involved with viral gene 50 RTA)</p>
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see Reese in Science 2014 6196:573</p>
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ancestral herpes (reptiles, birds, mammals)</p>
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gamma turns on promoter, IL turns it off.
<b>herpes has studied you for millions of years</b>!</p>
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two signal model for herpes reactivation in vivo.</p>
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cytokines control viral transcription.</p>
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next story:</p>
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Noroviruses... cruise ships... where is the reservoir (in this room)
if you make the mayonaisse for the church picnic and you're a shedder... watchout!</p>
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CR6 persists in the gut...</p>
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rx with antibiotic for 2 weeks...
did not become persistenly infected in mice (with infeciton by CR6 type of noro)
fecal transplant brought it back ...
Baldrige in 2015 in Science 347.</p>
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IFN = interferon lambda..
so how did Abx prevent the infeciton...</p>
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rx with IFN lambda prevents establishment of persistent intestinal norovirus infeciton</p>
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see Nice 2015 in Science 347 269.</p>
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rx with IFN lambda effectively cures persistent intest norovirus infection...</p>
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what genes are required...</p>
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seems that IFN lambda rx cures persistent intestinal norovirus infection
thru induction of sterilizing innate immunity.</p>
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(t cells and b cells are not required to sterilize this infeciton)</p>
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*</p>
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hypoth: changes in virome will be related to human diseases.</p>
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go to humans in this story...</p>
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Norman and Handley in 2015 in Cell 160...</p>
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in human gut: most of the viruses are RNA viruses (but not the adenoviruses, which are DNA)</p>
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cannot just search for partic RNAs cuz there is HUGE variation up to 20% or more...</p>
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story: role of enteric virome in chronic SIV and HIV in monkeys.</p>
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AIDS enteropathy (also in monkeys)</p>
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see Handley in cell in 2012.</p>
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pathogenic SIV infected monkey...
many viruses in all the enteric viruses in the monkey with this.
expansion of viruses.</p>
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expansion of enteric virome...</p>
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confirmed by PCR,
is it due to barrier breakdown, etc.</p>
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looked at HIV cohort in Uganda...</p>
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some dx with AIDS others are HIV negative.</p>
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looked at 40,40,42 (3 arm trial with those # of patients) :
HIV negative versus HIV on chronic ART versus HIV untreated (42)</p>
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looked at adenoviruses, anellovirsues and circoviruses
(are not changed, commensals)</p>
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but adenoviruses change (much more) as are anelloviruses...</p>
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almost all new viruses... (just discovered in these patients)</p>
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But bacterial microbiome does not change much in these HIV infectd patients.</p>
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HIV does not affect bacteriophages (in this Uganda study)</p>
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shows matrix that shows community structure
(which bateria + correlate with other families of bacteria)</p>
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in advanced HIV the community is dysregulated (in pts with CD4 < 200)</p>
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new story IBD</p>
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IBD = inflammatory bowel disease</p>
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study from cambridge in the UK
(of ulcerative colitis = UC and Crohns) studied by Miles Parkes
with household cotnrols !!!</p>
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see Norman and Handley in 2015 in CELL 160 447.</p>
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you really need household controls!!!</p>
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1) looked at Cambridge, Chicago, Boston populations.</p>
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pts with IBD have decreased diveristy and richness (how many species and counts)</p>
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but the phages go up! in IBD.</p>
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virsues in UC are different than the Crohns pts.</p>
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how do the phages relate to the bacteria???? (wonders a reviewer)</p>
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some correlate + and some -.
does one phage kill one bactreria that enables other populations to expand?</p>
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substantial difference btwn sick people and controls.</p>
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virome is quite distinct in Crohns</p>
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predator prey realtionship btwn viromes and bacteria</p>
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shows bear eating salmon and
lion eating zebra...</p>
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go to salad bar and get new bactreia... changes equiibrium state etc.</p>
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*
summary: trans-kingdom interactions versus host genetic variaiton etc.</p>
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leads to phenotype variation in systemic infalmmation, immunophenotype, etc.</p>
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audience Q: is it just predator prey relationship?
Answer: do the eagles kill all the rabbits... NO! the eagles just establish a new equilibrium
(our rationalization)</p>
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another comment: cyclical relationship... (but Jeff Gordon might observe that)
phage kills certain bacteria... and that results in a new set point...</p>
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aud Q: Norov virus: Rigae (sp)</p>
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USSR with phage rx (and no antibiotic)... Skip wants translation of those studies from Russian!</p>
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vaccinate against one pathogen may protect against other pathogens (Skip says)</p>
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aud Q: do any of these have clinical signif?</p>
<p>
we need tech development to characterize virome in humans... must do these studies;
this WILL change clin med in next decade!
(does change obesity and propensity to DM2)</p>
<p>
David Wang at WUSTL... enteric microbiome in Australia aborigines versus Perth vs Seattle vs St Louis.</p>
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huge differences.... eg kids shedding these are doing just fine (in the aborigines
but would cause huge diarrhea here)</p>
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huge diffs in virome in civilzied vs uncivilized.
</p>