The gut microbiome has fundamental effects on human health, which range from enhancing immune defense to inducing the inflammatory reactions that underlie inflammatory bowel diseases (IBD). Much progress has been made towards understanding how intestinal bacteria evoke these beneficial and harmful immuneresponsesfromthehost.Bycomparison,littleisknownabouthowintestinalhomeostasisisregulated bytheviralcomponentofthemicrobiome,thevirome,inlargepartowingtotheabsenceofanimalmodelsthat enable functional studies of commensal viruses. We found that murine norovirus (MNV) infection protects germ-freemiceandantibiotics-treatedmicefromintestinalinjury,indicatingthatanintestinalanimalviruscan replace the beneficial functions typically provided by commensal bacteria. We also demonstrated that MNV induces inflammatory pathologies in mice with a mutation in Atg16L1, an IBD susceptibility gene that is essential for the cellular degradative process of autophagy. Therefore, in a manner analogous to bacterial membersofthemicrobiome,MNVcanbebeneficialwhilealsomediatingdiseaseinageneticallysusceptible host.WeproposetouseMNVinfectionofmiceasamodeltoaddressfundamentalquestionssurroundinghow acommensalanimalvirusaffectsintestinalhomeostasis.Wewillgeneticallymanipulateboththehostandthe virus to define the molecular features of this underappreciated category of host-microbiome interaction. In addition to testing the role of specific immune pathways during virus-mediated protection against intestinal injury,wewillinvestigatehowmutationofAtg16L1disruptsthisotherwisebeneficialresponse.Moreover,we will determine whether the beneficial and adverse responses to MNV can be decoupled. Functional characterization of intestinal viruses, beyond their role as pathogens, will become increasingly necessary to improve the safety and efficacy of therapies that target the microbiome. We also anticipate identifying new bacteria-independentpathwaysinvolvedintheintestinalinjuryresponseandIBDpathogenesis.
Although the bacterial component of the gut microbiome has received much attention, it is unclear how the diversevirusesthatinhabitthegastrointestinaltractinfluencehostphysiologybeyondcausingacutedisease. Wepreviouslyshowedthatmurinenorovirus(MNV)behavessimilarlytobacterialmembersofthemicrobiome by protecting against intestinal damage, while also mediating inflammatory bowel disease in a genetically susceptible host. We will investigate the mechanisms of this novel type of host-microbiome interaction, consideringboththebeneficialandadverseeffectsofintestinalviralinfection.
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