SUPPRESSION OF ENTERIC NOROVIRUS INFECTION BY MICROBIOTA-REGULATED BILE ACIDS

Project SummaryAn immense population of microorganisms, collectively referred to as the microbiota, colonizes the mammalianhost. In addition to bacteria, nonpathogenic and pathogenic viruses enter hosts via the gastrointestinal tract. Ofparticular clinical importance are noroviruses, which are responsible for ~20% of pediatric diarrheal casesglobally, are the leading cause of severe childhood diarrhea, and are associated with devastating infections inimmunocompromised hosts. Considering that all enteric viruses encounter the intestinal microbiota as theytraverse the mammalian gastrointestinal tract, it is imperative to consider how virus-bacteria interactions mayimpact the outcome of viral infections. Indeed, over the past seven years it has become well-established thatcommensal bacteria profoundly regulate enteric virus infections. The focus of this application will be the influenceof the intestinal microbiota on noroviruses, using murine norovirus as a model system. We have recentlydiscovered that commensal bacteria suppress norovirus infection of the proximal region of the gastrointestinaltract, and that this inhibition is entirely dependent on type III interferon signaling. Furthermore, we can rescueinhibition in bacteria-depleted mice by supplementing their chow with a single bile acid. These data lead to ourworking model that bacterially metabolized bile acids prime type III interferon induction in the proximal gut,thereby inhibiting norovirus infection. The main objective of this proposal is to delineate the underlyingmechanism for bacterial suppression of norovirus infection in the proximal gut. To this end, we will test thespecific hypothesis that primary bile acids suppress murine norovirus infection of the proximal gut; determinewhether primary bile acids prime type III interferon induction in vivo; and uncover the molecular mechanism bywhich primary bile acids prime type III interferon production. Our findings could inform development of novelinterventions based on prebiotics or applied metabolomics.