The Role of Norovirus Interactions with the Epithelial Barrier in Acute Gastroenteritis

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Project Summary/Abstract Norovirus is the leading cause of severe childhood diarrhea around the world and a major cause of acute gastroenteritis in all age groups. There are no currently approved vaccines or targeted therapeutics for norovirus infection and very little is known about the pathogenic mechanisms underlying gastroenteritis symptoms. To gain further understanding of this important virus, murine norovirus has been used as a model system for many years and has led to significant advances in understanding norovirus biology. However, the absence of symptoms in immunocompetent adult mice infected with murine norovirus limits the applicability of this model to delineation of viral mechanisms of disease. We recently discovered that genetically wild-type neonatal mice develop acute, self-resolving diarrhea when infected with murine norovirus, a disease course that mirrors human norovirus infection. This novel small animal model of norovirus disease represents a major advance in the norovirus field since it will enable a complete characterization of viral disease mechanisms and ultimately serve as a platform to test the efficacy of antiviral compounds in vivo. Using this model, we have observed that murine norovirus infects subepithelial immune cells in the intestine but not intestinal epithelial cells. The mechanisms by which murine norovirus transcytoses the epithelial barrier to reach its immune cell targets during symptomatic infection is unknown and is the focus on Specific Aim 1 of my proposal. Specifically, I will test the hypothesis that murine norovirus uses two well-established routes for macromolecular transport across the intestinal epithelium, microfold cells and CX3CR1+ antigen presenting cells that express transepithelial dendrites. Although we did not observe viral replication in intestinal epithelial cells, there was abundant virus in these cells at the peak of diarrhea. This finding was surprising given that these cells do not express the virus receptor, nor do they support viral replication. In Specific Aim 2 of my proposal, I will test the hypothesis that progeny virus complexed with bile acids are endocytosed by intestinal epithelial cells via engagement of the apical sodium-dependent bile acid transporter. Overall, my research focuses on understanding norovirus interactions with the intestinal epithelium because these are undoubtedly key to the induction of diarrhea.