The interplay between early-life enteric virus infection and the development of oral tolerance

PROJECT SUMMARY Loss of mucosal tolerance is a major hallmark of digestive diseases, including inflammatory bowel disease and celiac disease. Mucosal tolerance to dietary antigens develops during early childhood, a time period that coincides with frequent enteric infections caused by viruses. One highly prevalent cause of viral diarrhea is astrovirus, which infects the vast majority of children by the age of ten. Although there is recent precedent for enteric viruses triggering a loss of tolerance to dietary antigens, we lack a complete understanding of the underlying molecular mechanisms. There are currently two main models for how enteric viruses trigger a break in tolerance– the first is through viral molecular mimicry of a dietary antigen and the second involves bystander activation of immune cells, both of which lead to inappropriate inflammation that can disrupt tolerogenic responses. In this proposal we aim to evaluate a third model that centers around the role of goblet cell-associated antigen passages (GAPs), which have been shown to be the primary pathway for establishing tolerance in the gut. Using the murine model for astrovirus, this proposal will examine how this goblet cell-tropic virus impacts the ability of GAPs to mediate tolerance to the dietary antigen, ovalbumin. In Aim 1, we will use T cell conversion assays and robust measurements to determine whether astrovirus infection leads to a loss of tolerance. We will also pioneer the use of spatial transcriptomics to determine how astrovirus infection alters the cross-talk between infected GAP-forming goblet cells and antigen presenting cells in the lamina propria. In Aim 2, we will test whether GAPs are co-opted by astrovirus to establish infection or aid immune evasion. Completion of these proposed aims will provide the first mechanistic insights to the role of GAPs during enteric virus infection and the consequences of infection on the ability of goblet cells to mediate tolerance. Together these studies will define an entirely new facet of astrovirus pathogenesis and initiate new lines of investigation into how enteric viruses contribute to the risk of digestive disease.