Astrovirus modulation of gut immunity via goblet cells

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PROJECT SUMMARY Astroviruses, positive-sense single-stranded RNA enteric viruses, are a leading cause of diarrhea worldwide. In comparison to other viruses that cause diarrhea astroviruses do not cause overt pathology, cell death, inflammation, or immune cell infiltration. We now believe this is related to their unique ability to infect small intestinal goblet cells, specialized epithelial cells that produce the mucus barrier and play a central role in the innate defenses of the gastrointestinal tract. Mucus not only protects against potential pathogens but also modulates interactions of the epithelial layer with commensal bacteria to promote a symbiotic environment that prevents self-digestion. Goblet cell dysfunction can trigger inflammation, and loss of the mucus barrier can impair host defenses against gastrointestinal diseases. Although the molecular interactions between goblet cells and bacteria have been characterized, few studies have focused on enteric virus interactions and their role in gut health. To fill this gap in knowledge, I propose using the murine model for astrovirus to study their unique tropism and the consequences of infection for gut health. My central hypothesis is that astrovirus hijacks the secretory pathway of goblet cells and this alters goblet cell immune and homeostatic functions. To test this hypothesis, in Aim 1 I will identify the molecular mechanisms by which astroviruses use secretory goblet cells for replication and in Aim 2 I will determine how infection alters the ability of goblet cells to form the mucus barrier and facilitate mucosal immune responses via the delivery of luminal antigens to the lamina propria. These data will reveal an entirely new facet of host-pathogen interactions that will be critical to our understanding of gut immunity and homeostasis in the context of viral infection.