Rotavirus interaction with gut intraepithelial lymphocytes

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Project Summary Small bowel intestinal epithelial cells (IECs) are the first line of defense against human enteric viruses, the most common and leading causes of diarrhea and death in infants and young children. How IECs communicate with intraepithelial lymphocytes (IELs) in the small intestine and orchestrate antiviral responses is heavily understudied. Our overall objectives are to better define the host immune signaling pathways in the gastrointestinal tract during infections and to use that information to develop therapeutic interventions to alleviate diarrhea and sequelae. Our preliminary results contrasted our expectation and demonstrated that the numbers of two IEL subsets are significantly reduced during early rotavirus infection in vivo. We also found that rotavirus infection alters the expression of several pro-inflammatory chemokines in infected human and mouse IECs. Based on these data and prior publications, we hypothesize that the IELs are important mediators of host defense against rotavirus infection and that rotavirus-encoded factors antagonize the antiviral activity of IELs in the host small intestine via inhibition of chemokine expression. Testing these hypotheses is currently hampered by the lack of suitable model systems. Accordingly, we have developed a highly tractable murine rotavirus reverse genetics method, a pathologically relevant neonatal mouse model, and several innovative primary human and murine small bowel organoid culturing systems, which will provide an unprecedented resolution of understanding of IEC-IEL crosstalk in the context of enteric viral infections. In Aim 1, we will define a functional antiviral role of IELs in rotavirus infection in vivo using immunological approaches and gene knockout mice. In Aim 2, we will identify the potential mechanism by which viral factors dampen chemokine expression in infected IECs. Collectively, we expect these studies to establish a new paradigm of mucosal antiviral immunity, especially early in life when most enteric infections occur. We also expect to identify novel rotavirus immune evasion strategies, which will inform new strategies to develop host- based broad-spectrum antiviral therapeutics and next-generation vaccine candidates.