DESCRIPTION (provided by applicant): Astroviruses are a leading cause of viral diarrhea in young children and can be associated with chronic diarrhea and even systemic infection in immunocompromised children. Vaccines and antiviral therapies for astrovirus infection are unavailable. In spite of their medical importance, the mechanism of astrovirus-induced disease is unknown. Recently, the laboratory of my collaborator, Dr. Stacey Schultz-Cherry, demonstrated for the first time that the astrovirus capsid protein alone induced diarrhea in an animal model suggesting that it functions as a novel viral enterotoxin (manuscript in preparation). In vitro and in vivo studies showed that the capsid protein induced diarrhea by increasing the permeability of intestinal epithelial cells by reorganizing the actin cytoskeleton and opening the cellular tight junctions. A fundamental gap in our knowledge is the structure of this unique viral enterotoxin. This information will not only lead to targeted antiviral approaches but may aid in the identification of other structurally similar proteins with toxin-like properties The goals of my research are to determine the structures and mechanism of disease of the astrovirus capsid protein. Further, I will identify the toxigenic domain and determine the structural basis for astrovirus antigenicity and species specificity. I will combine my expertise i structural biology and Dr. Schultz-Cherry's expertise with astrovirus biology to take a coordinated and hypothesis-driven approach to investigate the molecular mechanisms of astrovirus entry and pathogenesis by the capsid protein. We are uniquely suited to undertake these studies given our combined expertise in structural biology, biochemistry, cell biology, and virology leading to an interdisciplinary research program that will reveal the mechanism of astrovirus entry and pathogenesis. Furthermore, this work will be the basis for translational research in vaccine design, antiviral drug design, and development of astrovirus as a nanoparticle drug delivery vehicle.

PUBLIC)HEALTH)RELEVANCE)STATEMENT) ) Astroviruses) are) a) leading) cause) of) viral) diarrhea) in) young) children) and) a) cause) of) chronic) diarrhea) in) immunocompromised)patients.)These)studies)will)demonstrate)for)the)first)time)the)mechanism)of)astrovirus) entry)into)host)cells)and)mechanism)of)astrovirus)disease.))