The Molecular Determinants of Virus Induced Biliary Atresia

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DESCRIPTION (provided by applicant): Biliary atresia is the most common cause of pediatric end stage liver disease and the number one indication for pediatric liver transplantation. Because pathogenic viruses have been found in the liver of afflicted children, a proposed etiology for biliary atresia is a perinatal viral infection triggering immune mediated destruction of the biliary epithelium. The murine model of biliary atresia supports a viral pathogenesis as newborn mice infected with rhesus rotavirus (RRV) develop inflammation within the portal tract and extra- hepatic bile duct obstruction. RRV targets the cholangiocyte for infection and in addition to direct cholangiocyte injury also induces T-cell mediated injury to the biliary epithelium. Rotavirus is a dsRNA virus comprised of 11 gene segments. We hypothesized that specific rotavirus genes govern the ability to infect the cholangiocyte and induce immune mediated injury. To test this hypothesis, we generated a complete set of single gene reassortants derived from the parental strains RRV and TUCH. These reassortants give us a unique set of tools to determine how specific rotavirus genes contribute to the pathogenesis. In preliminary studies, we found that RRV segments 3, 4, 6, 8, 9 and 11 are genes of interest. Given the robust nature of the observations made with gene segment 4, we focused on this gene. We will use in vitro models of RRV - cholangiocyte infection and T-cell activation to determine the mechanisms by which gene segment 4 contributes to disease pathogenesis. We will also use reverse genetics to generate mutate gene segment 4 infectious virus to determine the basis in the more complex environment of the intact host. These complimentary approaches will generate new insight in viral induced biliary atresia. PUBLIC HEALTH RELEVANCE: Biliary atresia is the most common cause of pediatric end stage liver disease and the number one indication for pediatric liver transplantation. Because pathogenic viruses have been found in the liver of afflicted children, a proposed etiology for biliary atresia is a perinatal viral infection triggering immune mediated destruction of the biliary epithelium resulting in biliary obstruction. Our goal, using a unique set of rotavirus gene knockouts, is to determine the molecular basis for this process. In so doing develop we hope to develop new treatment strategies to alter the course of this challenging disease. This project is in complete accord with the NIH mission to reduce illness and disability.