Genetic basis of virus induced Biliary Atresia

Project Summary/Abstract Biliary atresia is the most common cause of pediatric end stage liver disease and the number one indication for pediatric liver transplantation. The presence of pathogenic viruses in the liver of afflicted children led to perinatal viral infection as a proposed etiology for biliary atresia as this infection triggers an immune mediated destruction of the biliary epithelium leading to liver fibrosis and ultimately, cirrhosis. The murine model of biliary atresia supports a viral pathogenesis as newborn mice infected with Rhesus rotavirus (RRV) develop portal inflammation extrahepatic bile duct obstruction; however, it is accompanied by high mortality rates precluding the ability to study hepatic fibrosis. We have developed two novel modified virus strains, TR(VP2, VP4) and RRVVP4-K187R, which induce biliary obstruction accompanied by high rates of hepatic fibrosis. We have demonstrated infection with these strains causes bile duct obstruction and hepatic fibrosis that mirrors the human phenotype better than conventional models, including carbon tetrachloride and bile duct ligation. These strains allow us to mechanistically interrogate the post-obstructive fibrotic pathway, a critical next step in the understanding of BA pathogenesis. We will use these strains to determine how infection of cholangiocytes alters the innate immune response leading to the recruitment and activation of monocytes/macrophages. We will also ascertain these modified rotavirus strains’ ability to infect and activate hepatic stellate cells inducing liver fibrosis. These complementary approaches will generate new insight into virus-induced biliary atresia and liver fibrosis.