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.
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.
|Lobeck, Inna; Donnelly, Bryan; Dupree, Phylicia et al. (2016) Rhesus rotavirus VP6 regulates ERK-dependent calcium influx in cholangiocytes. Virology 499:185-195|
|Mohanty, Sujit K; Donnelly, Bryan; Lobeck, Inna et al. (2016) The SRL peptide of Rhesus Rotavirus VP4 protein governs cholangiocyte infection and the murine model of biliary atresia. Hepatology :|
|Walther, Ashley; Mohanty, Sujit K; Donnelly, Bryan et al. (2015) Rhesus rotavirus VP4 sequence-specific activation of mononuclear cells is associated with cholangiopathy in murine biliary atresia. Am J Physiol Gastrointest Liver Physiol 309:G466-74|
|Poling, Holly M; Mohanty, Sujit K; Tiao, Greg M et al. (2014) A comprehensive analysis of aquaporin and secretory related gene expression in neonate and adult cholangiocytes. Gene Expr Patterns 15:96-103|
|Mohanty, Sujit K; Donnelly, Bryan; Bondoc, Alexander et al. (2013) Rotavirus replication in the cholangiocyte mediates the temporal dependence of murine biliary atresia. PLoS One 8:e69069|
|Walther, Ashley E; Mohanty, Sujit K; Donnelly, Bryan et al. (2013) Role of myeloid differentiation factor 88 in Rhesus rotavirus-induced biliary atresia. J Surg Res 184:322-9|
|Coots, Abigail; Donnelly, Bryan; Mohanty, Sujit K et al. (2012) Rotavirus infection of human cholangiocytes parallels the murine model of biliary atresia. J Surg Res 177:275-81|
|Bondoc, Alexander J; Taylor, Janice A; Alonso, Maria H et al. (2012) The beneficial impact of revision of Kasai portoenterostomy for biliary atresia: an institutional study. Ann Surg 255:570-6|
|Wang, Wei; Donnelly, Bryan; Bondoc, Alexander et al. (2011) The rhesus rotavirus gene encoding VP4 is a major determinant in the pathogenesis of biliary atresia in newborn mice. J Virol 85:9069-77|
|Superina, Riccardo; Magee, John C; Brandt, Mary L et al. (2011) The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival. Ann Surg 254:577-85|