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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091566-03
Application #
8449192
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$340,446
Indirect Cost
$117,932
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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
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
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
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