title: Rotavirus replication in the cholangiocyte mediates the temporal dependence of murine biliary atresia.
abstract: Biliary atresia (BA) is a neonatal disease that results in obliteration of the biliary tree. The murine model of BA, which mirrors the human disease, is based upon infection of newborn mice with rhesus rotavirus (RRV), leading to an obstructive cholangiopathy. The purpose of this study was to characterize the temporal relationship between viral infection and the induction of this model. BALB/c mice were infected with RRV on day of life (DOL) 0, 3, 5, and 7. Groups were characterized as early-infection (infection by DOL 3) or late-infection (infection after DOL 5). Early RRV infection induced symptoms in 95% of pups with a mortality rate of 80%. In contrast, late infection caused symptoms in only 50% of mice, and 100% of pups survived. The clinical findings correlated with histological analysis of extrahepatic biliary trees, cytokine expression, and viral titers. Primary murine cholangiocytes isolated, cultured, and infected with RRV yielded higher titers of infectious virus in those harvested from DOL 2 versus DOL 9 mice. Less interferon alpha and beta was produced in DOL 2 versus DOL 9 RRV infected primary cholangiocytes. Injection of BALB/c interferon alpha/beta receptor knockout (IFN-αβR(-/-)) pups at DOL 7 showed increased symptoms (79%) and mortality (46%) when compared to late infected wild type mice. In conclusion, the degree of injury sustained by relatively immature cholangiocytes due to more robust RRV replication correlated with more severe clinical manifestations of cholangiopathy and higher mortality. Interferon alpha production by cholangiocytes appears to play a regulatory role. These findings confirm a temporal dependence of RRV infection in murine BA and begin to define a pathophysiologic role of the maturing cholangiocyte.
authors.affiliation: Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Mohanty
authors.forename: Bryan
authors.initials: B
authors.lastname: Donnelly
authors.forename: Alexander
authors.initials: A
authors.lastname: Bondoc
authors.forename: Mubeen
authors.initials: M
authors.lastname: Jafri
authors.forename: Ashley
authors.initials: A
authors.lastname: Walther
authors.forename: Abigail
authors.initials: A
authors.lastname: Coots
authors.forename: Monica
authors.initials: M
authors.lastname: McNeal
authors.forename: David
authors.initials: D
authors.lastname: Witte
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Tiao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001652:Bile Ducts / Q000473:pathology* / Q000821:virology*; D001656:Biliary Atresia / Q000209:etiology* / Q000401:mortality; D004195:Disease Models, Animal; D007249:Inflammation / Q000235:genetics; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D051379:Mice; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D012401:Rotavirus / Q000502:physiology*; D012400:Rotavirus Infections / Q000378:metabolism / Q000821:virology*; D013997:Time Factors; D014779:Virus Replication
chemical_list: D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta