Temporal dependence of rotavirus induced model of murine biliary atresia

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Extra-hepatic biliary atresia (EHBA) is a unique disease of the newborn which results in obliteration of the biliary tree. Infection in the newborn period with viruses such as rotavirus, reovirus, and CMV may be a potential cause of EHBA. A murine model of biliary atresia has been established in which infection of newborn mice with rhesus rotavirus (RRV) leads to an obstructive cholangiopathy with histological changes that mirror the human disease. The purpose of the present study was to determine if there was a temporal dependence of viral infection and resulting disease. Methods: Balb/C mice were infected with RRV (1.5 × 106 ffu/pup) via intraperitoneal injection on day of life (DOL) 0, 3, 5, and 7. Clinical findings including jaundice, acholic stools, appearance of fur, bilirubinuria and weight were monitored for 21 days from injection or until death. A subset of mice was sacrificed seven days post infection and their livers were harvested and levels of RRV viral antigen was measured by ELISA. Saline injections served as controls. Statistical analysis consisted of Chi-squared for proportional data and ANOVA follwed by post-hoc t-test for viral antigen. Results: The precentage of mice that demonstrated symptoms, mortality by 21 post injection, and quantity of viral antigen corresponding to the day of injection are summarized in the table attached. No mice injected with saline developed disease. Chi square analysis demonstrated a significant difference (p < 0.05) between infection on DOL 0 or 3 when compared with DOL 5 or 7. ANOVA analysis demonstrated a significant difference (p < 0.05) between viral antigen detected in the livers of mice infected on DOL 0 or 3 when compared with DOL 7. Injecting the maximal dose of virus achievable (3.0 × 108 ffu/pup) at DOL 7 to account for growth did not change mortality or detectable viral antigen. Conclusion: The induction of the murine model of biliary atresia is dependent on the age at which the pups were infected with RRClinical manifestations and mortality rates were the highest in pups infected during the first three days of life. Some clinical symptoms were seen in pups infected after the third day of life, though these resolved and all pups survived. The decrease in mortality correlated with a decrease in detectable levels of viral antigen found within the liver suggesting that either susceptibility to infection or the ability to replicate within the liver changes in older mice. Further studies are necessary to determine why the temporal dependence of the murine model exists. These findings may help explain why biliary atresia is limited to the newborn period in humans.