Group A Rotaviruses Produce Extrahepatic Biliary Obstruction in Orally Inoculated Newborn Mice

Abstract

Extrahepatic biliary atresia is a devastating disease occurring in 1 in 10,000 to 14,000 infants annually in the United States. We have recently described preliminary data suggesting an association of group C rotavirus with biliary atresia in two infants. However, a group C rotavirus animal model of biliary atresia is not presently available. On the other hand, some strains of the better-characterized and much more common group A rotaviruses produce hepatobiliary disease in infant mice. This disease shares many characteristics of the human infection. The present report describes extrahepatic biliary obstruction in immunocompetent BALB/c infant mice infected with a human or animal strain of group A rotavirus. Two-d-old BALB/c mice orally inoculated with hepatobiliary tropic rotavirus were shown to have active virus replication in the biliary tract and liver as early as 48 h postinoculation. At approximately 7 d postinoculation, between one fourth and one half of infant mice, depending on the virus strain, showed signs of inflammation and swelling in the bile ducts. The obstruction was complete in about one half of symptomatic animals. Although there was no obvious atresia as described in human infants, the obstruction was irreversible about 50% of the time, and the resulting fibrosis and bile ductular proliferation in the liver were strikingly similar to those seen in the liver of the human infant with biliary atresia.

Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia

“…1d). This finding was consistent with the original report of this model by Riepenhoff-Talty et al [12], in which RRV was cleared in neonatal mice between the 1st and 2nd week post infection.…”

“…That study demonstrated that the portal tract inflammation which was unique to BA was composed of a CD4 + Th1 cell predominant process, characterized by an infiltrate of CD4 + and CD8 + T cells and macrophages with local cellular production of IL-2, IFN-γ and TNF-α. In order to better understand the kinetics of the pathologic immune events in BA, we are utilizing the rotavirus-induced murine model of BA [12][13][14][15].…”

“…In the Rhesus group A rotavirus (RRV) murine model of BA, newborn mice are infected with RRV in the first day of life which leads to progressive inflammation and obstruction of the extrahepatic bile duct by 2 weeks of age, closely mimicking the lesion in human BA [12][13][14][15]. Furthermore, in the original description of this model, it was noted that the virus was no longer detectable in the liver 2 weeks after infection, yet the inflammatory process was progressive and the mice died of liver failure by 1 month of age [12].…”

“…Furthermore, in the original description of this model, it was noted that the virus was no longer detectable in the liver 2 weeks after infection, yet the inflammatory process was progressive and the mice died of liver failure by 1 month of age [12]. Thus, despite the implication that immune-mediated injury is a key pathogenic component, the triggers and nature of this inflammatory response have not been clearly defined.…”

Th-17 cells infiltrate the liver in human biliary atresia and are related to surgical outcome

“…A wide range of enteric viruses has been implicated including REOvirus and cytomegalovirus (CMV) but clinical evidence of exposure and its relevance is conflicting whether derived from serological studies (7,8,9) or more directly from PCR studies on liver biopsies to detect viral nucleic acids (10).…”