Effect of Rotavirus Strain on the Murine Model of Biliary Atresia

Abstract

Biliary atresia is a devastating disorder of the newborn in which afflicted infants develop inflammation and fibrosis of the extrahepatic biliary tract, resulting in cirrhosis and end-stage liver disease. Infection with a virus is thought to be a contributing factor in the etiology of biliary atresia. In the murine model of biliary atresia, perinatal exposure to rhesus rotavirus (RRV) results in biliary epithelial cell infection causing bile duct obstruction. The purpose of this study was to determine if tropism for the biliary epithelial cell was unique to RRV. Newborn mice underwent intraperitoneal injection with five strains of rotavirus: RRV (simian), SA11-FM (simian/bovine), SA11-SM (simian), EDIM (murine), and Wa (human). RRV and SA11-FM caused clinical manifestations of bile duct obstruction and high mortality. SA11-SM caused clinical signs of hepatobiliary injury but the mortality was markedly reduced. EDIM and Wa caused no sign of hepatobiliary disease. The systemic and temporal distribution of viral protein and live virus varied according to the injected strain. Immunohistochemistry revealed that RRV and SA11-FM targeted the biliary epithelial cells. In contrast, SA11-SM was found in the liver but in not in the biliary epithelium. These results indicate that strain-specific characteristics dictate tropism for cells of hepatobiliary origin which in turn impact the ability to induce the murine model of biliary atresia.

Neonatal NK cells target the mouse duct epithelium via Nkg2d and drive tissue-specific injury in experimental biliary atresia

“…Although previous studies reported a tropism of RRV to cholangiocytes and the ability of RRV to replicate and lyse cholangiocytes in vitro (8,29), our data show that cholangiocyte infection alone is not sufficient to induce biliary atresia. Instead, it appears that infected cells are secondarily targeted by activated NK cells, which use the Nkg2d receptor to establish contact, injure cholangiocytes, and initiate a break in epithelial integrity.…”

“…Consistent with this function, the number of NK cells in the ducts substantially increased upon RRV challenge in the immediate postnatal period. This response aims at clearing infected cells, as supported by the ability of RRV-primed NK cells to promote lysis of cholangiocytes, one of the main cellular targets of neonatal RRV infection (8,29). In doing so, NK cells disrupt the duct mucosa, produce proinflammatory signals, and promote an extension of the injury that leads to duct obstruction.…”

“…Saline, NK depleted: n = 10; RRV, NK depleted: n = 25; RRV, control serum: n = 16; *P < 0.001. study tissues of affected infants. Alternatively, we favor the possibility that the difficulty in isolating an infectious agent is due to the ability of the neonatal immune system to effectively clear the infection (8,29). It remains to be determined whether the atresia phenotype results from a hyperimmune response by NK or CD8 + cells that may be linked to the immaturity of counterregulatory circuits in the neonatal period.…”

Cholangiocyte expression of α2β1-integrin confers susceptibility to rotavirus-induced experimental biliary atresia

“…Recently, it has been shown that in the murine model of biliary atresia, RRV targeted the biliary epithelial cell (cholangiocyte) for infection (1,31). To determine the basis for cholangiocyte susceptibility to RRV, an in vitro model of RRV infection of the two dominant cell types found within the liver (cholangiocytes and hepatocytes) was established.…”

Role of Rotavirus Enterotoxin NSP4 in the Inflammatory Response in Murine Macrophage RAW 264.7 Cells

“…It was also noted that NSP4 elicits systemic and intestinal antibody responses in gnotobiotic pig and rabbit models (17,21) and induces diarrhea in newborn mice (17,22). Recently, biliary atresia (BA), a fibroinflammatory pediatric liver disease that is the primary indication for liver transplantation in children, has been demonstrated to occur in rotavirus infection (3,23,24). Osteopontin (OPN), a glycoprotein with inflammatory and fibrogenic activity, may play a pathogenic role in BA (25).…”