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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/G16    most recent 00442.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Jafri, M. Articles by Tiao, G. PubMed PubMed Citation Articles by Jafri, M. Articles by Tiao, G.

LIVER AND BILIARY TRACT

Cholangiocyte expression of ₂β₁-integrin confers susceptibility to rotavirus-induced experimental biliary atresia

¹Department of Pediatric and Thoracic Surgery and the ²Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and ³Biogen Idec, Cambridge, Massachusetts

Submitted 27 September 2007 ; accepted in final form 18 April 2008

Inoculation of BALB/c mice with rhesus rotavirus (RRV) in the newborn period results in biliary epithelial cell (cholangiocyte) infection and the murine model of biliary atresia. Rotavirus infection of a cell requires attachment, which is governed in part by cell-surface expression of integrins such as ₂β₁. We hypothesized that cholangiocytes were susceptible to RRV infection because they express ₂β₁. RRV attachment and replication was measured in cell lines derived from cholangiocytes and hepatocytes. Flow cytometry was performed on these cell lines to determine whether ₂β₁ was present. Cholangiocytes were blocked with natural ligands, a monoclonal antibody, or small interfering RNA against the ₂-subunit and were infected with RRV. The extrahepatic biliary tract of newborn mice was screened for the expression of the ₂β₁-integrin. Newborn mice were pretreated with a monoclonal antibody against the ₂-subunit and were inoculated with RRV. RRV attached and replicated significantly better in cholangiocytes than in hepatocytes. Cholangiocytes, but not hepatocytes, expressed ₂β₁ in vitro and in vivo. Blocking assays led to a significant reduction in attachment and yield of virus in RRV-infected cholangiocytes. Pretreatment of newborn pups with an anti-₂ monoclonal antibody reduced the ability of RRV to cause biliary atresia in mice. Cell-surface expression of the ₂β₁-integrin plays a role in the mechanism that confers cholangiocyte susceptibility to RRV infection.

rhesus rotavirus; bile ducts; cholangiopathy