BioProject

Biliary atresia (BA) is the leading indication for pediatric liver transplantation. More...

Biliary atresia (BA) is the leading indication for pediatric liver transplantation. Rhesus rotavirus (RRV) induced murine BA develops an obstructive cholangiopathy that mirrors the human disease. We have previously demonstrated the "SRL" motif on RRV's VP4 protein binds to heat shock cognate 70 protein (Hsc70) facilitating entry into cholangiocytes. In this study, we analyzed how binding to Hsc70 affects viral endocytosis, intracellular trafficking, and uniquely activates the signaling pathway that induces murine BA. Inhibition of clathrin- and dynamin-mediated endocytosis in cholangiocytes following infection demonstrated blocking dynamin decreased the infectivity of RRV whereas clathrin inhibition had no eaffect. Blocking early endosome trafficking resulted in decreased viral titers of RRV while late endosome inhibition had no effect. Following infection, p-NF-?B levels and TLR3 expression increased in cholangiocytes, leading to increased release of CXCL9 and CXCL10. Infected mice knocked out for TLR3 had decreased levels of CXLC9 and CXCL10, resulting in reduced NK cell numbers. Human BA patients experienced an increase in CXCL10 levels, suggesting this as a possible pathway leading to biliary obstruction. Viruses that utilize Hsc70 for cell entry exploit a chlathrin-independent pathway and traffic to the early recycling endosome uniquely activating NF-kB through TLR3, releasing leading to the release of CXCL9 and CXCL10, and inducing NK cell recruitment. These results define how the "SRL" peptide found on RRV's VP4 protein modulates viral trafficking, inducing the host response leading to bile duct obstruction. Overall design: 3 infected and 3 non-infected (control) samples of cholangiocytes laser captured from 7 day old mouse bile ducts *** Submitters state that the complete processed/normalized data has been lost and thus only the reduced data set (of 633 data rows) after filtering for differential expression and fold-change is provided (as described in the sample data processing field)*** Less...