title: Rhesus rotavirus VP4 sequence-specific activation of mononuclear cells is associated with cholangiopathy in murine biliary atresia.
abstract: Biliary atresia (BA), a neonatal obstructive cholangiopathy, remains the most common indication for pediatric liver transplantation in the United States. In the murine model of BA, Rhesus rotavirus (RRV) VP4 surface protein determines biliary duct tropism. In this study, we investigated how VP4 governs induction of murine BA. Newborn mice were injected with 16 strains of rotavirus and observed for clinical symptoms of BA and mortality. Cholangiograms were performed to confirm bile duct obstruction. Livers and bile ducts were harvested 7 days postinfection for virus titers and histology. Flow cytometry assessed mononuclear cell activation in harvested cell populations from the liver. Cytotoxic NK cell activity was determined by the ability of NK cells to kill noninfected cholangiocytes. Of the 16 strains investigated, the 6 with the highest homology to the RRV VP4 (>87%) were capable of infecting bile ducts in vivo. Although the strain Ro1845 replicated to a titer similar to RRV in vivo, it caused no symptoms or mortality. A Ro1845 reassortant containing the RRV VP4 induced all BA symptoms, with a mortality rate of 89%. Flow cytometry revealed that NK cell activation was significantly increased in the disease-inducing strains and these NK cells demonstrated a significantly higher percentage of cytotoxicity against noninfected cholangiocytes. Rotavirus strains with >87% homology to RRV's VP4 were capable of infecting murine bile ducts in vivo. Development of murine BA was mediated by RRV VP4-specific activation of mononuclear cells, independent of viral titers.
authors.affiliation: Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Ashley
authors.initials: A
authors.lastname: Walther
authors.affiliation: Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Mohanty
authors.affiliation: Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Bryan
authors.initials: B
authors.lastname: Donnelly
authors.affiliation: Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Abigail
authors.initials: A
authors.lastname: Coots
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Celine S
authors.initials: CS
authors.lastname: Lages
authors.affiliation: Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Inna
authors.initials: I
authors.lastname: Lobeck
authors.affiliation: Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Phylicia
authors.initials: P
authors.lastname: Dupree
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Meller
authors.affiliation: Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and.
authors.forename: Monica
authors.initials: M
authors.lastname: McNeal
authors.affiliation: Tulane National Primate Research Center and Tulane University School of Medicine, Covington, Louisiana.
authors.forename: Karol
authors.initials: K
authors.lastname: Sestak
authors.affiliation: Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; greg.tiao@cchmc.org.
authors.forename: Greg
authors.initials: G
authors.lastname: Tiao
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000821:virology; D017734:Bile Ducts, Extrahepatic / Q000473:pathology; D001656:Biliary Atresia / Q000473:pathology*; D036022:Capsid Proteins / Q000235:genetics*; D002779:Cholestasis / Q000473:pathology*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D008099:Liver / Q000473:pathology; D008262:Macrophage Activation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010802:Phylogeny; D012401:Rotavirus / Q000235:genetics*; D012400:Rotavirus Infections / Q000401:mortality / Q000473:pathology*; D010948:Viral Plaque Assay; D014779:Virus Replication
chemical_list: D036022:Capsid Proteins; C060339:VP4 protein, Rotavirus; D007371:Interferon-gamma
keywords: RRV; VP4; cholangiocytes; natural killer cells; rotavirus