title: Role of myeloid differentiation factor 88 in Rhesus rotavirus-induced biliary atresia.
abstract: BACKGROUND
  Biliary atresia (BA) is a unique neonatal disease resulting from inflammatory and fibrosing obstruction of the extrahepatic biliary tree. Previous studies have demonstrated the critical role of innate immunity and the Th1 response to activated inflammatory cells and overexpressed cytokines in the pathogenesis of BA. Myeloid differentiation factor 88 (MyD88) is a critical adaptor molecule that has been shown to play a crucial role in immunity. We investigated the role of MyD88 in the inflammatory response and development of cholangiopathy in murine BA.
  
  
  METHODS
  MyD88 knockout (MyD88(-/-)) and wild-type (WT) BALB/c pups were injected with Rhesus rotavirus or saline on day 1 of life. The mice were monitored for clinical symptoms of BA, including jaundice, acholic stools, bilirubinuria, and death. The liver and extrahepatic bile ducts were harvested for histologic evaluation and the quantification of viral content, determination of cytokine expression, and detection of inflammatory cells.
  
  
  RESULTS
  Rhesus rotavirus infection produced symptoms in 100% of both MyD88(-/-) and WT pups, with survival of 18% of WT and 0% of MyD88(-/-) mice. Histologic analysis demonstrated bile duct obstruction in both MyD88(-/-) and WT mice. Viral titers obtained 7 d after infection and expression of interferon-γ and tumor necrosis factor-α at day 3, 5, 8, and 12 after infection revealed no significant differences between the WT and MyD88(-/-) mice. Flow cytometry demonstrated similar levels of activated CD8+ T cells and natural killer cells.
  
  
  CONCLUSIONS
  The pathogenesis of murine BA is independent of the MyD88 signaling inflammatory pathway, suggesting alternative mechanisms are crucial in the induction of the model.
authors.affiliation: Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Walther
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Mohanty
authors.forename: Bryan
authors.initials: B
authors.lastname: Donnelly
authors.forename: Abigail
authors.initials: A
authors.lastname: Coots
authors.forename: Monica
authors.initials: M
authors.lastname: McNeal
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Tiao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017734:Bile Ducts, Extrahepatic / Q000473:pathology / Q000821:virology; D001656:Biliary Atresia / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000276:immunology; D008099:Liver / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012401:Rotavirus / Q000276:immunology*; D012400:Rotavirus Infections / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Biliary atresia; Cholangiocytes; Myeloid differentiation factor 88; Rhesus rotavirus; Rotavirus