title: Myeloid differentiation factor-88 plays a crucial role in the pathogenesis of Coxsackievirus B3-induced myocarditis and influences type I interferon production.
abstract: BACKGROUND
  Myeloid differentiation factor (MyD)-88 is a key adaptor protein that plays a major role in the innate immune pathway. How MyD88 may regulate host response in inflammatory heart disease is unknown.
  
  
  RESULTS
  We found that the cardiac protein level of MyD88 was significantly increased in the hearts of wild-type mice after exposure to Coxsackievirus B3 (CVB3). MyD88(-/-) mice showed a dramatic higher survival rate (86%) in contrast to the low survival (35%) in the MyD88(+/+) mice after CVB3 infection (P<0.0001). Pathological examination showed a significant decrease of cardiac and pancreatic inflammation in the MyD88(-/-) mice. Viral concentrations in the hearts were significantly decreased in the MyD88(-/-) mice. Cardiac mRNA levels for interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and IL-18 were significantly decreased in the MyD88(-/-) mice. Similarly, serum levels of T-helper 1 cytokines were significantly decreased in the MyD88(-/-) mice. In contrast, cardiac protein levels of the activated interferon regulatory factor (IRF)-3 and IFN-beta were significantly increased in the MyD88(-/-) mice but not other usual upstream signals to IRF-3. The cardiac expression of coxsackie-adenoviral receptor and p56(lck) were also significantly decreased.
  
  
  CONCLUSIONS
  MyD88 appears to be a key contributor to cardiac inflammation, mediating cytokine production and T-helper-1/2 cytokine balance, increasing coxsackie-adenoviral receptor and p56(lck) expression and viral titers after CVB3 exposure. Absence of MyD88 confers host protection possibly through novel direct activation of IRF-3 and IFN-beta.
authors.affiliation: Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Division of Cardiology, University Health Network, Toronto, Canada.
authors.forename: Koichi
authors.initials: K
authors.lastname: Fuse
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.forename: Youan
authors.initials: Y
authors.lastname: Liu
authors.forename: Patrick
authors.initials: P
authors.lastname: Gudgeon
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
authors.forename: Manyin
authors.initials: M
authors.lastname: Chen
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Yeh
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017931:DNA Primers; D004195:Disease Models, Animal; D029822:Enterovirus B, Human; D004769:Enterovirus Infections / Q000150:complications* / Q000276:immunology; D006367:HeLa Cells; D006321:Heart / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D007370:Interferon Type I / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D009205:Myocarditis / Q000276:immunology / Q000503:physiopathology / Q000821:virology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D007370:Interferon Type I; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88