title: IRF3 polymorphisms induce different innate anti-Theiler's virus immune responses in RAW264.7 macrophages.
abstract: Persistent viral infections can lead to disease such as myocarditis. Theiler's murine encephalomyelitis virus (TMEV) infects macrophages of SJL/J (H-2s) mice establishing persistent infections leading to demyelinating disease. In contrast macrophages from B10.S (H-2s) mice clear TMEV. Activation of the transcription factor IRF3 induces IFNβ, ISG56, and apoptosis for viral clearance, but also inflammatory cytokines, such as IL-23 and IL6, which contribute to disease. Here we identify polymorphisms in the IRF3 of SJL/J versus B10.S mice that are located in DNA binding, nuclear localization, and autoinhibitory domains. SJL-IRF3 expression in RAW264.7 macrophage cells with or without TMEV infection decreased IL-23p19 promoter activity compared with B10S-IRF3. In contrast SJL-IRF3 increased IL-6, ISG56 and IFNβ in response to TMEV. B10S-IRF3 expression augmented apoptotic caspase activation and decreased viral RNA in TMEV-infected macrophages while SJL-IRF3 increased viral replication with less caspase activation. Therefore IRF3 polymorphisms contribute to viral persistence and altered cytokine expression.
authors.affiliation: School of Biological Sciences, University of Nebraska Lincoln, Lincoln, NE 68583-0740, USA.
authors.forename: Tyler C
authors.initials: TC
authors.lastname: Moore
authors.forename: Fahd M
authors.initials: FM
authors.lastname: Al-Salleeh
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Brown
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Petro
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D054884:Host-Pathogen Interactions; D050838:Interferon Regulatory Factor-3 / Q000235:genetics* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D051379:Mice; D011110:Polymorphism, Genetic; D017945:Theilovirus / Q000276:immunology* / Q000472:pathogenicity*
chemical_list: D016207:Cytokines; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse