title: West Nile virus noncoding subgenomic RNA contributes to viral evasion of the type I interferon-mediated antiviral response.
abstract: We previously showed that a noncoding subgenomic flavivirus RNA (sfRNA) is required for viral pathogenicity, as a mutant West Nile virus (WNV) deficient in sfRNA production replicated poorly in wild-type mice. To investigate the possible immunomodulatory or immune evasive functions of sfRNA, we utilized mice and cells deficient in elements of the type I interferon (IFN) response. Replication of the sfRNA mutant WNV was rescued in mice and cells lacking interferon regulatory factor 3 (IRF-3) and IRF-7 and in mice lacking the type I alpha/beta interferon receptor (IFNAR), suggesting a contribution for sfRNA in overcoming the antiviral response mediated by type I IFN. This was confirmed by demonstrating rescue of mutant virus replication in the presence of IFNAR neutralizing antibodies, greater sensitivity of mutant virus replication to IFN-α pretreatment, partial rescue of its infectivity in cells deficient in RNase L, and direct effects of transfected sfRNA on rescuing replication of unrelated Semliki Forest virus in cells pretreated with IFN-α. The results define a novel function of sfRNA in flavivirus pathogenesis via its contribution to viral evasion of the type I interferon response.
authors.affiliation: Australian Infectious Disease Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schuessler
authors.forename: Anneke
authors.initials: A
authors.lastname: Funk
authors.forename: Helen M
authors.initials: HM
authors.lastname: Lazear
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Cooper
authors.forename: Shessy
authors.initials: S
authors.lastname: Torres
authors.forename: Stephane
authors.initials: S
authors.lastname: Daffis
authors.forename: Babal Kant
authors.initials: BK
authors.lastname: Jha
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Paul
authors.initials: P
authors.lastname: Hertzog
authors.forename: Robert
authors.initials: R
authors.lastname: Silverman
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: David J
authors.initials: DJ
authors.lastname: Barton
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Khromykh
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D057131:Immune Evasion; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022661:RNA, Untranslated / Q000235:genetics / Q000276:immunology*; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology*; D014774:Virulence; D014901:West Nile Fever / Q000276:immunology* / Q000821:virology; D014902:West Nile virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity
chemical_list: D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D022661:RNA, Untranslated; D012367:RNA, Viral