Long double-stranded RNA induces an antiviral response independent of IFN regulatory factor 3, IFN-beta promoter stimulator 1, and IFN.
Virus infection elicits a robust innate antiviral response dominated by the production of type 1 IFN. In nonprofessional innate immune cells such as fibroblasts, type 1 IFN is rapidly produced following the recognition of viral dsRNA and the subsequent activation of the constitutively expressed transcription factor IFN regulatory factor 3 (IRF3). Although origin, localization, and length are factors in mediating dsRNA recognition and binding by cellular dsRNA-binding proteins, the biological significance of differential dsRNA binding is unclear, since the subsequent signaling pathways converge on IRF3. In this study, we show a dsRNA length-dependent activation of IRFs, IFNs, and IFN-stimulated genes in mouse fibroblasts. The length dependence was exacerbated in fibroblasts deficient in the mitochondria-associated adaptor IFN-beta promoter stimulator 1 and IRF3, suggesting that antiviral gene induction mediated by short and long dsRNA molecules is predominantly IFN-beta promoter stimulator 1 and IRF3 dependent and independent, respectively. Furthermore, we provide evidence of an innate antiviral response in fibroblasts in the absence of both IRF3 and type 1 IFN induction. Even with these key modulators missing, a 60-90% inhibition of virus replication was observed following 24-h treatment with short or long dsRNA molecules, respectively. These data provide evidence of a novel antiviral pathway that is dependent on dsRNA length, but independent of the type 1 IFN system.
Department of Pathology & Molecular Medicine, Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Stephanie J
SJ
DeWitte-Orr
Devangi R
DR
Mehta
Susan E
SE
Collins
Mehul S
MS
Suthar
Michael
M
Gale
Karen L
KL
Mossman
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D004266:DNA Virus Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D012327:RNA Virus Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D012330:RNA, Double-Stranded / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014780:Viruses / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D012330:RNA, Double-Stranded; C512612:MAVS protein, mouse