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Long Double-Stranded RNA Induces an Antiviral Response Independent of IFN Regulatory Factor 3, IFN-β Promoter Stimulator 1, and IFN¹

Stephanie J. DeWitte-Orr,^* Devangi R. Mehta,^* Susan E. Collins,^* MehulS. Suthar, Michael Gale, Jr., and Karen L. Mossman^2*

*Department of Pathology & Molecular Medicine, Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada; and Department of Immunology, School of Medicine, University of Washington, Seattle, WA 98195

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-β promoter stimulator 1 and IRF3, suggesting that antiviral gene induction mediated by short and long dsRNA molecules is predominantly IFN-β 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.

² Address correspondence and reprint requests to Dr. Karen L. Mossman, Department of Pathology & Molecular Medicine, McMaster University, 1200 Main Street West, MDCL 5026, Hamilton, Ontario, Canada, L8N 3Z5. E-mail address: mossk{at}mcmaster.ca

¹ This study was funded by the National Institutes of Health and the Canadian Institute for Health Research (MOP-57669).