HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900867v1 183/10/6545    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by DeWitte-Orr, S. J. Articles by Mossman, K. L. PubMed PubMed Citation Articles by DeWitte-Orr, S. J. Articles by Mossman, K. L.

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,^* Mehul S. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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

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

³ Abbreviations used in this paper: RIG-I, retinoic acid-inducible gene I; IPS-1, IFN-β promoter stimulator 1; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; MDA-5, melanoma differentiation-associated gene 5; MEF, mouse embryo fibroblast; NLR, nucleotide oligomerization domain-like receptor; poly(I:C), polyinosinic:polycytidylic acid; PKR, protein kinase regulated by RNA; TRIF, Toll/IL-1 receptor domain-containing adaptor inducing IFN-β; VSV, vesicular stomatitis virus; VSVgfp, VSV expressing GFP; HSV-1gfp, HSV-1 expressing GFP; WNv, West Nile virus; WT, wild type; MOI, multiplicity of infection; C_t, threshold cycle.

⁴ The online version of this article contains supplemental material.