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      Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid–inducible gene-I and melanoma differentiation–associated gene 5

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          Abstract

          The ribonucleic acid (RNA) helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation–associated gene 5 (MDA5) recognize distinct viral and synthetic RNAs, leading to the production of interferons. Although 5′-triphosphate single-stranded RNA is a RIG-I ligand, the role of RIG-I and MDA5 in double-stranded (ds) RNA recognition remains to be characterized. In this study, we show that the length of dsRNA is important for differential recognition by RIG-I and MDA5. The MDA5 ligand, polyinosinic-polycytidylic acid, was converted to a RIG-I ligand after shortening of the dsRNA length. In addition, viral dsRNAs differentially activated RIG-I and MDA5, depending on their length. Vesicular stomatitis virus infection generated dsRNA, which is responsible for RIG-I–mediated recognition. Collectively, RIG-I detects dsRNAs without a 5′-triphosphate end, and RIG-I and MDA5 selectively recognize short and long dsRNAs, respectively.

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          Most cited references21

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          Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

          Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.
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            Recognition of microorganisms and activation of the immune response.

            The mammalian immune system has innate and adaptive components, which cooperate to protect the host against microbial infections. The innate immune system consists of functionally distinct 'modules' that evolved to provide different forms of protection against pathogens. It senses pathogens through pattern-recognition receptors, which trigger the activation of antimicrobial defences and stimulate the adaptive immune response. The adaptive immune system, in turn, activates innate effector mechanisms in an antigen-specific manner. The connections between the various immune components are not fully understood, but recent progress brings us closer to an integrated view of the immune system and its function in host defence.
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              RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.

              Double-stranded RNA (dsRNA) produced during viral replication is believed to be the critical trigger for activation of antiviral immunity mediated by the RNA helicase enzymes retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We showed that influenza A virus infection does not generate dsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5'-phosphates. This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex with RIG-I in infected cells. These results identify RIG-I as a ssRNA sensor and potential target of viral immune evasion and suggest that its ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.
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                Author and article information

                Journal
                J Exp Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                7 July 2008
                : 205
                : 7
                : 1601-1610
                Affiliations
                [1 ]Laboratory of Host Defense, World Premiere International Immunology Frontier Research Center, [2 ]Research Institute for Microbial Diseases, [3 ]Institute for Scientific and Industrial Research, Osaka University, Suita, Osaka 565-0871, Japan
                [4 ]Department of Pharmacy, Hyogo University of Health Sciences, Cyuo-ku, Kobe, Hyogo 650-8530, Japan
                [5 ]Laboratory of Molecular Genetics, Institute for Virus Research, and [6 ]Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan
                [7 ]Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232
                Author notes

                CORRESPONDENCE Shizuo Akira: sakira@ 123456biken.osaka-u.ac.jp

                Article
                20080091
                10.1084/jem.20080091
                2442638
                18591409
                af362466-269e-4606-b116-9291f19f9059
                © 2008 Kato et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 14 January 2008
                : 4 June 2008
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