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      Processing of Genome 5′ Termini as a Strategy of Negative-Strand RNA Viruses to Avoid RIG-I-Dependent Interferon Induction

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          Abstract

          Innate immunity is critically dependent on the rapid production of interferon in response to intruding viruses. The intracellular pathogen recognition receptors RIG-I and MDA5 are essential for interferon induction by viral RNAs containing 5′ triphosphates or double-stranded structures, respectively. Viruses with a negative-stranded RNA genome are an important group of pathogens causing emerging and re-emerging diseases. We investigated the ability of genomic RNAs from substantial representatives of this virus group to induce interferon via RIG-I or MDA5. RNAs isolated from particles of Ebola virus, Nipah virus, Lassa virus, and Rift Valley fever virus strongly activated the interferon-beta promoter. Knockdown experiments demonstrated that interferon induction depended on RIG-I, but not MDA5, and phosphatase treatment revealed a requirement for the RNA 5′ triphosphate group. In contrast, genomic RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus did not trigger interferon induction. Sensitivity of these RNAs to a 5′ monophosphate-specific exonuclease indicates that the RIG-I-activating 5′ triphosphate group was removed post-transcriptionally by a viral function. Consequently, RIG-I is unable to bind the RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus. These results establish RIG-I as a major intracellular recognition receptor for the genome of most negative-strand RNA viruses and define the cleavage of triphosphates at the RNA 5′ end as a strategy of viruses to evade the innate immune response.

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          Most cited references40

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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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            Crimean-Congo haemorrhagic fever

            Summary Crimean-Congo haemorrhagic fever (CCHF) is an often fatal viral infection described in about 30 countries, and it has the most extensive geographic distribution of the medically important tickborne viral diseases, closely approximating the known global distribution of Hyalomma spp ticks. Human beings become infected through tick bites, by crushing infected ticks, after contact with a patient with CCHF during the acute phase of infection, or by contact with blood or tissues from viraemic livestock. Clinical features commonly show a dramatic progression characterised by haemorrhage, myalgia, and fever. The levels of liver enzymes, creatinine phosphokinase, and lactate dehydrogenase are raised, and bleeding markers are prolonged. Infection of the endothelium has a major pathogenic role. Besides direct infection of the endothelium, indirect damage by viral factors or virus-mediated host-derived soluble factors that cause endothelial activations and dysfunction are thought to occur. In diagnosis, enzyme-linked immunoassay and real-time reverse transcriptase PCR are used. Early diagnosis is critical for patient therapy and prevention of potential nosocomial infections. Supportive therapy is the most essential part of case management. Recent studies suggest that ribavirin is effective against CCHF, although definitive studies are not available. Health-care workers have a serious risk of infection, particularly during care of patients with haemorrhages from the nose, mouth, gums, vagina, and injection sites. Simple barrier precautions have been reported to be effective.
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              The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter.

              Most paramyxoviruses circumvent the IFN response by blocking IFN signaling and limiting the production of IFN by virus-infected cells. Here we report that the highly conserved cysteine-rich C-terminal domain of the V proteins of a wide variety of paramyxoviruses binds melanoma differentiation-associated gene 5 (mda-5) product. mda-5 is an IFN-inducible host cell DExD/H box helicase that contains a caspase recruitment domain at its N terminus. Overexpression of mda-5 stimulated the basal activity of the IFN-beta promoter in reporter gene assays and significantly enhanced the activation of the IFN-beta promoter by intracellular dsRNA. Both these activities were repressed by coexpression of the V proteins of simian virus 5, human parainfluenza virus 2, mumps virus, Sendai virus, and Hendra virus. Similar results to the reporter assays were obtained by measuring IFN production. Inhibition of mda-5 by RNA interference or by dominant interfering forms of mda-5 significantly inhibited the activation of the IFN-beta promoter by dsRNA. It thus appears that mda-5 plays a central role in an intracellular signal transduction pathway that can lead to the activation of the IFN-beta promoter, and that the V proteins of paramyxoviruses interact with mda-5 to block its activity.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2008
                30 April 2008
                : 3
                : 4
                : e2032
                Affiliations
                [1 ]Department of Virology, University of Freiburg, Freiburg, Germany
                [2 ]Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
                [3 ]Centre for Microbiological Preparedness, Swedish Institute for Infectious Disease Control, Solna, Sweden
                [4 ]Department of Virology, University of Marburg, Marburg, Germany
                [5 ]Immunobiology Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom
                Institut Pasteur Korea, Republic of Korea
                Author notes

                Conceived and designed the experiments: FW VW US MH AM IA JK AM AP. Performed the experiments: VW EM MH PZ IA JK AM MS. Analyzed the data: FW EM US MH AM PZ IA JK AM MS AP. Contributed reagents/materials/analysis tools: EM US AM IA JK AM MS. Wrote the paper: FW AP.

                Article
                07-PONE-RA-02860R1
                10.1371/journal.pone.0002032
                2323571
                18446221
                a09696f5-aa74-4fb5-ade1-23b3f62f73ca
                Habjan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 26 November 2007
                : 16 March 2008
                Page count
                Pages: 8
                Categories
                Research Article
                Virology
                Immunology/Immunomodulation
                Immunology/Innate Immunity
                Virology/Effects of Virus Infection on Host Gene Expression
                Virology/Emerging Viral Diseases
                Virology/Host Antiviral Responses
                Virology/Immune Evasion
                Virology/Persistence and Latency
                Infectious Diseases/Viral Infections

                Uncategorized
                Uncategorized

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