RIG-I and MDA-5 Detection of Viral RNA-dependent RNA Polymerase Activity Restricts Positive-Strand RNA Virus Replication
| Autor: | Tarmo Mölder, Andres Merits, Aleksei Lulla, Urve Toots, Valeria Lulla, Kaja Kiiver, Age Utt, Andres Männik, Rein Sikut, Andrei Nikonov, Mart Ustav |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
RNA viruses
Interferon-Induced Helicase IFIH1 Mouse viruses Virus Replication Biochemistry DEAD-box RNA Helicases chemistry.chemical_compound Mice Transcription (biology) Viral classification RNA polymerase Nucleic Acids Molecular Cell Biology Receptors Immunologic lcsh:QH301-705.5 Enzyme Classes Viral Immune Evasion Animal Models Non-coding RNA Innate Immunity Enzymes Host-Pathogen Interaction RNA silencing RNA editing Viral Enzymes DEAD Box Protein 58 RNA Viral Viral Clearance Research Article Signal Transduction lcsh:Immunologic diseases. Allergy Immunology RNA-dependent RNA polymerase Biology Microbiology Signaling Pathways Cell Line Viral Proteins Model Organisms Virology Genetics Viral Nucleic Acid Animals Humans Molecular Biology RNA Double-Stranded Alphavirus Infections Host Cells Immunity RNA RNA virus Interferon-beta biochemical phenomena metabolism and nutrition biology.organism_classification RNA-Dependent RNA Polymerase Semliki forest virus Viral Replication lcsh:Biology (General) chemistry Parasitology lcsh:RC581-607 Viral Transmission and Infection |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 9, Iss 9, p e1003610 (2013) |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Type I interferons (IFN) are important for antiviral responses. Melanoma differentiation-associated gene 5 (MDA-5) and retinoic acid-induced gene I (RIG-I) proteins detect cytosolic double-stranded RNA (dsRNA) or 5′-triphosphate (5′-ppp) RNA and mediate IFN production. Cytosolic 5′-ppp RNA and dsRNA are generated during viral RNA replication and transcription by viral RNA replicases [RNA-dependent RNA polymerases (RdRp)]. Here, we show that the Semliki Forest virus (SFV) RNA replicase can induce IFN-β independently of viral RNA replication and transcription. The SFV replicase converts host cell RNA into 5′-ppp dsRNA and induces IFN-β through the RIG-I and MDA-5 pathways. Inactivation of the SFV replicase RdRp activity prevents IFN-β induction. These IFN-inducing modified host cell RNAs are abundantly produced during both wild-type SFV and its non-pathogenic mutant infection. Furthermore, in contrast to the wild-type SFV replicase a non-pathogenic mutant replicase triggers increased IFN-β production, which leads to a shutdown of virus replication. These results suggest that host cells can restrict RNA virus replication by detecting the products of unspecific viral replicase RdRp activity. Author Summary Type I interferons (IFN) are critical for mounting effective antiviral responses by the host cells. For RNA viruses, it is believed that IFN is triggered exclusively by viral double-stranded RNA (dsRNA) or RNA containing a 5′-triphosphate (5′-ppp) that is produced during viral genome replication or transcription driven by viral replicases. Here, we provide strong evidence suggesting that the viral replicase also generates 5′-ppp dsRNA using cellular RNA templates, which trigger IFN. This finding indicates that viral replicase is capable of activating the host innate immune response, deviating from the paradigm that viral nucleic acid replication or transcription must be initiated in the host cell to trigger IFN production. Using Semliki Forest virus (SFV) as a model, we show that the magnitude of innate immune response activation by the viral replicase plays a decisive role in establishing viral infection. We demonstrate that in contrast to the wild-type SFV replicase, a non-pathogenic mutant replicase triggers increased IFN production, which leads to a shutdown of virus replication. Consequently, excessive IFN induction by the viral replicase can be dangerous for an RNA virus. Thus, we delineate a novel mechanism by which an RNA virus triggers the host cell immune response leading to RNA virus replication shutdown. |
| Databáze: | OpenAIRE |
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