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      Ten Strategies of Interferon Evasion by Viruses

      review-article
      1 , 2 , 3 ,
      Cell Host & Microbe
      Elsevier Inc.

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          Abstract

          Viruses infecting vertebrate hosts must overcome the interferon (IFN)-mediated antiviral response to replicate and propagate to new hosts. The complex regulation of the IFN response allows viruses to antagonize IFN at multiple levels. However, no single strategy appears to be the golden ticket, and viruses have adopted multiple means to dampen this host defense. This Review does not exhaustively cover all mechanisms of viral IFN antagonism. Rather it examines the ten most common strategies that viruses use to subvert the IFN response with examples from publications appearing in the last 10 years of Cell Host & Microbe. The virus-host interactions involved in induction and evasion of IFN represent a fertile area of research due to the significant large number of host and viral products that regulate this response, resulting in an intricate dance between hosts and their pathogens to achieve an optimal balance between virus replication, host disease, and survival.

          Abstract

          Viruses are formidable pathogens that take advantage of the infected cell machinery while disarming the antiviral host defenses. García-Sastre reviews the most common mechanisms used by viruses to antagonize the antiviral interferon response, illustrating the complexity of pathways that sense viral infection and regulate antiviral innate immune responses.

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          Most cited references48

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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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            TLR signaling.

            The Toll-like receptor (TLR) family plays an instructive role in innate immune responses against microbial pathogens, as well as the subsequent induction of adaptive immune responses. TLRs recognize specific molecular patterns found in a broad range of microbial pathogens such as bacteria and viruses, triggering inflammatory and antiviral responses and dendritic cell maturation, which result in the eradication of invading pathogens. Individual TLRs interact with different combinations of adapter proteins and activate various transcription factors such as nuclear factor (NF)-kappaB, activating protein-1 and interferon regulatory factors, driving a specific immune response. This review outlines the recent advances in our understanding of TLR-signaling pathways and their roles in immune responses. Further, we also discuss a new concept of TLR-independent mechanisms for recognition of microbial pathogens.
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              Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I.

              The ubiquitin ligase TRIM25 mediates Lysine 63-linked ubiquitination of the N-terminal CARD domains of the viral RNA sensor RIG-I to facilitate type I interferon (IFN) production and antiviral immunity. Here, we report that the influenza A virus nonstructural protein 1 (NS1) specifically inhibits TRIM25-mediated RIG-I CARD ubiquitination, thereby suppressing RIG-I signal transduction. A novel domain in NS1 comprising E96/E97 residues mediates its interaction with the coiled-coil domain of TRIM25, thus blocking TRIM25 multimerization and RIG-I CARD domain ubiquitination. Furthermore, a recombinant influenza A virus expressing an E96A/E97A NS1 mutant is defective in blocking TRIM25-mediated antiviral IFN response and loses virulence in mice. Our findings reveal a mechanism by which influenza virus inhibits host IFN response and also emphasize the vital role of TRIM25 in modulating antiviral defenses.
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                Author and article information

                Contributors
                Journal
                Cell Host Microbe
                Cell Host Microbe
                Cell Host & Microbe
                Elsevier Inc.
                1931-3128
                1934-6069
                9 August 2017
                9 August 2017
                9 August 2017
                : 22
                : 2
                : 176-184
                Affiliations
                [1 ]Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                [2 ]Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                [3 ]Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                Author notes
                []Corresponding author adolfo.garcia-sastre@ 123456mssm.edu
                Article
                S1931-3128(17)30295-0
                10.1016/j.chom.2017.07.012
                5576560
                28799903
                7733d930-2c45-492e-b1c8-ac091b17c37d
                © 2017 Elsevier Inc.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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                Microbiology & Virology
                Microbiology & Virology

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