Activation of Interferon Regulatory Factor 3 Is Inhibited by the Influenza A Virus NS1 Protein

Talon, Julie; Horvath, Curt M.; Polley, Rosalind; Basler, Christopher F.; Muster, Thomas; Palese, Peter; Garcı́a-Sastre, Adolfo

doi:10.1128/jvi.74.17.7989-7996.2000

Cited by 531 publications

(471 citation statements)

References 40 publications

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“…The NS1 protein inhibits activation of NF-jB and induction of . Activation of IRF3 and IRF7 is inhibited by influenza A virus NS1 protein [27,28]. Here we present the first report that influenza A virus encodes an immunomodulatory function, which directly interferes with IFN-c-stimulated signal transduction via the Jak/ Stat pathway and enables the virus to inhibit IFN-c-inducible gene expression.…”

mentioning

confidence: 89%

“…The influenza virus-encoded NS1 has been shown to inhibit the host-cell antiviral responses [1,15,[23][24][25][26][27][28]. To elucidate the mechanism by which influenza A virus infection inhibits IFN-c-induced tyrosine phosphorylation of Stat1, we next analyzed the effect of NS1 protein on the Stat1 phosphorylation.…”

Section: Ns1 Does Not Inhibit Ifn-c-induced Tyrosine Phosphorylation mentioning

confidence: 99%

“…The influenza A NS1 protein, which is known to be an IFN antagonist [1,15,[23][24][25][26][27][28], did not affect IFN-c-induced tyrosine phosphorylation of Stat1. However, surprisingly, there was a dramatic decrease of Jak1 and IFNGR1 proteins in influenza A virus-infected cells, indicating that this is the cause of a disruption of the IFN-c signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

“…The influenza-virus-encoded nonstructural protein 1 (NS1), which binds dsRNA and forms dimers in vivo, has been shown to inhibit the host cell antiviral response by multiple mechanisms. These mechanisms include the inhibition of the IFN-inducible dsRNA activated-protein kinase (PKR) [24,25] and the blocking of IFN-b production by preventing nuclear factor (NF)-jB [26], IRF3 [27], and IRF7 activation [28]. Influenza virus infection induces the local production of IFN-c by T cells and NK cells in the respiratory tract [29].…”

Section: Introductionmentioning

confidence: 99%

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Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

et al. 2008

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The innate immunity to viral infections induces a potent antiviral response mediated by interferons (IFN). Although IFN-c is detected during the acute stages of illness in the upper respiratory tract secretions and in the serum of influenza A virus-infected individuals, control of influenza A virus is not dependent upon IFN-c as evidenced by studies using anti-IFN-c Ab and IFN-c -/-mice. Thus, we hypothesized that IFN-c is not critical in host survival because influenza A virus has mechanisms to evade the antiviral activity of IFN-c. To test this, A549 cells, an epithelial cell line derived from lung adenocarcinoma, were infected with influenza virus strain A/Aichi/2/68 (H3N2) (Aichi) and/or stimulated with IFN-c to detect IFN-c-stimulated MHC class II expression. Influenza A virus infection inhibited IFN-c-induced up-regulation of HLA-DRa mRNA and the IFN-c induction of class II transactivator (CIITA), an obligate mediator of MHC class II expression. Nuclear translocation of Stat1a upon IFN-c stimulation was significantly inhibited in influenza A virus-infected cells and this was associated with a decrease in Tyr701 and Ser727 phosphorylation of Stat1a. Thus, influenza A virus subverts antiviral host defense mediated by IFN-c through effects on the intracellular signaling pathways. IntroductionInfluenza A viruses are negative-strand RNA viruses that have a segmented genome with a coding capacity for 11 polypeptides. The virus genome is composed of eight different RNA segments, which are tightly associated with the viral nucleoprotein and polymerases in ribonucleoprotein complexes [1]. Influenza A viruses, causing acute infections, continuously escape from recognition by virus neutralizing Ab as a result of accumulation of mutations in their surface glycoproteins hemagglutinin and neuraminidase (antigenic drift) or by introduction of new subtypes of these glycoproteins (antigenic shift) [2,3]. Recent outbreaks of highly pathogenic avian influenza A virus infections in poultry and in humans have raised concerns that a new influenza pandemic will occur in the near future [4]. Thus, prediction of the severity of continuously emerging human influenza virus strains remains a high public health priority, but it is limited by our incomplete understanding of the molecular determinants of pathogenicity in this disease. Although factors dictating the severity of virus disease are complex, interaction between inherent viral properties and host cellular response ultimately determines disease outcome. The first site of viral contact with the host and main target of infection and inflammation is the airway mucosal epithelium. Epithelial cells at the airway mucosal surface have a variety of inflammatory and immune defense mechanisms to deal with virus, including Eur. J. Immunol. 2008. 38: 1559-1573 Immunity to infection expression of cytokines with chemoattractant and proinflammatory functions [5], intercellular adhesion molecule-1 (ICAM-1) [6], IFN regulatory factor 1 (IRF-1) [7], nitric oxide synthase 2 (NOS2) [8], and MHC ...

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mentioning

confidence: 89%

Section: Ns1 Does Not Inhibit Ifn-c-induced Tyrosine Phosphorylation mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

et al. 2008

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“…Several human viruses, including hepatitis C virus (HCV, 3), vaccinia virus (4), Ebola virus (5), and influenza virus (6), have evolved strategies to target and inhibit distinct steps in the early signaling events that lead to IFN-I induction, indicating the importance of IFN-I in the host's antiviral response. The viral protease NS3/4A encoded by HCV has recently been shown to block the activation of IRF-3 by targeting multiple signaling steps.…”

Section: Clinical Relevancementioning

confidence: 99%

NS1 Protein of Influenza A Virus Inhibits the Function of Intracytoplasmic Pathogen Sensor, RIG-I

Guo

Chen

Zeng

et al. 2007

Am J Respir Cell Mol Biol

267

221

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Retinoic acid-inducible gene I (RIG-I) has recently been identified as one of the key intracellular sensors of virus infection. RIG-I binds to cytosolic double-stranded RNA and initiates a signaling cascade that leads to the activation of transcription factors required for expression of type I interferon (IFN-I). Previous evidence suggests that nonstructural protein 1 (NS1) encoded by influenza A virus (IAV) suppresses IFN-I secretion in virus-infected cells by an unknown mechanism. In the present study, we demonstrate that RIG-I is required

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Influenza Virus: Highly Pathogenic Avian Influenza

Snoeck

Gerloff

Tanasa

et al. 2012

BSL3 and BSL4 Agents

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Activation of Interferon Regulatory Factor 3 Is Inhibited by the Influenza A Virus NS1 Protein

Cited by 531 publications

References 40 publications

Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

NS1 Protein of Influenza A Virus Inhibits the Function of Intracytoplasmic Pathogen Sensor, RIG-I

Influenza Virus: Highly Pathogenic Avian Influenza

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