Influenza A Virus NS1 Protein Prevents Activation of NF-κB and Induction of Alpha/Beta Interferon

Wang, Xiuyan; Li, Ming O.; Zheng, Hongyong; Muster, Thomas; Palese, Peter; Beg, Amer A.; García‐Sastre, Adolfo

doi:10.1128/jvi.74.24.11566-11573.2000

Cited by 502 publications

(444 citation statements)

References 64 publications

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“…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 NS1 protein of influenza A virus counteracts PKR-mediated phosphorylation to prevent the establishment of an antiviral state [24,25]. The NS1 protein inhibits activation of NF-jB and induction of IFN-a and -b [26]. Activation of IRF3 and IRF7 is inhibited by influenza A virus NS1 protein [27,28].…”

Section: Influenza a Virus Interferes With The Ifn-c Signaling Pathwamentioning

confidence: 99%

“…Therefore, the influenza-induction of IRF- 1 and ICAM-1 may be mediated through NF-jB. Although influenza A virus NS1 protein is reported to prevent activation of NF-jB in mouse embryonic fibroblasts [26], A549 cells show NF-jB activation in response to Aichi. In conclusion, influenza A virus, similar to other RNA viruses [21,38], inhibits IFN-c-regulated gene expression such as MHC class II DRa, CIITA, ICAM-1, and IRF-1 in human respiratory epithelial cells by interfering with the IFN-c-stimulated signal transduction (Jak/ Stat) pathway (Fig.…”

Section: Influenza a Virus Interferes With The Ifn-c Signaling Pathwamentioning

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].…”

mentioning

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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