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

Abstract

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 ...

Protective Role for Protease-Activated Receptor-2 against Influenza Virus Pathogenesis via an IFN-γ-Dependent Pathway

“…From our results, PAR 2 seems to trigger a signal that counteracts the IAV-mediated inhibitory signal for IFN-␥ release. In line with this hypothesis, it was recently shown that IAV abrogates the IFN-␥ response to evade its antiviral activity (48). Thus, a balance between inhibitory and activating signals could determine the release of IFN-␥ after IAV infection, and full activation of PAR 2 would overcome IAV-induced-inhibition of IFN-␥ release.…”

Influenza A Virus Infection Impairs Mycobacteria-Specific T Cell Responses and Mycobacterial Clearance in the Lung during Pulmonary Coinfection

“…Influenza virus can infect DCs and other APCs, and alter the cell Ag-processing machinery-for instance, by elevating active cathepsin B levels (39). In this regard, influenza A virus infection of epithelial cells inhibited the IFN-g-induced CIITA, resulting in decreased processing of Ags through the MHC II pathway and altered peptide presentation to CD4 T cells (40). It will be relevant to determine in the future if a similar effect occurs in the DCs of mice infected with mycobacteria and influenza virus.…”

Molecular Signatures Associated with Mx1-Mediated Resistance to Highly Pathogenic Influenza Virus Infection: Mechanisms of Survival

“…One of the initial consequences during influenza virus infection is the rapid virus-mediated antagonism of the host innate response to avoid the generation of a strong antiviral state (8). This is accomplished by several tactics, such as inhibition of the RIG-I signaling pathway (7,17,19), dysregulation of gene expression (18,23), downregulation of type I and II interferon receptor signaling (20,24,34), inhibition of PKR (12,14) and OAS (14), and modulation of apoptosis (5,13,16,36,38,39). Consequently, on one hand, the 1918 virus antagonizes the innate response, but on the other hand, Mx1 competent animals are able to partially control virus growth.…”