Journal Article

Respiratory Syncytial Virus Impairs Macrophage IFN-α/β– and IFN-γ–Stimulated Transcription by Distinct Mechanisms

Lei, Wanli, Clay, Candice C., Campbell, Stephanie A., Witt, Teah L., Taylor, Reed H., Tipper, Jennifer L., Martinez, M. Juanita, Senft, Albert P., Harrod, Kevin S.

2010

Overview

Abstract Macrophages are the primary lung phagocyte and are instrumental in maintenance of a sterile, noninflamed microenvironment. IFNs are produced in response to bacterial and viral infection, and activate the macrophage to efficiently counteract and remove pathogenic invaders. Respiratory syncytial virus (RSV) inhibits IFN-mediated signaling mechanisms in epithelial cells; however, the effects on IFN signaling in the macrophage are currently unknown. We investigated the effect of RSV infection on IFN-mediated signaling in macrophages. RSV infection inhibited IFN-β– and IFN-γ–activated transcriptional mechanisms in primary alveolar macrophages and macrophage cell lines, including the transactivation of important Nod-like receptor family genes, Nod1 and class II transactivator. RSV inhibited IFN-β– and IFN-γ–mediated transcriptional activation by two distinct mechanisms. RSV impaired IFN-β–mediated signal transducer and activator of transcription (STAT)-1 phosphorylation through a mechanism that involves inhibition of tyrosine kinase 2 phosphorylation. In contrast, RSV-impaired transcriptional activation after IFN-γ stimulation resulted from a reduction in the nuclear STAT1 interaction with the transcriptional coactivator, CBP, and was correlated with increased phosphorylation of STAT1β, a dominant-negative STAT1 splice variant, in response to IFN-γ. In support of this concept, overexpression of STAT1β was sufficient to repress the IFN-γ–mediated expression of class II transactivator. These results demonstrate that RSV inhibits IFN-mediated transcriptional activation in macrophages, and suggests that paramyxoviruses modulate an important regulatory mechanism that is critical in linking innate and adaptive immune mechanisms after infection.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Adaptive Immunity / Alternative splicing / Alveoli / Animals / Cell activation / Cell Line / Cell lines / CIITA protein / CREB-Binding Protein - immunology / CREB-Binding Protein - metabolism / Epithelial cells / Female / Immunity, Innate / Interferon-alpha - biosynthesis / Interferon-alpha - immunology / Interferon-beta - biosynthesis / Interferon-beta - immunology / Interferon-gamma - biosynthesis / Interferon-gamma - immunology / Macrophages / Macrophages, Alveolar - immunology / Macrophages, Alveolar - metabolism / Macrophages, Alveolar - virology / Mice / Mice, Inbred BALB C / Microenvironments / Nod1 protein / Nod1 Signaling Adaptor Protein - immunology / Nod1 Signaling Adaptor Protein - metabolism / Phosphorylation / Phosphorylation - immunology / Respiratory syncytial virus / Respiratory Syncytial Virus Infections - immunology / Respiratory Syncytial Virus Infections - metabolism / Respiratory Syncytial Virus Infections - virology / Respiratory Syncytial Viruses - immunology / Respiratory Syncytial Viruses - metabolism / Signal Transduction - immunology / Stat1 protein / STAT1 Transcription Factor - immunology / STAT1 Transcription Factor - metabolism / Transcription activation / Transcription, Genetic - immunology / TYK2 Kinase - immunology / TYK2 Kinase - metabolism / Viral infections / α-Interferon / β-Interferon / γ-Interferon