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Respiratory syncytial virus impairs macrophage IFN-alpha/beta- and IFN-gamma-stimulated transcription by distinct mechanisms.

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-beta- and IFN-gamma-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-beta- and IFN-gamma-mediated transcriptional activation by two distinct mechanisms. RSV impaired IFN-beta-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-gamma stimulation resulted from a reduction in the nuclear STAT1 interaction with the transcriptional coactivator, CBP, and was correlated with increased phosphorylation of STAT1beta, a dominant-negative STAT1 splice variant, in response to IFN-gamma. In support of this concept, overexpression of STAT1beta was sufficient to repress the IFN-gamma-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.

journal_name

Am J Respir Cell Mol Biol

journal_title

American journal of respiratory cell and molecular biology

authors

Senft AP,Taylor RH,Lei W,Campbell SA,Tipper JL,Martinez MJ,Witt TL,Clay CC,Harrod KS

doi

10.1165/rcmb.2008-0229OC

subject

Has Abstract

pub_date

2010-04-01 00:00:00

pages

404-14

issue

eissn

1044-1549

issn

1535-4989

pii

2008-0229OC

journal_volume

pub_type

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Respiratory syncytial virus impairs macrophage IFN-alpha/beta- and IFN-gamma-stimulated transcription by distinct mechanisms.