title: 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.
authors.affiliation: Infectious Diseases Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA. asenft@lrri.org
authors.forename: Albert P
authors.initials: AP
authors.lastname: Senft
authors.forename: Reed H
authors.initials: RH
authors.lastname: Taylor
authors.forename: Wanli
authors.initials: W
authors.lastname: Lei
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Campbell
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Tipper
authors.forename: M Juanita
authors.initials: MJ
authors.lastname: Martinez
authors.forename: Teah L
authors.initials: TL
authors.lastname: Witt
authors.forename: Candice C
authors.initials: CC
authors.lastname: Clay
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Harrod
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D050882:CREB-Binding Protein / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D005260:Female; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D053474:Nod1 Signaling Adaptor Protein / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D053634:TYK2 Kinase / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology*
chemical_list: D016898:Interferon-alpha; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D016899:Interferon-beta; D007371:Interferon-gamma; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse