Respiratory Syncytial Virus Impairs Macrophage IFN-α/β- and IFN-γ-Stimulated Transcription by Distinct Mechanisms
Respiratory Syncytial Virus Impairs Macrophage IFN-α/β- and IFN-γ-Stimulated Transcription by Distinct Mechanisms
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DOI：
10.1165/rcmb.2008-0229oc
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发表时间：
2010-04-01
影响因子：
6.4
通讯作者：
Harrod, Kevin S.
中科院分区：
文献类型：
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作者：
Senft, Albert P.;Taylor, Reed H.;Harrod, Kevin S.
巨噬细胞是主要的肺吞噬细胞，并有助于维持无菌、非炎症的微环境。IFN是响应细菌和病毒感染而产生的，并激活巨噬细胞以有效地抵抗和清除致病性入侵者。呼吸道合胞病毒（RSV）抑制上皮细胞中IFN介导的信号传导机制;然而，对巨噬细胞中IFN信号传导的影响目前尚不清楚。我们研究了RSV感染对巨噬细胞中IFN介导的信号传导的影响。RSV感染抑制了原代肺泡巨噬细胞和巨噬细胞系中IFN-β和IFN-γ激活的转录机制，包括重要的Nod样受体家族基因、Nod 1和II类反式激活因子的反式激活。RSV通过两种不同的机制抑制IFN-β和IFN-γ介导的转录激活。RSV通过涉及抑制酪氨酸激酶2磷酸化的机制损害IFN-β介导的信号转导和转录激活因子（STAT）-1磷酸化。相反，干扰素-γ刺激后RSV受损的转录激活是由于核STAT 1与转录共激活因子CBP相互作用的减少，并且与STAT 1 β（一种显性负性STAT 1剪接变体）响应干扰素-γ的磷酸化增加相关。为了支持这一观点，STAT 1 β的过表达足以抑制IFN-γ介导的II类反式激活因子的表达。这些结果表明，RSV抑制IFN介导的转录激活巨噬细胞，并表明副粘病毒调节一个重要的调节机制，这是至关重要的连接先天性和适应性免疫机制感染后。
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 STAT1 beta, a dominant-negative STAT1 splice variant, in response to IFN-gamma. In support of this concept, overexpression of STAT1 beta 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.