Human metapneumovirus inhibits IFN-α signaling through inhibition of STAT1 phosphorylation
Human metapneumovirus inhibits IFN-α signaling through inhibition of STAT1 phosphorylation
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DOI：
10.1165/rcmb.2007-0285oc
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发表时间：
2008-06-01
影响因子：
6.4
通讯作者：
Harrod, Kevin S.
中科院分区：
文献类型：
--
作者：
Dinwiddie, Darrell L.;Harrod, Kevin S.
最近发现的人类偏肺病毒（hMPV）是全球上下呼吸道感染的主要原因。急性病毒感染启动干扰素应答，其在介导病毒清除、病毒宿主防御和适应性免疫的发展中至关重要。小鼠感染模型表明，hMPV可引起持续性肺部感染，但逃避宿主病毒清除的机制尚不清楚。在这里，我们报告说，hMPV可以颠覆主机I型干扰素信号的机制不同于其他副粘病毒。两种肺上皮细胞系和原代正常人支气管上皮细胞（NHBE）对hMPV是允许的，与其对呼吸道的嗜性一致。用外源性IFN-α处理hMPV感染的细胞未能减少病毒复制。此外，在肺上皮细胞中，hMPV感染阻止了IFN-α介导的干扰素刺激反应元件（ISRE）的反式激活和干扰素刺激基因（ISGs）的上调。对IFN-α信号级联的进一步研究表明，hMPV感染阻止了IFN-α诱导的磷酸化和STAT 1的核转位。紫外线灭活hMPV对STAT 1磷酸化和转位的抑制作用被消除。hMPV对STAT 1的调节是特异性的，正如IFN-alpha对STAT 2、Tyk 2和Jak 1的磷酸化一样。IFN-α受体的表达不受hMPV感染的影响。这些结果表明，hMPV可以通过调节STAT 1磷酸化抑制I型干扰素反应，并提供了重要的见解hMPV感染的呼吸道病毒的发病机制。
The recently discovered human metapneumovirus (hMPV) is a major cause of lower and upper respiratory tract infections worldwide. Acute viral infection initiates the interferon response that is critical in mediating viral clearance, viral host defense, and development of adaptive immunity. Mouse models of infection suggest that hMPV can cause persistent lung infections, yet the mechanisms of evading host viral clearance are unknown. Here we report that hMPV can subvert host type I interferon signaling by a mechanism distinct from other paramyxoviruses. Two lung epithelial cell lines and primary normal human bronchial epithelial cells (NHBE) were permissive for hMPV, consistent with its tropism for the respiratory tract. Treatment of hMPV-infected cells with exogenous IFN-alpha failed to reduce viral replication. Moreover, in lung epithelial cells, hMPV infection prevented IFN-alpha-mediated transactivation of the interferon-stimulated response element (ISRE) and up-regulation of interferon-stimulated genes (ISGs). Further examination of the IFN-alpha signaling cascade showed that hMPV infection prevented IFN-alpha-incluced phosphorylation and nuclear translocation of STAT1. The inhibitory effects of hMPV on STAT1 phosphorylation and translocation were abolished by ultraviolet inactivation. Regulation of STAT1 by hMPV was specific, as phosphorylation of STAT2, Tyk2, and Jak1 by IFN-alpha. and the surface expression of the IFN-a receptor were unaltered by hMPV infection. These findings demonstrate that hMPV can inhibit the type I interferon response through regulation of STAT1 phosphorylation, and provide important insight into the viral pathogenesis of hMPV infection in the respiratory tract.