Vaccinia virus blocks Stat1-dependent and Stat1-independent gene expression induced by type I and type II Interferons
Vaccinia virus blocks Stat1-dependent and Stat1-independent gene expression induced by type I and type II Interferons
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DOI：
10.1089/jir.2007.0113
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发表时间：
2008-01-01
影响因子：
2.3
通讯作者：
Kaplan, Mark H.
中科院分区：
文献类型：
--
作者：
Mann, Brandon A.;Huang, Julia He;Kaplan, Mark H.
阻断Stat（信号换能器和转录激活器）蛋白的功能是抗病毒反应的关键，已发展成为病原体免疫逃避的常见机制。痘病毒编码的磷酸酶H1对病毒复制至关重要，并且可能通过去磷酸化Stat1和阻断干扰素（IFN）刺激的先天免疫反应，在逃避宿主防御中发挥额外的作用。牛痘病毒（VACV） H1在ifn - γ刺激上皮细胞后可以抑制转录因子Stat1的磷酸化，大大削弱ifn诱导的生物学功能。在这项研究中，我们证明了在I型或II型ifn刺激成纤维细胞或骨髓源性巨噬细胞后，VACV感染能够抑制Stat1和Stat2的磷酸化，但在两种细胞类型中都没有抑制Stat3或Stat5的激活。利用重组蛋白进行体外实验，我们观察到，尽管对Stat靶点具有相似的选择性，但天花病毒H1比VACV H1更有活性。在诱导ifn刺激基因方面，VACV感染的影响是不同的，一些基因被VACV感染完全抑制，而另一些基因受影响较小。尽管ifn - γ在vacv感染的细胞中诱导了一些基因的表达，但ifn - γ无法挽救vacv介导的MHC II类抗原呈递的抑制。此外，VACV感染可以影响ifn诱导的stat1依赖和stat1独立基因的表达，这表明该病毒可能靶向其他ifn激活途径。因此，在逃避抗病毒免疫反应中，VACV靶向多种信号通路。
Blocking the function of Stat (signal transducer and activator of transcription) proteins, which are critical for antiviral responses, has evolved as a common mechanism for pathogen immune evasion. The poxvirus-encoded phosphatase H1 is critical for viral replication, and may play an additional role in the evasion of host defense by dephosphorylating Stat1 and blocking interferon (IFN)-stimulated innate immune responses. Vaccinia virus (VACV) H1 can inhibit the phosphorylation of the transcription factor Stat1 after IFN-gamma stimulation of epithelial cells, greatly attenuating IFN-induced biological functions. In this study, we demonstrate that VACV infection is capable of inhibiting the phosphorylation of Stat1 and Stat2 after stimulation of fibroblasts or bone marrow derived macrophages with either type I or type II IFNs, but did not inhibit the activation of Stat3 or Stat5 in either cell type. By using recombinant proteins for in vitro assays, we observe that variola virus H1 is more active than VACV H1, although it has similar selectivity for Stat targets. Differential effects of VACV infection were observed on the induction of IFN-stimulated genes, with complete inhibition of some genes by VACV infection, while others were less affected. Despite the IFN-gamma-induced expression of some genes in VACV-infected cells, IFN-gamma was unable to rescue the VACV-mediated inhibition of MHC class II antigen presentation. Moreover, VACV infection can affect the IFN-induced expression of Stat1-dependent and Stat1-independent genes, suggesting that the virus may target additional IFN-activated pathways. Thus, VACV targets multiple signaling pathways in the evasion of antiviral immune responses.