Early Events in Alphavirus Replication Determine the Outcome of Infection
Early Events in Alphavirus Replication Determine the Outcome of Infection
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DOI：
10.1128/jvi.07223-11
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发表时间：
2012-05-01
影响因子：
5.4
通讯作者：
Frolova, Elena I.
中科院分区：
文献类型：
--
作者：
Frolov, Ilya;Akhrymuk, Maryna;Frolova, Elena I.
甲病毒是一组重要的人类和动物病原体。它们在体内和许多常用的脊椎动物来源的细胞系中有效地复制至高滴度。它们还进化出了干扰先天免疫反应发展的有效手段。然而，已知大多数甲病毒在体内诱导I型干扰素（IFN）应答。这项研究的结果表明，感染后的第一个小时在感染传播和抗病毒反应的发展中起着关键作用。在此期间，病毒在脊椎动物细胞中的复制和传播与IFN应答发展之间达到平衡。最重要的发现如下：（i）在感染后的前2至4小时内，甲病毒感染的细胞变得不能对IFN-β产生应答，并且这发生在病毒诱导的STAT 1磷酸化响应于IFN处理的降低之前。(ii)最重要的是，在未感染细胞中不诱导抗病毒应答的非常低的亚保护剂量的IFN-β对细胞表达I型IFN和在随后的辛德毕斯病毒（SINV）感染期间激活干扰素刺激的基因的能力具有非常强的刺激作用。(iii)SINV nsP 2蛋白的微小变化影响其抑制细胞转录和IFN释放的能力。因此，I型IFN诱导和病毒发展进一步感染的能力之间的平衡在病毒复制的最初几个小时内确定，此时仅涉及少量细胞和感染性病毒。
Alphaviruses are a group of important human and animal pathogens. They efficiently replicate to high titers in vivo and in many commonly used cell lines of vertebrate origin. They have also evolved effective means of interfering with development of the innate immune response. Nevertheless, most of the alphaviruses are known to induce a type I interferon (IFN) response in vivo. The results of this study demonstrate that the first hours postinfection play a critical role in infection spread and development of the antiviral response. During this window, a balance is struck between virus replication and spread in vertebrate cells and IFN response development. The most important findings are as follows: (i) within the first 2 to 4 h postinfection, alphavirus-infected cells become unable to respond to IFN-beta, and this occurs before the virus-induced decrease in STAT1 phosphorylation in response to IFN treatment. (ii) Most importantly, very low, subprotective doses of IFN-beta, which do not induce the antiviral response in uninfected cells, have a very strong stimulatory effect on the cells' ability to express type I IFN and activate interferon-stimulated genes during subsequent infection with Sindbis virus (SINV). (iii) Small changes in SINV nsP2 protein affect its ability to inhibit cellular transcription and IFN release. Thus, the balance between type I IFN induction and the ability of the virus to develop further rounds of infection is determined in the first few hours of virus replication, when only low numbers of cells and infectious virus are involved.