Sindbis Virus Can Exploit a Host Antiviral Protein To Evade Immune Surveillance
Sindbis Virus Can Exploit a Host Antiviral Protein To Evade Immune Surveillance
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辛德比斯病毒可以利用宿主抗病毒蛋白来逃避免疫监视
DOI：
10.1128/jvi.01487-16
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发表时间：
2016-11-01
影响因子：
5.4
通讯作者：
Gao, Guangxia
中科院分区：
文献类型：
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作者：
Wang, Xinlu;Li, Melody M. H.;Gao, Guangxia
病毒感染诱导产生I型干扰素（IFN），其刺激多种抗病毒因子的表达以抑制病毒复制。为了建立有效的感染，病毒需要制定策略来逃避免疫反应。具有神经侵袭特性的神经毒性辛德毕斯病毒株（SVNI）在小鼠中引起致死性脑炎，并且其在培养细胞中的复制被锌指抗病毒蛋白（ZAP）抑制，锌指抗病毒蛋白是一种宿主因子，其通过结合病毒mRNA、抑制靶mRNA的翻译并促进靶mRNA的降解来特异性抑制某些病毒的复制。我们在这里报告说，小鼠胚胎成纤维细胞ZAP基因敲除小鼠支持更有效的SVNI复制比野生型细胞。SVNI感染10日龄乳鼠导致基因敲除小鼠存活率降低。然而，出乎意料的是，SVNI感染23天龄的断奶小鼠，其免疫系统比乳鼠更发达，导致ZAP敲除小鼠的存活率显著提高。进一步的分析显示，在断奶敲除小鼠中，SVNI在感染后早期在淋巴组织中复制更有效，并诱导更高水平的IFN产生，这限制了病毒向中枢神经系统的传播。通过使用受体中和抗体阻断IFN活性使基因敲除小鼠比野生型小鼠对SVNI感染更敏感。这些结果揭示了SVNI利用宿主抗病毒因子逃避先天免疫监视的机制。辛德毕斯病毒是甲病毒属的原型成员，多年来一直用于研究小鼠急性病毒性脑炎的发病机制。该病毒如何逃避免疫监视以建立有效感染在很大程度上尚不清楚。ZAP是一种宿主抗病毒因子，可有效抑制细胞培养中的辛德毕斯病毒复制。我们在这里表明，ZAP敲除乳鼠感染SVNI导致更快的疾病进展。然而，断奶小鼠的SVNI感染导致基因敲除小鼠的疾病进展较慢。进一步的分析显示，在断奶敲除小鼠中，SVNI在感染后早期在淋巴组织中复制更有效，并诱导更高水平的干扰素产生，这限制了病毒向中枢神经系统的传播。这些结果揭示了SVNI利用宿主抗病毒因子逃避先天免疫监视并增强神经侵袭的机制。
ABSTRACT Viral infection induces production of type I interferons (IFNs), which stimulate the expression of a variety of antiviral factors to inhibit viral replication. To establish effective infection, viruses need to develop strategies to evade the immune responses. A neurovirulent Sindbis virus strain with neuroinvasive properties (SVNI) causes lethal encephalitis in mice, and its replication in cultured cells is inhibited by the zinc finger antiviral protein (ZAP), a host factor that specifically inhibits the replication of certain viruses by binding to the viral mRNAs, repressing the translation of target mRNA, and promoting the degradation of target mRNA. We report here that murine embryonic fibroblast cells from ZAP knockout mice supported more efficient SVNI replication than wild-type cells. SVNI infection of 10-day-old suckling mice led to reduced survival in the knockout mice. Unexpectedly, however, SVNI infection of 23-day-old weanling mice, whose immune system is more developed than that of the suckling mice, resulted in significantly improved survival in ZAP knockout mice. Further analyses revealed that in the weanling knockout mice, SVNI replicated more efficiently in lymphoid tissues at early times postinfection and induced higher levels of IFN production, which restricted viral spread to the central nervous system. Blocking IFN activity through the use of receptor-neutralizing antibodies rendered knockout mice more sensitive to SVNI infection than wild-type mice. These results uncover a mechanism by which SVNI exploits a host antiviral factor to evade innate immune surveillance. IMPORTANCE Sindbis virus, a prototypic member of the Alphavirus genus, has been used to study the pathogenesis of acute viral encephalitis in mice for many years. How the virus evades immune surveillance to establish effective infection is largely unknown. ZAP is a host antiviral factor that potently inhibits Sindbis virus replication in cell culture. We show here that infection of ZAP knockout suckling mice with an SVNI led to faster disease progression. However, SVNI infection of weanling mice led to slower disease progression in knockout mice. Further analyses revealed that in weanling knockout mice, SVNI replicated more efficiently in lymphoid tissues at early times postinfection and induced higher levels of interferon production, which restricted viral spread to the central nervous system. These results uncover a mechanism by which SVNI exploits a host antiviral factor to evade innate immune surveillance and allow enhanced neuroinvasion.