Wang Xinlu, Li Melody M H, Zhao Jing, Li Shenglan, MacDonald Margaret R, Rice Charles M, Gao Xiang, Gao Guangxia
CAS Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
The Rockefeller University, New York, New York, USA.
J Virol. 2016 Oct 28;90(22):10247-10258. doi: 10.1128/JVI.01487-16. Print 2016 Nov 15.
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.
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.
病毒感染会诱导I型干扰素（IFN）的产生，I型干扰素会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。一种具有神经侵袭特性的神经毒力辛德毕斯病毒株（SVNI）在小鼠中会导致致命性脑炎，并且它在培养细胞中的复制受到锌指抗病毒蛋白（ZAP）的抑制，ZAP是一种宿主因子，通过与病毒mRNA结合、抑制靶mRNA的翻译以及促进靶mRNA的降解来特异性抑制某些病毒的复制。我们在此报告，来自ZAP基因敲除小鼠的鼠胚胎成纤维细胞比野生型细胞支持更高效的SVNI复制。对10日龄乳鼠进行SVNI感染导致基因敲除小鼠的存活率降低。然而，出乎意料的是，对23日龄断奶小鼠（其免疫系统比乳鼠更发达）进行SVNI感染，结果ZAP基因敲除小鼠的存活率显著提高。进一步分析表明，在断奶基因敲除小鼠中，SVNI在感染后早期在淋巴组织中复制更高效，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，多年来一直被用于研究小鼠急性病毒性脑炎的发病机制。病毒如何逃避免疫监视以建立有效的感染在很大程度上尚不清楚。ZAP是一种宿主抗病毒因子，能有效抑制辛德毕斯病毒在细胞培养中的复制。我们在此表明，用SVNI感染ZAP基因敲除乳鼠会导致疾病进展更快。然而，用SVNI感染断奶小鼠会导致基因敲除小鼠的疾病进展更慢。进一步分析表明，在断奶基因敲除小鼠中，SVNI在感染后早期在淋巴组织中复制更高效，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实现增强的神经侵袭的机制。
