Similarities and Differences in Antagonism of Neuron Alpha/Beta Interferon Responses by Venezuelan Equine Encephalitis and Sindbis Alphaviruses
Similarities and Differences in Antagonism of Neuron Alpha/Beta Interferon Responses by Venezuelan Equine Encephalitis and Sindbis Alphaviruses
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DOI：
10.1128/jvi.01209-09
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发表时间：
2009-10-01
影响因子：
5.4
通讯作者：
Klimstra, William B.
中科院分区：
文献类型：
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作者：
Yin, Jun;Gardner, Christina L.;Klimstra, William B.
委内瑞拉马脑炎病毒（VEEV）在成年实验室小鼠中具有高度毒性，而辛德毕斯病毒（SINV）无论剂量或接种途径如何都是无毒的，这取决于功能性α/β干扰素（IFN-α/β）反应。我们通过用病毒或缺乏结构蛋白的病毒衍生复制子感染IFN-α/β处理或未处理的原代培养物，检查了每种病毒对神经元中IFN-α/β反应的抗性和/或拮抗作用，神经元是两种病毒在小鼠中靶向的细胞类型。在感染前用IFN-α/β引发揭示了VEEV复制和子代病毒体产生对已建立的抗病毒状态具有抗性，而SINV的那些更敏感。感染后IFN-α/β治疗显示，STAT 1和STAT 2的磷酸化被部分阻断感染病毒，依赖于非结构蛋白（nsP）的表达，但不是结构蛋白（sP）。然而，STAT磷酸化的VEEV复制子的抑制与干扰素刺激的基因（ISG）mRNA诱导的抑制无关，但ISG诱导时，sP的存在受到抑制。即使用IFN-α/β预处理细胞，宿主翻译也被VEEV nsP抑制。SINV阻断ISG诱导和翻译，与nsP介导的大分子合成的关闭相关，但这两种活性对IFN-α/β预处理敏感。我们的结论是，VEEV和SINV限制ISG诱导感染的神经元通过关闭主机的转录和翻译，但抑制VEEV是更耐IFN-α/β启动。同样，两种病毒都抑制IFN受体启动的信号传导，尽管对宿主应答的影响尚不清楚。最后，VEEV似乎对预先建立的抗病毒状态的效应物更具抗性。
Venezuelan equine encephalitis virus (VEEV) is highly virulent in adult laboratory mice, while Sindbis virus (SINV) is avirulent regardless of dose or inoculation route, dependent upon functioning alpha/beta interferon (IFN-alpha/beta) responses. We have examined each virus' resistance to and/or antagonism of IFN-alpha/beta responses in neurons, a cell type targeted by both viruses in mice, by infecting IFN-alpha/beta-treated or untreated primary cultures with viruses or virus-derived replicons that lacked the structural proteins. Priming with IFN-alpha/beta prior to infection revealed that VEEV replication and progeny virion production were resistant to an established antiviral state while those of SINV were more sensitive. Postinfection IFN-alpha/beta treatment revealed that phosphorylation of STAT1 and STAT2 was partially blocked by infection with either virus, dependent upon expression of nonstructural proteins (nsP), but not structural proteins (sP). However, inhibition of STAT phosphorylation by VEEV replicons was not correlated with inhibition of IFN-stimulated gene (ISG) mRNA induction, yet ISG induction was inhibited when sP were present. Host translation was inhibited by VEEV nsP even when cells were pretreated with IFN-alpha/beta. SINV blocked ISG induction and translation, associated with nsP-mediated shutoff of macromolecular synthesis, but both activities were sensitive to IFN-alpha/beta pretreatment. We conclude that both VEEV and SINV limit ISG induction in infected neurons through shutoff of host transcription and translation but that inhibition by VEEV is more resistant to IFN-alpha/beta priming. Likewise, both viruses inhibit IFN receptor-initiated signaling, although the effect upon host responses is not clear. Finally, VEEV appears to be more resistant to effectors of the preestablished antiviral state.