Herpes simplex virus 2 ICP34.5 confers neurovirulence by regulating the type I interferon response
Herpes simplex virus 2 ICP34.5 confers neurovirulence by regulating the type I interferon response
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DOI：
10.1016/j.virol.2014.08.015
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发表时间：
2014-11-01
期刊：
影响因子：
3.7
通讯作者：
Morrison, Lynda A.
中科院分区：
文献类型：
--
作者：
Davis, Katie L.;Korom, Maria;Morrison, Lynda A.
单纯疱疹病毒2型的734.5基因编码ICP34.5，其增强单纯疱疹病毒神经毒力的机制未知。我们发现，HSV-2伽马34.5缺失突变体(伽马34.5(-/-))在野生型小鼠胚胎成纤维细胞(MEF)和干扰素β诱导的细胞中的复制速度低于其救援病毒(伽马34.5R)。EIF2α磷酸化增加与Gamma 34.5(-/-)衰减相关。然而，在缺乏I型干扰素受体(干扰素α/βR-/-)或缺乏蛋白激酶R的MEF中，Gamma 34.5(-/-)的效价相当于Gamma 34.5R。与Gamma 34.5R相比，Gamma 34.5(-/-)在野生型小鼠的阴道黏膜中复制很差，几乎没有引起生殖器炎症，并以较低的水平扩散到神经系统。然而，在干扰素α/βR-/-小鼠中，伽玛34.5(-/-)在阴道感染或直接接种到中枢神经系统后，恢复了复制和引起相当于伽马34.5R的疾病的能力。因此，HSV-2 ICP34.5在体内阻断I型干扰素反应的能力在很大程度上决定了其神经毒力。(C)2014 Elsevier Inc.保留所有权利。
The 734.5 gene of herpes simplex virus (HSV) 2 encodes ICP34.5, which enhances HSV-2 neurovirulence by an unknown mechanism. We found that an HSV-2 gamma 34.5-null mutant (gamma 34.5(-/-)) replicated less robustly than its rescue virus (gamma 34.5R) in wild-type mouse embryo fibroblasts (MEFs), and in cells primed with IFN beta. Increased eIF2 alpha phosphorylation correlated with gamma 34.5(-/-) attenuation. However, gamma 34.5(-/-) achieved titers equivalent to gamma 34.5R in MEFs lacking the type I IFN receptor (IFN alpha/beta R-/-) or lacking protein kinase R. gamma 34.5(-/-) also replicated poorly in the vaginal mucosa of wild-type mice, caused little genital inflammation, and spread to the nervous system at lower levels compared to gamma 34.5R. In IFN alpha/beta R-/- mice, however, gamma 34.5(-/-) regained the capacity to replicate and cause disease equivalent to gamma 34.5R after intravaginal infection or direct inoculation into the central nervous system. Thus, the capacity of HSV-2 ICP34.5 to interdict the type I IFN response in vivo largely determines its neurovirulence. (C) 2014 Elsevier Inc. All rights reserved.