Strnadova Pavla, Ren Hongwei, Valentine Robert, Mazzon Michela, Sweeney Trevor R, Brierley Ian, Smith Geoffrey L
Department of Pathology, University of Cambridge, Cambridge, United Kingdom; Department of Virology, Faculty of Medicine, Imperial College London, London, United Kingdom.
Department of Virology, Faculty of Medicine, Imperial College London, London, United Kingdom.
PLoS Pathog. 2015 Sep 3;11(9):e1005151. doi: 10.1371/journal.ppat.1005151. eCollection 2015 Sep.
Vaccinia virus (VACV) is the prototypic orthopoxvirus and the vaccine used to eradicate smallpox. Here we show that VACV strain Western Reserve protein 169 is a cytoplasmic polypeptide expressed early during infection that is excluded from virus factories and inhibits the initiation of cap-dependent and cap-independent translation. Ectopic expression of protein 169 causes the accumulation of 80S ribosomes, a reduction of polysomes, and inhibition of protein expression deriving from activation of multiple innate immune signaling pathways. A virus lacking 169 (vΔ169) replicates and spreads normally in cell culture but is more virulent than parental and revertant control viruses in intranasal and intradermal murine models of infection. Intranasal infection by vΔ169 caused increased pro-inflammatory cytokines and chemokines, infiltration of pulmonary leukocytes, and lung weight. These alterations in innate immunity resulted in a stronger CD8+ T-cell memory response and better protection against virus challenge. This work illustrates how inhibition of host protein synthesis can be a strategy for virus suppression of innate and adaptive immunity.
痘苗病毒（VACV）是正痘病毒的原型，也是用于根除天花的疫苗。在此我们表明，VACV西储株蛋白169是一种在感染早期表达的胞质多肽，它被排除在病毒工厂之外，并抑制帽依赖性和帽非依赖性翻译的起始。蛋白169的异位表达导致80S核糖体积累、多聚核糖体减少，并通过激活多种先天免疫信号通路抑制蛋白质表达。缺失169的病毒（vΔ169）在细胞培养中正常复制和传播，但在鼻内和皮内小鼠感染模型中比亲本和回复对照病毒更具致病性。vΔ169的鼻内感染导致促炎细胞因子和趋化因子增加、肺白细胞浸润和肺重量增加。先天免疫的这些改变导致更强的CD8 + T细胞记忆反应和更好的抗病毒攻击保护。这项工作说明了抑制宿主蛋白质合成如何能够成为病毒抑制先天免疫和适应性免疫的一种策略。
