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J Virol:郑春福等I型单纯疱疹病毒拮抗宿主天然免疫研究获进展

来源:武汉病毒研究所 2012-05-21 16:52

近期,国际病毒学核心刊物Journal of Virology在线刊登了中科院武汉病毒研究所郑春福研究员学科组的研究论文“HSV-1 Tegument Protein US11 down-modulates RLR Signaling Pathway via Direct Interaction with RIG-I and MDA-5,”,文章中,研究者介绍了该学科组在I型单纯疱疹病毒拮抗宿主天然免疫反应机制研究中取得的新进展。

天然免疫系统是宿主抵抗病毒入侵的第一道防线,I型单纯疱疹病毒(HSV-1)已经进化出多种策略逃逸宿主天然免疫,从而形成裂解感染导致口腔疱疹、严重的脑炎死亡等疾病,以及终生潜伏感染。然而,HSV-1逃逸宿主天然免疫的具体机制还未完全阐明。

在郑春福研究员的指导下,博士生邢俊吉等研究首次发现,HSV-1皮层蛋白US11能够抑制β干扰素的产生,是一个新的拮抗RIG-I样模式识别受体(RLR)介导的天然免疫信号通路的HSV-1蛋白。研究人员通过荧光素酶双报告系统和免疫共沉淀等多种实验方法,最终阐明其作用的分子机制为:US11蛋白通过与内源性模式识别受体RIG-I和MDA-5相互作用,干扰它们与接头蛋白MAVS的相互作用,从而抑制RLR介导的天然免疫下游信号通路IRF3的激活,阻止β干扰素的产生。

这是第一次报道HSV-1能干扰RLR信号通路下游的RIG-I和MDA-5。这些发现揭示了HSV-1逃逸宿主抗病毒应答的一种全新的机制,为预防HSV-1感染以及揭示新的药物作用靶点提供了理论依据。

该研究得到了国家973计划、国家自然科学基金和百人计划的资助。(生物谷Bioon.com)

HSV-1 Tegument Protein US11 down-modulates RLR Signaling Pathway via Direct Interaction with RIG-I and MDA-5

Junji Xing1, Shuai Wang1, Rongtuan Lin2, Karen L. Mossman3 and Chunfu Zheng1,*

The interferon (IFN)-mediated antiviral response is a major defense of the host immune system. In order to complete their life cycle, viruses must modulate host IFN-mediated immune responses. Herpes simplex virus 1 (HSV-1) is a large DNA virus containing over 80 genes, many of which encode proteins that are involved in virus-host interactions and show immune modulatory capabilities. In this study, we demonstrate that the US11 protein, an RNA binding tegument protein of HSV-1, is a novel antagonism of the IFN-β pathway. US11 significantly inhibited Sendai virus (SeV)-induced IFN-β production, and its dsRNA binding domain was indispensable for this inhibition activity. Additionally, wild type HSV-1 co-infection showed stronger inhibition than US11-mutant HSV-1 in SeV-induced IFN-β production. Co-immunoprecipitation analysis demonstrated that the US11 protein in HSV-1 infected cells interacts with endogenous RIG-I and MDA-5 through its C-terminal RNA-binding domain, which was RNA-independent. Expression of US11 in both transfected and HSV-1 infected cells interferes with the interaction between MAVS and RIG-I or MDA-5. Finally, US11 dampens SeV-mediated IRF3 activation. Taken together, the combined data indicate that HSV-1 US11 binds to RIG-I and MDA-5 and inhibits their downstream signaling pathway, preventing the production of IFN-β, which may contribute to the pathogenesis of HSV-1 infection.

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