Machupo等致病性新世界沙粒病毒挟持TfR1发生晚期内体转运的机制研究

Pathogenic New World arenaviruses are a kind of rat-derived, enveloped, RNA virus, and Machupo virus is included. They use human transferrin receptor 1 (TfR1) to infect human, which determines their pathogenicity. However, the underlying mechanism remains unclear. Here, we presume that virion hijacks TfR1 trafficking to the late endosome, which deviates from the early endosome, is one of the reasons to that. Hence, thoroughly studying the virion transporting pathway between the early and late endosome and analyzing the important host factors involving in, is of great importance for elaborating the pathogenicity and discovering new intervention targets. Our study will adopt transcriptomics in addition to cell imagining technologies, firstly try to figure out the virion transport between the early and late endosome, then discover the important host factors involving in, next clarify their influence on the endosome trafficking and virion entry, finally explain the relationship between the endosome trafficking and pathogenicity. This study is beneficial to illuminate the process of arenavirus entry, and provide theoretical basis for the pathogenicity of arenavirus.

致病性新世界沙粒病毒是一类鼠源RNA包膜病毒，Machupo病毒是其中一员。此类病毒感染人时对转铁蛋白受体1（TfR1）的利用决定了其致病性，然而其中机理尚不明确。我们推测，病毒挟持TfR1转运至晚期内体从而偏离早期内体是原因之一。深入研究Machupo等致病性新世界沙粒病毒在早/晚期内体间的转运过程并解析与此相关的重要宿主因子，将对解释其致病性和发现针对病毒进入阶段的药物干预靶点具有重要意义。本项目拟在细胞成像技术的基础上辅以组学分析，试图明晰病毒粒子在早/晚期内体间的转运过程，并发现参与此过程的重要宿主因子，阐明其对内体转运和病毒进入的影响，最终解释内体转运与此类病毒致病性的关系。开展本研究有助于阐明沙粒病毒进入靶细胞的过程机制，为深入了解此类病毒的致病性提供理论依据。

致病性新世界沙粒病毒胡宁病毒、马秋波病毒、瓜纳瑞托病毒、萨比亚病毒和查帕尔病毒等无特异性治疗手段，因而被定义为生物安全四级病原。本项目致力于研究这些病毒的进入机制机理、发现重要的与入侵相关的宿主因子，进而发现病毒进入抑制剂。围绕这些目标，我们成功建立了5个致病性新世界沙粒病毒的假病毒感染模型，这为研究病毒的进入相关的因子和药物提供了研究基础。在此基础上，我们发现了一系列影响病毒入侵的宿主因子，如HSP90、EPOR等，这为解析病毒的入侵机制进一步奠定了理论基础。另外，我们还发现了一系列针对胡宁病毒病毒囊膜蛋白的中和性单抗以及马源抗体片段，未来有希望用于高致病性新世界沙粒病毒的治疗。

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