Ebola virus entry requires the cholesterol transporter Niemann-Pick C1.
Ebola virus entry requires the cholesterol transporter Niemann-Pick C1.
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DOI：
10.1038/nature10348
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发表时间：
2011-08-24
期刊：
影响因子：
64.8
通讯作者：
Brummelkamp, Thijn R.
中科院分区：
文献类型：
--
作者：
Carette, Jan E.;Raaben, Matthijs;Wong, Anthony C.;Herbert, Andrew S.;Obernosterer, Gregor;Mulherkar, Nirupama;Kuehne, Ana I.;Kranzusch, Philip J.;Griffin, April M.;Ruthel, Gordon;Dal Cin, Paola;Dye, John M.;Whelan, Sean P.;Chandran, Kartik;Brummelkamp, Thijn R.
埃博拉病毒和马尔堡丝状病毒感染可导致人类快速致死性出血热，目前尚无获批的抗病毒药物。丝状病毒进入由病毒刺突糖蛋白（GP）介导，其将病毒颗粒附着于细胞表面，将其递送至内体并催化病毒和内体膜之间的融合。内体区室中的其他宿主因子可能是病毒膜融合所需的;然而，尽管付出了相当大的努力，这些关键的宿主因子仍无法进行分子鉴定。在这里，我们描述了一个全基因组的人类细胞单倍体遗传筛选，以确定埃博拉病毒进入所需的宿主因子。我们的筛选发现了67个突变破坏了同型融合和液泡蛋白分选（HOPS）多亚基拴系复合物的所有6个成员，该复合物参与了内体与溶酶体的融合，以及39个破坏内/溶酶体胆固醇转运蛋白尼曼-匹克C1（NPC 1）的独立突变。HOPS复合物或NPC 1功能缺陷的细胞，包括来源于人尼曼-匹克C1型疾病患者的原代成纤维细胞，对埃博拉病毒和马尔堡病毒的感染具有抗性，但对一系列不相关的病毒仍然完全敏感。我们表明，膜融合介导的丝状病毒糖蛋白和病毒逃逸囊泡隔室需要NPC 1蛋白，独立于其已知的功能，胆固醇运输。我们的研究结果揭示了丝状病毒进入途径的独特特征，并指出了对抗这些致命病原体的潜在抗病毒策略。
Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification,,. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann–Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann–Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.
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影响因子：
5.4
作者：
Maruyama, T;Rodriguez, LL;Burton, DR
通讯作者：
Burton, DR
DOI：
10.1073/pnas.1007152107
发表时间：
2010-11-16
影响因子：
11.1
作者：
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作者：
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