Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment.
Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment.
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DOI：
10.1126/science.1258758
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发表时间：
2015-02-27
期刊：
影响因子：
--
通讯作者：
Davey RA
中科院分区：
文献类型：
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作者：
Sakurai Y;Kolokoltsov AA;Chen CC;Tidwell MW;Bauta WE;Klugbauer N;Grimm C;Wahl-Schott C;Biel M;Davey RA
埃博拉病毒引起人类致死性出血热的零星爆发，目前尚无批准的治疗方法。细胞通过巨胞饮作用摄取埃博拉病毒，然后通过内体囊泡运输。然而，很少有控制内体病毒运动的因素是已知的。在这里，我们发现埃博拉病毒进入宿主细胞需要称为双孔通道（TPC）的内体钙通道。通过基因敲除破坏TPC功能，小干扰RNA或小分子抑制剂阻止病毒运输并防止感染。汉防己甲素是我们测试的最有效的小分子，它抑制了人体巨噬细胞的感染，人体巨噬细胞是埃博拉病毒的主要靶点，在小鼠中也显示出治疗效果。因此，TPC蛋白在埃博拉病毒感染中起关键作用，并可能成为抗病毒治疗的有效靶点。
Ebolavirus causes sporadic outbreaks of lethal hemorrhagic fever in humans with no currently approved therapy. Cells take up Ebolavirus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebolavirus entry into host cells requires the endosomal calcium channels called two pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs or small molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule we tested, inhibited infection of human macrophages, the primary target of Ebolavirus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebolavirus infection and may be effective targets for antiviral therapy.