Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment

被引：440

作者：

Sakurai, Yasuteru ^{[1
]}

Kolokoltsov, Andrey A. ^{[2
]}

Chen, Cheng-Chang ^{[3
]}

Tidwell, Michael W. ^{[4
]}

Bauta, William E. ^{[4
]}

Klugbauer, Norbert ^{[5
]}

Grimm, Christian ^{[3
]}

Wahl-Schott, Christian ^{[3
]}

Biel, Martin ^{[3
]}

Davey, Robert A. ^{[1
]}

机构：

[1] Texas Biomed Res Inst, San Antonio, TX 78227 USA

[2] Univ Texas Med Branch, Galveston, TX 77555 USA

[3] Univ Munich, Ctr Drug Res, Dept Pharm, CIPSM, Munich, Germany

[4] SW Res Inst, San Antonio, TX USA

[5] Univ Freiburg, Inst Expt & Clin Pharmacol & Toxicol, D-79106 Freiburg, Germany

来源：

SCIENCE | 2015年 / 347卷 / 6225期

关键词：

NIEMANN-PICK C1; NAADP; CALCIUM; INFECTION; IDENTIFICATION; TETRANDRINE; MICE;

D O I：

10.1126/science.1258758

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus 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 that we tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy.

引用

页码：995 / 998

页数：4

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