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

Science. 2015 Feb 27;347(6225):995-8. doi: 10.1126/science.1258758.

Yasuteru Sakurai ¹, Andrey A Kolokoltsov ², Cheng-Chang Chen ³, Michael W Tidwell ⁴, William E Bauta ⁴, Norbert Klugbauer ⁵, Christian Grimm ³, Christian Wahl-Schott ³, Martin Biel ³, Robert A Davey ⁶

Affiliations

1 Texas Biomedical Research Institute, San Antonio, TX, USA.
2 The University of Texas Medical Branch, Galveston, TX, USA.
3 Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany.
4 Southwest Research Institute, San Antonio, TX, USA.
5 Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
6 Texas Biomedical Research Institute, San Antonio, TX, USA. rdavey@txbiomed.org.

PMID: 25722412 DOI: 10.1126/science.1258758

Abstract

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.

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