Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment.
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.
Texas Biomedical Research Institute, San Antonio, TX, USA.
Yasuteru
Y
Sakurai
The University of Texas Medical Branch, Galveston, TX, USA.
Andrey A
AA
Kolokoltsov
Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany.
Cheng-Chang
CC
Chen
Southwest Research Institute, San Antonio, TX, USA.
Michael W
MW
Tidwell
Southwest Research Institute, San Antonio, TX, USA.
William E
WE
Bauta
Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
Norbert
N
Klugbauer
Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany.
Christian
C
Grimm
Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany.
Christian
C
Wahl-Schott
Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany.
Martin
M
Biel
Texas Biomedical Research Institute, San Antonio, TX, USA. rdavey@txbiomed.org.
Robert A
RA
Davey
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D041702:BALB 3T3 Cells; D044182:Benzylisoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D029043:Ebolavirus / Q000187:drug effects / Q000502:physiology*; D005260:Female; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy / Q000628:therapy* / Q000821:virology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D051379:Mice; D058990:Molecular Targeted Therapy; D009249:NADP / Q000031:analogs & derivatives / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014700:Verapamil / Q000494:pharmacology / Q000627:therapeutic use; D053586:Virus Internalization / Q000187:drug effects*; D000097903:Two-Pore Channels
D000998:Antiviral Agents; D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D009249:NADP; D014700:Verapamil; C407357:TPCN1 protein, human; D000097903:Two-Pore Channels; C546784:TPCN1 protein, mouse; C530224:TPCN2 protein, human; C546785:TPCN2 protein, mouse; C009438:tetrandrine; C024376:NAADP