SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052.

Markus Hoffmann ¹, Hannah Kleine-Weber ², Simon Schroeder ³, Nadine Krüger ⁴, Tanja Herrler ⁵, Sandra Erichsen ⁶, Tobias S Schiergens ⁷, Georg Herrler ⁸, Nai-Huei Wu ⁸, Andreas Nitsche ⁹, Marcel A Müller ¹⁰, Christian Drosten ³, Stefan Pöhlmann ¹¹

Affiliations

1 Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany. Electronic address: mhoffmann@dpz.eu.
2 Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany; Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany.
3 Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, Berlin, Germany; German Centre for Infection Research, associated partner Charité, Berlin, Germany.
4 Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany; Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany.
5 BG Unfallklinik Murnau, Murnau, Germany.
6 Institute for Biomechanics, BG Unfallklinik Murnau, Murnau, Germany; Institute for Biomechanics, Paracelsus Medical University Salzburg, Salzburg, Austria.
7 Biobank of the Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
8 Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany.
9 Robert Koch Institute, ZBS 1 Highly Pathogenic Viruses, WHO Collaborating Centre for Emerging Infections and Biological Threats, Berlin, Germany.
10 Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, Berlin, Germany; German Centre for Infection Research, associated partner Charité, Berlin, Germany; Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov University, Moscow, Russia.
11 Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany; Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany. Electronic address: spoehlmann@dpz.eu.

PMID: 32142651 DOI: 10.1016/j.cell.2020.02.052

Abstract

The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV Infection and identify a potential target for Antiviral intervention.

Keywords

ACE2; COVID-19; SARS-CoV-2; TMPRSS2; coronavirus; entry; neutralization; priming; spike.

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