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

Markus Hoffmann1 Hannah Kleine-Weber2,3 Simon Schroeder4,5 Nadine Krüger6,7 Tanja Herrler8 Sandra Erichsen9,10 Tobias S Schiergens11 Georg Herrler12 Nai-Huei Wu12 Andreas Nitsche13 Marcel A Müller4,14,15 Christian Drosten4,5 Stefan Pöhlmann2,16
Affiliations 16 institutions
  1. Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany. Electronic address: [email protected].
  2. Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany
  3. Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany.
  4. Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, Berlin, Germany
  5. German Centre for Infection Research, associated partner Charité, Berlin, Germany.
  6. Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany
  7. Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany.
  8. BG Unfallklinik Murnau, Murnau, Germany.
  9. Institute for Biomechanics, BG Unfallklinik Murnau, Murnau, Germany
  10. Institute for Biomechanics, Paracelsus Medical University Salzburg, Salzburg, Austria.
  11. Biobank of the Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
  12. Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany.
  13. Robert Koch Institute, ZBS 1 Highly Pathogenic Viruses, WHO Collaborating Centre for Emerging Infections and Biological Threats, Berlin, Germany.
  14. German Centre for Infection Research, associated partner Charité, Berlin, Germany
  15. Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov University, Moscow, Russia.
  16. Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany. Electronic address: [email protected].
PMID32142651 DOI10.1016/j.cell.2020.02.052 Year2020 Journal Cell Languageeng Statusppublish

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.

Supporting text Virus Host Location
ACE2 54 coronavirus 195 COVID-19 467 entry 7 neutralization 9 priming 1 SARS-CoV-2 550 spike 25 TMPRSS2 5 Ammonium Chloride 1 Angiotensin-Converting Enzyme 2 177 Animals 1948 Antibodies, Neutralizing 80 Antibodies, Viral 212 Betacoronavirus 78 Cell Line 158 Coronavirus 92 Coronavirus Infections 171 COVID-19 425 COVID-19 Serotherapy 8 Drug Development 1 Esters 1 Gabexate 1 Guanidines 2

Evidence records

1 total
Functional Mechanism
1 records · 1 evidence types
Evidence type Receptor Usage
1 records
OVE11416 Receptor Usage
Key finding

SARS-CoV-2 employs the ACE2 receptor for cell entry and requires the serine protease TMPRSS2 for spike protein priming, confirming shared entry determinants with SARS-CoV.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
human Homo sapiens Experimental system
Location
Not specified
Supporting text

Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.

Method
cell entry assay | protease inhibition experiment | receptor binding study
Receptors
ACE2
Host factors
TMPRSS2