SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor
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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.
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ACE-2 receptors are expressed in type II pneumocytes, nasal mucosa, lung, kidney and heart epithelial cells, small intestine enterocytes, and blood vessel endothelial cells, making these tissues vulnerable to SARS-CoV-2.
“The ACE-2 receptors are normally expressed in type II pneumocytes in the alveoli, nasal mucosa, epithelial cells of lungs, kidney, and heart, enterocytes of the small intestine, and endothelial cells of blood vessels, making them vulnerable to SARS-CoV-2 [8].”
From Waves and variants of SARS-CoV-2: understanding the causes and effect of the COVID-19 catastrophe (2022) · cites this paper as [8]
The Results establish that SARS-CoV-2 uses ACE2 for cell entry. The Discussion says ACE2 is present beyond the lung, mentions expression in the upper respiratory tract, and suggests that SARS-CoV-2 could reach other ACE2-positive tissues. It does not establish ACE2 expression in each specific cell type and organ listed in the claim, or demonstrate their vulnerability to SARS-CoV-2. Page numbers were unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe interaction between the spike protein and ACE-2 determines the efficiency of SARS-CoV-2 transmission.
“This interaction with the ACE-2 determines the efficiency of SARS-CoV-2 transmissibility [8].”
From Waves and variants of SARS-CoV-2: understanding the causes and effect of the COVID-19 catastrophe (2022) · cites this paper as [8]
The Results show that SARS-CoV-2 spike uses ACE2 for cell entry. The Introduction identifies efficient ACE2 use as a determinant of SARS-CoV transmissibility, not SARS-CoV-2 transmissibility; the Discussion treats the latter as speculative. The paper therefore does not establish that spike–ACE2 interaction determines how efficiently SARS-CoV-2 transmits. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe SARS-CoV-2 S protein mediates viral entry into host cells by binding to ACE2 through the RBD at the C terminus of the S1 subunit, subsequently causing fusion between the viral envelope and host cell membrane through the S2 subunit.
“First, the S protein mediates viral entry into host cells by binding to its receptor, angiotensin-converting enzyme 2 (ACE2), through the receptor-binding domain (RBD) at the C terminus of the S1 subunit, which subsequently causes fusion between the viral envelope and the host cell membrane through the S2 subunit (Hoffmann et al., 2020).”
From A thermostable mRNA vaccine against COVID-19 (2020) · cites this paper as Hoffmann et al., 2020
The Results section (‘SARS-CoV-2 Employs the SARS-CoV Receptor for Host Cell Entry’; page unavailable) identifies ACE2 as the receptor and the receptor-binding motif within the RBD as contacting ACE2. The Introduction (page unavailable) says S1 mediates receptor binding and S2 drives membrane fusion after protease priming. Our copy does not state that the RBD is at the C terminus of S1. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe spike protein of SARS-CoV-2 binds ACE2 and is cleaved by human type II TMPRSS2, facilitating viral entry into the cytosol.
“The spike protein of SARS-CoV-2 binds ACE2 and is cleaved by human type II TMPRSS2 (transmembrane serine protease-2) facilitating viral entry into the cytosol.”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [6]
ACE2 had been identified as the receptor for SARS-CoV and SARS-CoV-2.
“Importantly, ACE2 (angiotensin-converting enzyme 2) had been identified as the receptor for SARS-CoV 4,5 and SARS-CoV-2.”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [6]
SARS-CoV-2 uses angiotensin-converting enzyme 2 as a receptor.
“Since SARS-CoV-2 uses angiotensin-converting enzyme (ACE) 2 as a receptor (342, 343), it is speculated that SARS-CoV-2 induces pro-inflammatory cytokines through angiotensin II (AngII)/angiotensin type 1 receptor (AT1R) (15) as SARS-CoV-1 does (344–346).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [343]
The spike protein is a class I fusion protein that binds ACE2 on host cells and triggers virus-cell membrane fusion.
“The S protein is a class I fusion protein that facilitates binding of the virus to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell surface, which triggers fusion between the virus and cell membrane110,148,149.”
From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [148]
ACE2 is a major cellular entry point for SARS-CoV-2.
“the angiotensin-converting enzyme 2 (ACE2), was also a major cellular entry point for SARS-CoV-2 (Hoffmann et al., 2020).”
From COVID-19 and the human innate immune system (2021) · cites this paper as Hoffmann et al., 2020
The RBD is contained in the S1 subunit of spike and is responsible for interacting with ACE2.
“The RBD is contained in the S1 subunit of spike and is responsible for interacting with the SARS-CoV-2 cellular receptor angiotensin-converting enzyme-2 (ACE2) (Hoffmann et al., 2020).”
From Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera (2021) · cites this paper as Hoffmann et al., 2020
Host TMPRSS2 promotes Spike protein priming and facilitates SARS-CoV-2 entry.
“Host transmembrane protease serine 2 (TMPRSS2) promotes S protein priming and facilitates viral entry38.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [38]
The ACE2 interaction surface is a small 25-amino-acid patch at the apex of spike, presented to ACE2 when the RBD swings upward.
“The ACE2 interaction surface is a small 25-amino-acid patch at the apex of spike, presented to ACE2 when the RBD swings upward”
From Antibody evasion by the P.1 strain of SARS-CoV-2 (2021) · cites this paper as Hoffmann et al., 2020
The RBD interacts with ACE2, which is expressed on diverse cell types including cells in the upper and lower respiratory tracts, allowing SARS-CoV-2 to cause respiratory infection.
“The RBD interacts with the cellular receptor angiotensin converting enzyme 2 (ACE2), which is expressed on diverse cell types, including cells in the upper and lower respiratory tracts, allowing SARS-CoV-2 to cause respiratory infection.”
From Antibody evasion by the P.1 strain of SARS-CoV-2 (2021) · cites this paper as Hoffmann et al., 2020
Olfactory cells express ACE-2 and TMPRSS-2, which may represent the viral entry point to the CNS.
“Olfactory cells express angiotensin-converting enzyme isoform 2 (ACE-2) and type II serine protease (TMPRSS-2), which may represent the viral entry point to the CNS [163].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [163]
The interaction between SARS-CoV-2 S protein and ACE2 requires cleavage of the S protein, likely by TMPRSS2, although other proteases such as Cathepsin B and L may also be involved.
“This interaction requires cleavage of the S protein, likely by the cell surface protease TMPRSS2, although other proteases (such as Cathepsin B and L, CTSB/CTSL) may also be involved (4-6, 22-25).”
From Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia (2020) · cites this paper as [22]
SARS-CoV-2 infects cells through interactions between its spike (S) protein and the ACE2 protein on target cells.
“CoV-2 — like SARS-CoV — infects cells through interactions between its spike (S) protein and the ACE2 protein on target cells.”
From Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia (2020) · cites this paper as [22]
SARS-CoV-2 uses ACE2 as its main receptor to infect lung epithelial and endothelial cells.
“SARS-CoV-2 spike protein uses ACE2 as its main receptor, suggesting that the Renin-Angiotensin System (RAS) could play a role in COVID-19 pathology.”
ACE2 is the functional entry receptor for both SARS-CoV and SARS-CoV-2.
“ACE2 is the functional entry receptor for both severe acute respiratory syndrome (SARS) coronaviruses, SARS-CoV (36) and SARS-CoV-2 (37).”
From TCRD and pharos 2021: mining the human proteome for disease biology (2021) · cites this paper as [37]
The S protein is cleaved into S1 and S2 subunits during viral infection by the Furin enzyme and TMPRSS2.
“The S protein is cleaved into S1 and S2 subunits during viral infection by the Furin enzyme and transmembrane serine protease 2 (TMPRSS2).231,232”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [232]
The entire surface spike (S) glycoprotein of SARS-CoV-2 or the receptor binding domain (RBD) of the S protein represent the most widely selected and suitable antigen target sites in COVID-19 vaccine development.
“The entire surface spike (S) glycoprotein of SARS-CoV-2 or the receptor binding domain (RBD) of the S protein, which is critical for viral entry into the host cell,61 represent the most widely selected and suitable antigen target sites in COVID-19 vaccine development.”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [61]
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References 67 · Cited by 20,286
- Authors
- Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N.-H., Nitsche, A., Müller, M. A., Drosten, C., & Pöhlmann, S.
- Affiliations
- German Primate Center (DE)
- Humboldt-Universität zu Berlin (DE)
- University of Veterinary Medicine Hannover, Foundation (DE)
- Berufsgenossenschaftliche Unfallklinik Murnau (DE)
- Paracelsus Medical University (AT)
- Ludwig-Maximilians-Universität München (DE)
- Robert Koch Institute (DE)
- Sechenov University (RU)
- Corresponding author
- Hoffmann, Markus
- Pöhlmann, Stefan
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-04
- Volume
- 181
- Issue
- 2
- Pages
- 271-280.e8
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7102627
- OpenAlex
- W3009912996
- Cited by
- 20,286
- References
- 67
- Citations by year
- 2026: 469 · 2025: 865 · 2024: 1526 · 2023: 2286 · 2022: 3774 · 2021: 5711 · 2020: 5614 · 2019: 11 · 2018: 5 · 2015: 1 · 2014: 1 · 2013: 3 · 2012: 2
- FWCI
- 571.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- PUBLISSO (German National Library of Medicine) (submittedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Funders
- Bundesministerium für Bildung und Forschung (01KI1723D, 01KI1723A)
- Deutsche Forschungsgemeinschaft (WU 929/1-1)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- SARS-CoV-2, viral entry, ACE2, TMPRSS2, serine protease inhibitors, antiviral therapy, SARS-CoV, cross-neutralization, convalescent sera, receptor binding
- MeSH terms
- Betacoronavirus, Drug Development, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, COVID-19 Serotherapy, Ammonium Chloride, Animals, Antibodies, Viral, Cell Line, Esters, Guanidines, Humans, Immunization, Passive, Peptidyl-Dipeptidase A, Leucine, Pneumonia, Viral, Protease Inhibitors, Receptors, Virus, Serine Endopeptidases, Gabexate, Coronavirus, Vesiculovirus, Coronavirus Infections, Severe acute respiratory syndrome-related coronavirus, Virus Internalization, Antibodies, Neutralizing, Pandemics, Spike Glycoprotein, Coronavirus
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