Cited by 3,109SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections StudiesZoonotic diseases and public health

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

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Letko, Michael, Marzi, Andrea, Munster, Vincent·2020·Nature Microbiology

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Abstract

Over the past 20 years, several coronaviruses have crossed the species barrier into humans, causing outbreaks of severe, and often fatal, respiratory illness. Since SARS-CoV was first identified in animal markets, global viromics projects have discovered thousands of coronavirus sequences in diverse animals and geographic regions. Unfortunately, there are few tools available to functionally test these viruses for their ability to infect humans, which has severely hampered efforts to predict the next zoonotic viral outbreak. Here, we developed an approach to rapidly screen lineage B betacoronaviruses, such as SARS-CoV and the recent SARS-CoV-2, for receptor usage and their ability to infect cell types from different species. We show that host protease processing during viral entry is a significant barrier for several lineage B viruses and that bypassing this barrier allows several lineage B viruses to enter human cells through an unknown receptor. We also demonstrate how different lineage B viruses can recombine to gain entry into human cells, and confirm that human ACE2 is the receptor for the recently emerging SARS-CoV-2.

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  • The SARS-CoV-2 Spike protein mediates binding of coronaviruses to ACE2 on the surface of various cell types including epithelial cells of the pulmonary alveolus.

    “The S protein mediates binding of coronaviruses to angiotensin converting enzyme 2 (ACE2) on the surface of various cell types including epithelial cells of the pulmonary alveolus (4–6).”

    From An <i>Alphavirus</i> -derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates (2020) · cites this paper as [5]

    The Results (‘Receptor usage of SARS-CoV-2’; page not provided) report that a spike chimera containing the SARS-CoV-2 receptor-binding domain entered cells expressing human ACE2. The paper does not establish ACE2 binding on pulmonary alveolar epithelial cells. Its Main section also identifies a different receptor for MERS-CoV, so the ACE2 statement does not apply to coronaviruses generally. (LLM, conf=0.87)

    Experimental — accuracy not yet measured
  • The SARS-CoV-2 spike RBD directly interacts with ACE2, the cellular receptor that mediates host cell entry.

    “it directly interacts with the cellular receptor angiotensin converting enzyme 2 (ACE2) which mediates host cell entry”
  • SARS-CoV-2 is a single-stranded RNA β-coronavirus and a member of the subgenus Sarbecovirus (beta-CoV lineage B).

    “SARS-CoV-2 is a single-stranded RNA β-coronavirus and a member of the subgenus Sarbecovirus (beta-CoV lineage B).”

    From Oral Microbiome and SARS-CoV-2: Beware of Lung Co-infection (2020) · cites this paper as Letko et al., 2020

  • SARS-CoV-2 is the seventh member of the Coronaviridae known to infect humans, two of which, SARS-CoV and MERS-CoV, caused global health threats previously.

    “It is the seventh member of the Coronaviridae known to infect humans so far, two of which, SARS-CoV and MERS-CoV, caused global health threats previously (Guarner, 2020; Letko et al., 2020).”

    From Oral Microbiome and SARS-CoV-2: Beware of Lung Co-infection (2020) · cites this paper as Letko et al., 2020

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Authors
Letko, M., Marzi, A., & Munster, V.
Affiliations
  • National Institutes of Health (US)
  • National Institute of Allergy and Infectious Diseases (US)
Corresponding author
  • Letko, Michael
  • Munster, Vincent
Venue
Nature Microbiology
Published
2020-02-24
Volume
5
Issue
4
Pages
562-569
ISSN
2058-5276 (ISSN-L)
OpenAlex
W3008394341
Cited by
3,109
References
38
Citations by year
2026: 47 · 2025: 122 · 2024: 198 · 2023: 287 · 2022: 571 · 2021: 874 · 2020: 1002 · 2019: 2 · 2018: 4
FWCI
89.66
Type
journal article
Language
en
Open access
Locations
  • Nature Microbiology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Chinese Center for Disease Control and Prevention
  • Chinese Academy of Medical Sciences
  • Peking Union Medical College
  • National Institute of Allergy and Infectious Diseases
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Zoonotic diseases and public health
Keywords
SARS-CoV-2, SARS-CoV, cell entry, ACE2 receptor, zoonotic transmission, viral recombination, cross-species infection
MeSH terms
Protein Domains, Betacoronavirus, Receptors, Coronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Animals, Cell Line, Humans, Peptidyl-Dipeptidase A, Mutation, Pneumonia, Viral, Receptors, Virus, Recombinant Fusion Proteins, Trypsin, Coronavirus Infections, Dipeptidyl Peptidase 4, CD13 Antigens, Severe acute respiratory syndrome-related coronavirus, Virus Internalization, Pandemics, Spike Glycoprotein, Coronavirus

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