Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis
Open accessAbstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-a new coronavirus that has led to a worldwide pandemic 1-has a furin cleavage site (PRRAR) in its spike protein that is absent in other group-2B coronaviruses 2. To explore whether the furin cleavage site contributes to infection and pathogenesis in this virus, we generated a mutant SARS-CoV-2 that lacks the furin cleavage site (ΔPRRA). Here we report that replicates of ΔPRRA SARS-CoV-2 had faster kinetics, improved fitness in Vero E6 cells and reduced spike protein processing, as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. Despite reduced disease, the ΔPRRA mutant conferred protection against rechallenge with the parental SARS-CoV-2. Importantly, the neutralization values of sera from patients with coronavirus disease 2019 (COVID-19) and monoclonal antibodies against the receptor-binding domain of SARS-CoV-2 were lower against the ΔPRRA mutant than against parental SARS-CoV-2, probably owing to an increased ratio of particles to plaque-forming units in infections with the former. Together, our results demonstrate a critical role for the furin cleavage site in infection with SARS-CoV-2 and highlight the importance of this site for evaluating the neutralization activities of antibodies.
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Propagation in Vero-TMPRSS2 and Vero-hACE2-TMPRSS2 cells prevented adventitious spike mutations, especially near furin cleavage site.
“Recombinant viruses and B.1.1.7 were propagated in Vero-TMPRSS2 and Vero-hACE2-TMPRSS2 cells expressing transmembrane protease serine 2 (TMPRSS2) and human angiotensin converting enzyme 2 (hACE2) to prevent the development of adventitious mutations in the spike, especially at or near the furin cleavage site”
From Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies (2021) · cites this paper as [16]
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References 48 · Cited by 694
Research works printed but not linked: 2
- [28]Harcourt J, Severe Acute Respiratory Syndrome Coronavirus 2 from Patient with 2019 Novel Coronavirus Disease, United States. Emerg Infect Dis 26(2020). PMC7258473 32160149
- [32]Xie X, An Infectious cDNA Clone of SARS-CoV-2. Cell host & microbe 27, 841–848 e843 (2020). PMC7153529 32289263
- Authors
- Johnson, B. A., Xie, X., Bailey, A. L., Kalveram, B., Lokugamage, K. G., Muruato, A., Zou, J., Zhang, X., Juelich, T., Smith, J. K., Zhang, L., Bopp, N., Schindewolf, C., Vu, M., Vanderheiden, A., Winkler, E. S., Swetnam, D., Plante, J. A., Aguilar, P., Plante, K. S., Popov, V., Lee, B., Weaver, S. C., Suthar, M. S., Routh, A. L., Ren, P., Ku, Z., An, Z., Debbink, K., Diamond, M. S., Shi, P.-Y., Freiberg, A. N., & Menachery, V. D.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Washington University in St. Louis (US)
- Emory University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
- Bowie State University (US)
- Corresponding author
- Menachery, Vineet D.
- ORCID
- Johnson, Bryan A.
- Xie, Xuping
- Bailey, Adam L.
- Zou, Jing
- Zhang, Xianwen
- Juelich, Terry
- Smith, Jennifer K.
- Zhang, Lihong
- Schindewolf, Craig
- Vu, Michelle
- Vanderheiden, Abigail
- Winkler, Emma S.
- Swetnam, Daniele
- Plante, Jessica A.
- Plante, Kenneth S.
- Popov, Vsevolod
- Lee, Benhur
- Weaver, Scott C.
- Suthar, Mehul S.
- Routh, Andrew L.
- Ren, Ping
- Ku, Zhiqiang
- An, Zhiqiang
- Debbink, Kari
- Diamond, Michael S.
- Shi, Pei-Yong
- Freiberg, Alexander N.
- Menachery, Vineet D.
- Venue
- Nature
- Published
- 2021-01-25
- Volume
- 591
- Issue
- 7849
- Pages
- 293-299
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8175039
- OpenAlex
- W3122148095
- Cited by
- 694
- References
- 48
- Citations by year
- 2026: 30 · 2025: 52 · 2024: 92 · 2023: 112 · 2022: 215 · 2021: 185 · 2020: 8
- FWCI
- 47.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- John S. Dunn Foundation (AI145617)
- University of Texas System
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (AI134907)
- National Institutes of Health (HR001117S0019, AG049042, AI145617, AI142759, UL1TR001439)
- Centers for Disease Control and Prevention
- National Institute on Aging (AI142759, AG049042, R00AG049092)
- National Institute of Allergy and Infectious Diseases (R01AI157155, R43AI145617, F30AI152327, AI142759, R24AI120942, R01AI134907, R01AI123449, HR001117S0019, R21AI145400, U19AI142759, R01AI153602, AI153602, AG049042, AI134907, AI145617, T32AI007526, T32AI007163)
- National Center for Advancing Translational Sciences
- 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 › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, furin cleavage site, viral attenuation, viral replication kinetics, neutralizing antibodies, receptor binding domain, COVID-19 pandemic, hamster model, plaque-forming units
- MeSH terms
- COVID-19, SARS-CoV-2, Amino Acid Sequence, Animals, Cell Line, Chlorocebus aethiops, Female, Cricetinae, Humans, Lung Diseases, Male, Mice, Transgenic, Models, Molecular, Mutation, Serine Endopeptidases, Vero Cells, Virus Replication, Furin, Mutant Proteins, Mice, Antibodies, Neutralizing, Proteolysis, Spike Glycoprotein, Coronavirus
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