Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis

Bryan A. Johnson, Xuping Xie, Adam L. Bailey, Birte Kalveram, Kumari G. Lokugamage, Antonio Muruato, Jing Zou, Xianwen Zhang, Terry Juelich, Jennifer K. Smith, Lihong Zhang, Nathen Bopp, Craig Schindewolf, Michelle Vu, Abigail Vanderheiden, Emma S. Winkler, Daniele Swetnam, Jessica A. Plante, Patricia Aguilar, Kenneth S. Plante, Vsevolod Popov, Benhur Lee, Scott C. Weaver, Mehul S. Suthar, Andrew L. Routh, Ping Ren, Zhiqiang Ku, Zhiqiang An, Kari Debbink, Michael S. Diamond, Pei-Yong Shi, Alexander N. Freiberg and Vineet D. Menachery ()
Additional contact information
Bryan A. Johnson: University of Texas Medical Branch
Xuping Xie: University of Texas Medical Branch
Adam L. Bailey: Washington University School of Medicine
Birte Kalveram: University of Texas Medical Branch
Kumari G. Lokugamage: University of Texas Medical Branch
Antonio Muruato: University of Texas Medical Branch
Jing Zou: University of Texas Medical Branch
Xianwen Zhang: University of Texas Medical Branch
Terry Juelich: University of Texas Medical Branch
Jennifer K. Smith: University of Texas Medical Branch
Lihong Zhang: University of Texas Medical Branch
Nathen Bopp: University of Texas Medical Branch
Craig Schindewolf: University of Texas Medical Branch
Michelle Vu: University of Texas Medical Branch
Abigail Vanderheiden: Emory University School of Medicine
Emma S. Winkler: Washington University School of Medicine
Daniele Swetnam: University of Texas Medical Branch
Jessica A. Plante: University of Texas Medical Branch
Patricia Aguilar: University of Texas Medical Branch
Kenneth S. Plante: University of Texas Medical Branch
Vsevolod Popov: University of Texas Medical Branch
Benhur Lee: Icahn School of Medicine at Mount Sinai
Scott C. Weaver: University of Texas Medical Branch
Mehul S. Suthar: Emory University School of Medicine
Andrew L. Routh: University of Texas Medical Branch
Ping Ren: University of Texas Medical Branch
Zhiqiang Ku: University of Texas Health Science Center at Houston
Zhiqiang An: University of Texas Health Science Center at Houston
Kari Debbink: Department of Natural Sciences Bowie State University
Michael S. Diamond: Washington University School of Medicine
Pei-Yong Shi: University of Texas Medical Branch
Alexander N. Freiberg: University of Texas Medical Branch
Vineet D. Menachery: University of Texas Medical Branch

Nature, 2021, vol. 591, issue 7849, 293-299

Abstract: Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—a new coronavirus that has led to a worldwide pandemic1—has a furin cleavage site (PRRAR) in its spike protein that is absent in other group-2B coronaviruses2. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03237-4

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