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. PlanteVsevolod 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, Vineet D. Menachery

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)293-299
Number of pages7
JournalNature
Volume591
Issue number7849
DOIs
StatePublished - Mar 11 2021

ASJC Scopus subject areas

  • General

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