Bryan A. Johnson, Xuping Xie, Adam Leitman Bailey, Birte Kalveram, K. Lokugamage, Antonio E. Muruato, Jing Zou, Xianwen Zhang, T. Juelich, Jennifer K. Smith, Lihong Zhang, Nathen E. Bopp, Craig Schindewolf, M. Vu, A. Vanderheiden, Emma S. Winkler, D. Swetnam, J. Plante, P. Aguilar, K. Plante, V. Popov, Benhur Lee, S. Weaver, M. Suthar, A. Routh, Ping Ren, Z. Ku, Z. An, K. Debbink, M. Diamond, P. Shi, Alexander N. Freiberg, V. Menachery
Nature, 2021
SARS-CoV-2, a novel coronavirus (CoV)-producing worldwide pandemic1, has a furin cleavage site (PRRAR) in its spike protein that is absent in other group 2B CoVs2. To explore whether the furin cleavage site contributes to infection and pathogenesis, we generated a mutant SARS-CoV-2 deleting the furin cleavage site (ΔPRRA). SARS-CoV-2 ΔPRRA replicates 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, COVID-19 patient sera and receptor-binding domain (RBD) monoclonal antibodies had lower neutralization values against the ΔPRRA mutant versus parental SARS-CoV-2, likely due to increased particle/PFU ratio. Together, these results demonstrate a critical role for the furin cleavage site in SARS-CoV-2 infection and highlight the importance of this site in evaluating antibody neutralization activity.
Cited by 90 publications.
Field of study: Medicine