tetano
Editor, Senior Moderator
Nature
. 2021 Jan 25.
doi: 10.1038/s41586-021-03237-4. Online ahead of print.
Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis
Bryan A Johnson[SUP] #[/SUP][SUP] 1 [/SUP], Xuping Xie[SUP] #[/SUP][SUP] 2 [/SUP], Adam L Bailey[SUP] #[/SUP][SUP] 3 [/SUP], Birte Kalveram[SUP] 4 [/SUP], Kumari G Lokugamage[SUP] 1 [/SUP], Antonio Muruato[SUP] 1 [/SUP], Jing Zou[SUP] 2 [/SUP], Xianwen Zhang[SUP] 2 [/SUP], Terry Juelich[SUP] 4 [/SUP], Jennifer K Smith[SUP] 4 [/SUP], Lihong Zhang[SUP] 4 [/SUP], Nathen Bopp[SUP] 4 [/SUP], Craig Schindewolf[SUP] 1 [/SUP], Michelle Vu[SUP] 1 [/SUP], Abigail Vanderheiden[SUP] 3 5 6 [/SUP], Emma S Winkler[SUP] 3 7 [/SUP], Daniele Swetnam[SUP] 2 [/SUP], Jessica A Plante[SUP] 1 [/SUP], Patricia Aguilar[SUP] 4 [/SUP], Kenneth S Plante[SUP] 1 [/SUP], Vsevolod Popov[SUP] 4 [/SUP], Benhur Lee[SUP] 8 [/SUP], Scott C Weaver[SUP] 1 9 [/SUP], Mehul S Suthar[SUP] 5 6 10 [/SUP], Andrew L Routh[SUP] 2 [/SUP], Ping Ren[SUP] 4 [/SUP], Zhiqiang Ku[SUP] 11 [/SUP], Zhiqiang An[SUP] 11 [/SUP], Kari Debbink[SUP] 12 [/SUP], Michael S Diamond[SUP] 3 7 13 [/SUP], Pei Yong Shi[SUP] 2 9 [/SUP], Alexander N Freiberg[SUP] 4 9 [/SUP], Vineet D Menachery[SUP] 14 15 [/SUP]
Affiliations
Abstract
SARS-CoV-2, a novel coronavirus (CoV)-producing worldwide pandemic[SUP]1[/SUP], has a furin cleavage site (PRRAR) in its spike protein that is absent in other group 2B CoVs[SUP]2[/SUP]. 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.
. 2021 Jan 25.
doi: 10.1038/s41586-021-03237-4. Online ahead of print.
Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis
Bryan A Johnson[SUP] #[/SUP][SUP] 1 [/SUP], Xuping Xie[SUP] #[/SUP][SUP] 2 [/SUP], Adam L Bailey[SUP] #[/SUP][SUP] 3 [/SUP], Birte Kalveram[SUP] 4 [/SUP], Kumari G Lokugamage[SUP] 1 [/SUP], Antonio Muruato[SUP] 1 [/SUP], Jing Zou[SUP] 2 [/SUP], Xianwen Zhang[SUP] 2 [/SUP], Terry Juelich[SUP] 4 [/SUP], Jennifer K Smith[SUP] 4 [/SUP], Lihong Zhang[SUP] 4 [/SUP], Nathen Bopp[SUP] 4 [/SUP], Craig Schindewolf[SUP] 1 [/SUP], Michelle Vu[SUP] 1 [/SUP], Abigail Vanderheiden[SUP] 3 5 6 [/SUP], Emma S Winkler[SUP] 3 7 [/SUP], Daniele Swetnam[SUP] 2 [/SUP], Jessica A Plante[SUP] 1 [/SUP], Patricia Aguilar[SUP] 4 [/SUP], Kenneth S Plante[SUP] 1 [/SUP], Vsevolod Popov[SUP] 4 [/SUP], Benhur Lee[SUP] 8 [/SUP], Scott C Weaver[SUP] 1 9 [/SUP], Mehul S Suthar[SUP] 5 6 10 [/SUP], Andrew L Routh[SUP] 2 [/SUP], Ping Ren[SUP] 4 [/SUP], Zhiqiang Ku[SUP] 11 [/SUP], Zhiqiang An[SUP] 11 [/SUP], Kari Debbink[SUP] 12 [/SUP], Michael S Diamond[SUP] 3 7 13 [/SUP], Pei Yong Shi[SUP] 2 9 [/SUP], Alexander N Freiberg[SUP] 4 9 [/SUP], Vineet D Menachery[SUP] 14 15 [/SUP]
Affiliations
- PMID: 33494095
- DOI: 10.1038/s41586-021-03237-4
Abstract
SARS-CoV-2, a novel coronavirus (CoV)-producing worldwide pandemic[SUP]1[/SUP], has a furin cleavage site (PRRAR) in its spike protein that is absent in other group 2B CoVs[SUP]2[/SUP]. 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.