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

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 (Delta PRRA). Here we report that replicates of Delta PRRA 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 Delta PRRA 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 Delta PRRA 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 Delta PRRA 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.

Automated summary

The genetic mutation in SARS-CoV-2 resulted in better fitness in some cells but lower replication capacity in human respiratory cell lines. Despite reducing disease symptoms, the Delta PRRA mutant provided protection against rechallenge with the wildtype SARS-CoV-2.