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Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis #MMPMID33494095
Johnson BA; Xie X; Bailey AL; Kalveram B; Lokugamage KG; Muruato A; Zou J; Zhang X; Juelich T; Smith JK; Zhang L; Bopp N; Schindewolf C; Vu M; Vanderheiden A; Winkler ES; Swetnam D; Plante JA; Aguilar P; Plante KS; Popov V; Lee B; Weaver SC; Suthar MS; Routh AL; Ren P; Ku Z; An Z; Debbink K; Diamond MS; Shi PY; Freiberg AN; Menachery VD
Nature 2021[Mar]; 591 (7849): 293-299 PMID33494095show ga
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 (DeltaPRRA). Here we report that replicates of DeltaPRRA 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 DeltaPRRA 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 DeltaPRRA 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 DeltaPRRA 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.