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Natural Polymorphisms Are Present in the Furin Cleavage Site of the SARS-CoV-2 Spike Glycoprotein.

ABSTRACT: The furin cleavage site in the spike glycoprotein of the SARS-CoV-2 coronavirus is considered important for the virus to enter the host cells. By analyzing 45828 SARS-CoV-2 genome sequences, we identified 103 strains of SARS-CoV-2 with various DNA mutations including 18 unique non-synonymous point mutations, one deletion, and six gains of premature stop codon that may affect the furin cleavage site. Our results revealed that the furin cleavage site might not be required for SARS-CoV-2 to enter human cells in vivo. The identified mutants may represent a new subgroup of SARS-CoV-2 coronavirus with reduced tropism and transmissibility as potential live-attenuated vaccine candidates.

SUBMITTER: Xing Y

PROVIDER: S-EPMC7379507 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Natural Polymorphisms Are Present in the Furin Cleavage Site of the SARS-CoV-2 Spike Glycoprotein.

Xing Yue Y Li Xiao X Gao Xiang X Dong Qunfeng Q

Frontiers in genetics 20200717

The furin cleavage site in the spike glycoprotein of the SARS-CoV-2 coronavirus is considered important for the virus to enter the host cells. By analyzing 45828 SARS-CoV-2 genome sequences, we identified 103 strains of SARS-CoV-2 with various DNA mutations including 18 unique non-synonymous point mutations, one deletion, and six gains of premature stop codon that may affect the furin cleavage site. Our results revealed that the furin cleavage site might not be required for SARS-CoV-2 to enter h ...[more]

PMID: 32765596

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Project description:SARS-CoV-2 has resulted in a global pandemic and shutdown economies around the world. Sequence analysis indicates that the novel coronavirus (CoV) has an insertion of a furin cleavage site (PRRAR) in its spike protein. Absent in other group 2B CoVs, the insertion may be a key factor in the replication and virulence of SARS-CoV-2. To explore this question, we generated a SARS-CoV-2 mutant lacking the furin cleavage site (ΔPRRA) in the spike protein. This mutant virus replicated with faster kinetics and improved fitness in Vero E6 cells. The mutant virus also had reduced spike protein processing as compared to wild-type SARS-CoV-2. In contrast, the ΔPRRA had reduced replication in Calu3 cells, a human respiratory cell line, and had attenuated disease in a hamster pathogenesis model. Despite the reduced disease, the ΔPRRA mutant offered robust protection from SARS-CoV-2 rechallenge. Importantly, plaque reduction neutralization tests (PRNT 50 ) with COVID-19 patient sera and monoclonal antibodies against the receptor-binding domain found a shift, with the mutant virus resulting in consistently reduced PRNT 50 titers. Together, these results demonstrate a critical role for the furin cleavage site insertion in SARS-CoV-2 replication and pathogenesis. In addition, these findings illustrate the importance of this insertion in evaluating neutralization and other downstream SARS-CoV-2 assays.ImportanceAs COVID-19 has impacted the world, understanding how SARS-CoV-2 replicates and causes virulence offers potential pathways to disrupt its disease. By removing the furin cleavage site, we demonstrate the importance of this insertion to SARS-CoV-2 replication and pathogenesis. In addition, the findings with Vero cells indicate the likelihood of cell culture adaptations in virus stocks that can influence reagent generation and interpretation of a wide range of data including neutralization and drug efficacy. Overall, our work highlights the importance of this key motif in SARS-CoV-2 infection and pathogenesis.Article summaryA deletion of the furin cleavage site in SARS-CoV-2 amplifies replication in Vero cells, but attenuates replication in respiratory cells and pathogenesis in vivo. Loss of the furin site also reduces susceptibility to neutralization in vitro .

Dataset Information

Natural Polymorphisms Are Present in the Furin Cleavage Site of the SARS-CoV-2 Spike Glycoprotein.

Publications

Natural Polymorphisms Are Present in the Furin Cleavage Site of the SARS-CoV-2 Spike Glycoprotein.

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