The furin cleavage site in the SARS-CoV-2 spike protein is required for transmission in ferrets
By T. Peacock, Daniel H. Goldhill, Jie Zhou, L. Baillon, R. Frise, O. Swann, R. Kugathasan, R. Penn, Jonathan C. Brown, Raul Y. Sanchez-David and 10 more. Nature Microbiology, 2021
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SARS-CoV-2 entry requires sequential cleavage of the spike glycoprotein at the S1/S2 and the S2ʹ cleavage sites to mediate membrane fusion. SARS-CoV-2 has a polybasic insertion (PRRAR) at the S1/S2 cleavage site that can be cleaved by furin. Using lentiviral pseudotypes and a cell-culture-adapted SARS-CoV-2 virus with an S1/S2 deletion, we show that the polybasic insertion endows SARS-CoV-2 with a selective advantage in lung cells and primary human airway epithelial cells, but impairs replication in Vero E6, a cell line used for passaging SARS-CoV-2. Using engineered spike variants and live virus competition assays and by measuring growth kinetics, we find that the selective advantage in lung and primary human airway epithelial cells depends on the expression of the cell surface protease TMPRSS2, which enables endosome-independent virus entry by a route that avoids antiviral IFITM proteins. SARS-CoV-2 virus lacking the S1/S2 furin cleavage site was shed to lower titres from infected ferrets and was not transmitted to cohoused sentinel animals, unlike wild-type virus. Analysis of 100,000 SARS-CoV-2 sequences derived from patients and 24 human postmortem tissues showed low frequencies of naturally occurring mutants that harbour deletions at the polybasic site. Taken together, our findings reveal that the furin cleavage site is an important determinant of SARS-CoV-2 transmission. Efficient transmission of SARS-CoV-2 among infected ferrets requires a functional furin cleavage site in the SARS-CoV-2 spike protein.
View Paper: https://www.semanticscholar.org/paper/8f71a2db36d3bf672729221cc30472508eb41d64
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Citations in the corpus
- Omicron variant of SARS‐CoV‐2: Genomics, transmissibility, and responses to current COVID‐19 vaccines (2022, background): “Omicron variant mutations H655Y and N679K are present near the furin cleavage site (FCS) and can increase spike cleavage, making the virus more contagious.(27,28)”
- Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant (2021, background): “Type I IFN restriction of SARS-CoV-2 is mediated in part by interferon induced membrane protein 2 (IFITM2) suppression of viral entry, and IFITM2 sensitivity is influenced by the Spike sequence 33,34 .”