The furin cleavage site of SARS-CoV-2 spike protein is a key determinant for transmission due to enhanced replication in airway cells.
Peacock, T. P.; Goldhill, D. H.; Zhou, J.; Baillon, L.; Frise, R.; Swann, O. C.; Kugathasan, R.; Penn, R.; Brown, J. C.; Sanchez-David, R. Y.; Braga, L.; Williamson, M. K.; Hassard, J. A.; Staller, E.; Hanley, B.; Osborn, M.; Giacca, M.; Davidson, A. D.; Matthews, D. A.; Barclay, W. S.
Show abstract
SARS-CoV-2 enters cells via its spike glycoprotein which must be cleaved sequentially at the S1/S2, then the S2 cleavage sites (CS) to mediate membrane fusion. SARS-CoV-2 has a unique polybasic insertion at the S1/S2 CS, which we demonstrate can be cleaved by furin. Using lentiviral pseudotypes and a cell-culture adapted SARS-CoV-2 virus with a S1/S2 deletion, we show that the polybasic insertion is selected for in lung cells and primary human airway epithelial cultures but selected against in Vero E6, a cell line used for passaging SARS-CoV-2. We find this selective advantage depends on expression of the cell surface protease, TMPRSS2, that allows virus entry independent of endosomes thus avoiding antiviral IFITM proteins. SARS-CoV-2 virus lacking the S1/S2 furin CS was shed to lower titres from infected ferrets and was not transmitted to cohoused sentinel animals. Thus, the polybasic CS is a key determinant for efficient SARS-CoV-2 transmission.
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