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The furin cleavage site of SARS-CoV-2 spike protein is a key determinant for transmission due to enhanced replication in airway cells

2020; Cold Spring Harbor Laboratory; Linguagem: Inglês

10.1101/2020.09.30.318311

Thomas P. Peacock, Daniel H. Goldhill, Jie Zhou, Laury Baillon, Rebecca Frise, Olivia C. Swann, Ruthiran Kugathasan, Rebecca Penn, Jonathan C. Brown, Raul Y. Sanchez-David, Luca Braga, Maia Kavanagh Williamson, Jack A. Hassard, Ecco Staller, Brian Hanley, Michael Osborn, Mauro Giacca, Andrew D. Davidson, David A. Matthews, William Barclay,

Respiratory viral infections research

Summary 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.