The Polybasic Cleavage Site in SARS-CoV-2 Spike Modulates Viral Sensitivity to Type I Interferon and IFITM2

• DOI: 10.1128/jvi.02422-20
• Publication Date: 2021-02-10T13:17:12Z
• Authors: Helena Winstone; Maria Jose Lista; Alisha C. Reid; Clement Bouton; Suzanne Pickering; Rui Pedro Galao; Claire Kerridge; Katie J. Doores; Chad M. Swanson; Stuart J. D. Neil
• Keywords: Furin; Cleavage (geology); Coronavirus

The cellular entry of severe acute respiratory syndrome-associated coronaviruses types 1 and 2 (SARS-CoV-1 -2) requires sequential protease processing the viral spike glycoprotein. presence a polybasic cleavage site in SARS-CoV-2 at S1/S2 boundary has been suggested to be factor increased transmissibility compared SARS-CoV-1 by facilitating maturation precursor furin-like proteases producer cells rather than endosomal cathepsins target. We investigate relevance route consequences this for sensitivity interferons (IFNs) and, more specifically, IFN-induced transmembrane (IFITM) protein family that inhibit diverse enveloped viruses. found is restricted predominantly IFITM2, IFITM3, degree restriction governed entry. Importantly, removal renders highly pH cathepsin dependent late endosomes, where, like spike, it sensitive IFITM2 restriction. Furthermore, we potent inhibition replication type I but not II IFNs alleviated targeted depletion expression. propose allows mediate pH-independent manner, part mitigate against IFITM-mediated promote transmission. This suggests therapeutic strategies target furin-mediated may reduce through activity IFNs.