Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant

• Published in: Cell Reports 2022-05, Vol.39 (7), p.110829-110829, Article 110829
• Main Authors: Liu, Yang, Liu, Jianying, Johnson, Bryan A., Xia, Hongjie, Ku, Zhiqiang, Schindewolf, Craig, Widen, Steven G., An, Zhiqiang, Weaver, Scott C., Menachery, Vineet D., Xie, Xuping, Shi, Pei-Yong
• Format: Article
• Language: English
• Subjects: COVID-19 - genetics; CP: Microbiology; Delta variant; fitness; human airway culture; Humans; Mutation - genetics; S1/S2 cleavage; SARS-CoV-2; SARS-CoV-2 - genetics; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - genetics; spike P681R; viral entry
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110829

We report that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta spike mutation P681R plays a key role in the Alpha-to-Delta variant replacement during the coronavirus disease 2019 (COVID-19) pandemic. Delta SARS-CoV-2 efficiently outcompetes the Alpha variant in human lung epithelial cells and primary human airway tissues. The Delta spike mutation P681R is located at a furin cleavage site that separates the spike 1 (S1) and S2 subunits. Reverting the P681R mutation to wild-type P681 significantly reduces the replication of the Delta variant to a level lower than the Alpha variant. Mechanistically, the Delta P681R mutation enhances the cleavage of the full-length spike to S1 and S2, which could improve cell-surface-mediated virus entry. In contrast, the Alpha spike also has a mutation at the same amino acid (P681H), but the cleavage of the Alpha spike is reduced compared with the Delta spike. Our results suggest P681R as a key mutation in enhancing Delta-variant replication via increased S1/S2 cleavage. [Display omitted] •SARS-CoV-2 spike P681R mutation contributes to Alpha-to-Delta variant replacement•Delta P681R mutation enhances the cleavage of full-length spike to S1 and S2•Mutations affecting S1/S2 cleavage must be closely monitored in variant surveillance It is important to identify mutations that account for the emergence of SARS-CoV-2 variants. Liu et al. show that the Delta spike mutation P681R enhances the cleavage of full-length spike to S1 and S2, which improves cell-surface-mediated virus entry and leads to the Alpha-to-Delta variant replacement.