Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant
Yang Liu,
Jianying Liu,
Bryan A. Johnson,
Hongjie Xia,
Zhiqiang Ku,
Craig Schindewolf,
Steven G. Widen,
Zhiqiang An,
Scott C. Weaver,
Vineet D. Menachery,
Xuping Xie,
Pei-Yong Shi
Affiliations
Yang Liu
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA
Jianying Liu
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
Bryan A. Johnson
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
Hongjie Xia
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
Zhiqiang Ku
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Craig Schindewolf
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
Steven G. Widen
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
Zhiqiang An
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Scott C. Weaver
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
Vineet D. Menachery
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
Xuping Xie
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA; Corresponding author
Pei-Yong Shi
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA; Corresponding author
Summary: 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.
