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Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant.
bioRxiv. 2021 Sep 05B

Abstract

SARS-CoV-2 Delta variant has rapidly replaced the Alpha variant around the world. The mechanism that drives this global replacement has not been defined. Here we report that Delta spike mutation P681R plays a key role in the Alpha-to-Delta variant replacement. In a replication competition assay, Delta SARS-CoV-2 efficiently outcompeted the Alpha variant in human lung epithelial cells and primary human airway tissues. Delta SARS-CoV-2 bearing the Alpha-spike glycoprotein replicated less efficiently than the wild-type Delta variant, suggesting the importance of Delta spike in enhancing viral replication. The Delta spike has accumulated mutation P681R located at a furin cleavage site that separates the spike 1 (S1) and S2 subunits. Reverting the P681R mutation to wild-type P681 significantly reduced the replication of Delta variant, to a level lower than the Alpha variant. Mechanistically, the Delta P681R mutation enhanced the cleavage of the full-length spike to S1 and S2, leading to increased infection via cell surface entry. In contrast, the Alpha spike also has a mutation at the same amino acid (P681H), but the spike cleavage from purified Alpha virions was reduced compared to the Delta spike. Collectively, our results indicate P681R as a key mutation in enhancing Delta variant replication via increased S1/S2 cleavage. Spike mutations that potentially affect furin cleavage efficiency must be closely monitored for future variant surveillance.

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Authors+Show Affiliations

Liu Y
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.
Liu J
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.
Johnson BA
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA.
Xia H
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA.
Ku Z
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Schindewolf C
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.
Widen SG
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA.
An Z
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Weaver SC
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.
Menachery VD
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.
Xie X
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA.
Shi PY
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.

Pub Type(s)

Preprint

Language

eng

PubMed ID

34462752

Citation

Liu, Yang, et al. "Delta Spike P681R Mutation Enhances SARS-CoV-2 Fitness Over Alpha Variant." BioRxiv : the Preprint Server for Biology, 2021.
Liu Y, Liu J, Johnson BA, et al. Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant. bioRxiv. 2021.
Liu, Y., Liu, J., Johnson, B. A., Xia, H., Ku, Z., Schindewolf, C., Widen, S. G., An, Z., Weaver, S. C., Menachery, V. D., Xie, X., & Shi, P. Y. (2021). Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant. BioRxiv : the Preprint Server for Biology. https://doi.org/10.1101/2021.08.12.456173
Liu Y, et al. Delta Spike P681R Mutation Enhances SARS-CoV-2 Fitness Over Alpha Variant. bioRxiv. 2021 Sep 5; PubMed PMID: 34462752.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant. AU - Liu,Yang, AU - Liu,Jianying, AU - Johnson,Bryan A, AU - Xia,Hongjie, AU - Ku,Zhiqiang, AU - Schindewolf,Craig, AU - Widen,Steven G, AU - An,Zhiqiang, AU - Weaver,Scott C, AU - Menachery,Vineet D, AU - Xie,Xuping, AU - Shi,Pei-Yong, Y1 - 2021/09/05/ PY - 2021/9/1/pubmed PY - 2021/9/1/medline PY - 2021/8/31/entrez JF - bioRxiv : the preprint server for biology JO - bioRxiv N2 - SARS-CoV-2 Delta variant has rapidly replaced the Alpha variant around the world. The mechanism that drives this global replacement has not been defined. Here we report that Delta spike mutation P681R plays a key role in the Alpha-to-Delta variant replacement. In a replication competition assay, Delta SARS-CoV-2 efficiently outcompeted the Alpha variant in human lung epithelial cells and primary human airway tissues. Delta SARS-CoV-2 bearing the Alpha-spike glycoprotein replicated less efficiently than the wild-type Delta variant, suggesting the importance of Delta spike in enhancing viral replication. The Delta spike has accumulated mutation P681R located at a furin cleavage site that separates the spike 1 (S1) and S2 subunits. Reverting the P681R mutation to wild-type P681 significantly reduced the replication of Delta variant, to a level lower than the Alpha variant. Mechanistically, the Delta P681R mutation enhanced the cleavage of the full-length spike to S1 and S2, leading to increased infection via cell surface entry. In contrast, the Alpha spike also has a mutation at the same amino acid (P681H), but the spike cleavage from purified Alpha virions was reduced compared to the Delta spike. Collectively, our results indicate P681R as a key mutation in enhancing Delta variant replication via increased S1/S2 cleavage. Spike mutations that potentially affect furin cleavage efficiency must be closely monitored for future variant surveillance. UR - https://www.unboundmedicine.com/medline/citation/34462752/Delta_spike_P681R_mutation_enhances_SARS_CoV_2_fitness_over_Alpha_variant_ DB - PRIME DP - Unbound Medicine ER -