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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
doi: https://doi.org/10.1101/2021.08.12.456173
Yang Liu
1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
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Jianying Liu
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston TX, USA
4Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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Bryan A. Johnson
4Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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Hongjie Xia
1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
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Zhiqiang Ku
5Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Craig Schindewolf
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston TX, USA
4Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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Steven G. Widen
1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
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Zhiqiang An
5Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Scott C. Weaver
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston TX, USA
4Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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Vineet D. Menachery
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston TX, USA
4Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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Xuping Xie
1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
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  • For correspondence: xuxie@UTMB.edu peshi@UTMB.edu
Pei-Yong Shi
1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston TX, USA
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  • For correspondence: xuxie@UTMB.edu peshi@UTMB.edu
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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.

Competing Interest Statement

X.X., V.D.M., and P.-Y.S. have filed a patent on the reverse genetic system and reporter SARS-CoV-2. Other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 05, 2021.
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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
bioRxiv 2021.08.12.456173; doi: https://doi.org/10.1101/2021.08.12.456173
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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
bioRxiv 2021.08.12.456173; doi: https://doi.org/10.1101/2021.08.12.456173

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