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The N501Y spike substitution enhances SARS-CoV-2 transmission

Yang Liu, Jianying Liu, Kenneth S. Plante, Jessica A. Plante, Xuping Xie, Xianwen Zhang, Zhiqiang Ku, Zhiqiang An, Dionna Scharton, Craig Schindewolf, Vineet D. Menachery, Pei-Yong Shi, Scott C. Weaver
doi: https://doi.org/10.1101/2021.03.08.434499
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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Kenneth S. Plante
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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Jessica A. Plante
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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Xianwen Zhang
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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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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Dionna Scharton
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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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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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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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: peshi@UTMB.edu sweaver@utmb.edu
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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  • For correspondence: peshi@UTMB.edu sweaver@utmb.edu
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Summary

Beginning in the summer of 2020, a variant of SARS-CoV-2, the cause of the COVID-19 pandemic, emerged in the United Kingdom (UK). This B.1.1.7 variant increased rapidly in prevalence among sequenced strains, attributed to an increase in infection and/or transmission efficiency. The UK variant has 19 nonsynonymous mutations across its viral genome including 8 substitutions or deletions in the spike protein, which interacts with cellular receptors to mediate infection and tropism. Here, using a reverse genetics approach, we show that, of the 8 individual spike protein substitutions, only N501Y exhibited consistent fitness gains for replication in the upper airway in the hamster model as well as primary human airway epithelial cells. The N501Y substitution recapitulated the phenotype of enhanced viral transmission seen with the combined 8 UK spike mutations, suggesting it is a major determinant responsible for increased transmission of this variant. Mechanistically, the N501Y substitution improved the affinity of the viral spike protein for cellular receptors. As suggested by its convergent evolution in Brazil and South Africa, our results indicate that N501Y substitution is a major adaptive spike mutation of major concern.

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.

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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 March 09, 2021.
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The N501Y spike substitution enhances SARS-CoV-2 transmission
Yang Liu, Jianying Liu, Kenneth S. Plante, Jessica A. Plante, Xuping Xie, Xianwen Zhang, Zhiqiang Ku, Zhiqiang An, Dionna Scharton, Craig Schindewolf, Vineet D. Menachery, Pei-Yong Shi, Scott C. Weaver
bioRxiv 2021.03.08.434499; doi: https://doi.org/10.1101/2021.03.08.434499
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The N501Y spike substitution enhances SARS-CoV-2 transmission
Yang Liu, Jianying Liu, Kenneth S. Plante, Jessica A. Plante, Xuping Xie, Xianwen Zhang, Zhiqiang Ku, Zhiqiang An, Dionna Scharton, Craig Schindewolf, Vineet D. Menachery, Pei-Yong Shi, Scott C. Weaver
bioRxiv 2021.03.08.434499; doi: https://doi.org/10.1101/2021.03.08.434499

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