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The N501Y spike substitution enhances SARS-CoV-2 infection and transmission

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Abstract

Beginning in the summer of 2020, a variant of SARS-CoV-2, the cause of the COVID-19 pandemic, emerged in the United Kingdom. This B.1.1.7 variant, also known as Alpha, increased rapidly in prevalence, attributed to an increase in infection and/or transmission efficiency1. The Alpha 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 Alpha spike mutations, suggesting it is a major determinant of 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, South Africa, and elsewhere2,3, our results indicate that N501Y substitution is a major adaptive spike mutation of major concern.

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Correspondence to Pei-Yong Shi or Scott C. Weaver.

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Supplementary Tables

This file contains Supplementary Tables 1-3. Supplementary Table 1 contains input and output virus ratios in competition assays, Supplementary Table 2 shows total numbers of the 8 single substitutions in the Alpha spike gene among sequenced SARS-CoV-2 genomes and Supplementary Table 3 contains a list of primers used for mutation construction, RT-PCR, qPCR and sequencing.

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Liu, Y., Liu, J., Plante, K.S. et al. The N501Y spike substitution enhances SARS-CoV-2 infection and transmission. Nature (2021). https://doi.org/10.1038/s41586-021-04245-0

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