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The lethal triad: SARS-CoV-2 Spike, ACE2 and TMPRSS2. Mutations in host and pathogen may affect the course of pandemic

View ORCID ProfileMatteo Calcagnile, View ORCID ProfilePatricia Forgez, Marco Alifano, View ORCID ProfilePietro Alifano
doi: https://doi.org/10.1101/2021.01.12.426365
Matteo Calcagnile
1Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
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Patricia Forgez
2INSERM UMR-S 1124 T3S, Eq 5 CELLULAR HOMEOSTASIS, CANCER and THERAPY, University of Paris, Campus Saint Germain, Paris, France
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Marco Alifano
3Thoracic Surgery Department, Cochin Hospital, APHP Centre, University of Paris, France; INSERM U1138 Team «Cancer, Immune Control, and Escape», Cordeliers Research Center, University of Paris, France
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  • For correspondence: pietro.alifano@unisalento.it marco.alifano@aphp.fr
Pietro Alifano
1Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
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  • For correspondence: pietro.alifano@unisalento.it marco.alifano@aphp.fr
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Abstract

Variants of SARS-CoV-2 have been identified rapidly after the beginning of pandemic. One of them, involving the spike protein and called D614G, represents a substantial percentage of currently isolated strains. While research on this variant was ongoing worldwide, on December 20th 2020 the European Centre for Disease Prevention and Control reported a Threat Assessment Brief describing the emergence of a new variant of SARS-CoV-2, named B.1.1.7, harboring multiple mutations mostly affecting the Spike protein. This viral variant has been recently associated with a rapid increase in COVID-19 cases in South East England, with alarming implications for future virus transmission rates. Specifically, of the nine amino acid replacements that characterize the Spike in the emerging variant, four are found in the region between the Fusion Peptide and the RBD domain (namely the already known D614G, together with A570D, P681H, T716I), and one, N501Y, is found in the Spike Receptor Binding Domain – Receptor Binding Motif (RBD-RBM). In this study, by using in silico biology, we provide evidence that these amino acid replacements have dramatic effects on the interactions between SARS-CoV-2 Spike and the host ACE2 receptor or TMPRSS2, the protease that induces the fusogenic activity of Spike. Mostly, we show that these effects are strongly dependent on ACE2 and TMPRSS2 polymorphism, suggesting that dynamics of pandemics are strongly influenced not only by virus variation but also by host genetic background.

Competing Interest Statement

The authors have declared no competing interest.

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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. All rights reserved. No reuse allowed without permission.
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Posted January 14, 2021.
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The lethal triad: SARS-CoV-2 Spike, ACE2 and TMPRSS2. Mutations in host and pathogen may affect the course of pandemic
Matteo Calcagnile, Patricia Forgez, Marco Alifano, Pietro Alifano
bioRxiv 2021.01.12.426365; doi: https://doi.org/10.1101/2021.01.12.426365
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The lethal triad: SARS-CoV-2 Spike, ACE2 and TMPRSS2. Mutations in host and pathogen may affect the course of pandemic
Matteo Calcagnile, Patricia Forgez, Marco Alifano, Pietro Alifano
bioRxiv 2021.01.12.426365; doi: https://doi.org/10.1101/2021.01.12.426365

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