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Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2

Samuel J. Dicken, View ORCID ProfileMatthew J. Murray, View ORCID ProfileLucy G. Thorne, View ORCID ProfileAnn-Kathrin Reuschl, View ORCID ProfileCalum Forrest, Maaroothen Ganeshalingham, View ORCID ProfileLuke Muir, View ORCID ProfileMphatso D. Kalemera, View ORCID ProfileMachaela Palor, View ORCID ProfileLaura E. McCoy, View ORCID ProfileClare Jolly, Greg J. Towers, View ORCID ProfileMatthew B. Reeves, View ORCID ProfileJoe Grove
doi: https://doi.org/10.1101/2021.03.22.436468
Samuel J. Dicken
1Division of Infection and Immunity, University College London, UK
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Matthew J. Murray
1Division of Infection and Immunity, University College London, UK
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  • ORCID record for Matthew J. Murray
Lucy G. Thorne
1Division of Infection and Immunity, University College London, UK
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Ann-Kathrin Reuschl
1Division of Infection and Immunity, University College London, UK
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Calum Forrest
1Division of Infection and Immunity, University College London, UK
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Maaroothen Ganeshalingham
1Division of Infection and Immunity, University College London, UK
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Luke Muir
1Division of Infection and Immunity, University College London, UK
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Mphatso D. Kalemera
1Division of Infection and Immunity, University College London, UK
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Machaela Palor
1Division of Infection and Immunity, University College London, UK
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Laura E. McCoy
1Division of Infection and Immunity, University College London, UK
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Clare Jolly
1Division of Infection and Immunity, University College London, UK
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Greg J. Towers
1Division of Infection and Immunity, University College London, UK
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Matthew B. Reeves
1Division of Infection and Immunity, University College London, UK
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Joe Grove
1Division of Infection and Immunity, University College London, UK
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  • For correspondence: j.grove@ucl.ac.uk
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Abstract

The recent emergence of SARS-CoV-2 variants with increased transmission, pathogenesis and immune resistance has jeopardised the global response to the COVID-19 pandemic. Determining the fundamental biology of viral variants and understanding their evolutionary trajectories will guide current mitigation measures, future genetic surveillance and vaccination strategies. Here we examine virus entry by the B.1.1.7 lineage, commonly referred to as the UK/Kent variant. Pseudovirus infection of model cell lines demonstrate that B.1.1.7 entry is enhanced relative to the Wuhan-Hu-1 reference strain, particularly under low expression of receptor ACE2. Moreover, the entry characteristics of B.1.1.7 were distinct from that of its predecessor strain containing the D614G mutation. These data suggest evolutionary tuning of spike protein function. Additionally, we found that amino acid deletions within the N-terminal domain (NTD) of spike were important for efficient entry by B.1.1.7. The NTD is a hotspot of diversity across sarbecoviruses, therefore, we further investigated this region by examining the entry of closely related CoVs. Surprisingly, Pangolin CoV spike entry was 50-100 fold enhanced relative to SARS-CoV-2; suggesting there may be evolutionary pathways by which SARS-CoV-2 may further optimise entry. Swapping the NTD between Pangolin CoV and SARS-CoV-2 demonstrates that changes in this region alone have the capacity to enhance virus entry. Thus, the NTD plays a hitherto unrecognised role in modulating spike activity, warranting further investigation and surveillance of NTD mutations.

Competing Interest Statement

The authors have declared no competing interest.

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 4.0 International license.
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Posted March 22, 2021.
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Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2
Samuel J. Dicken, Matthew J. Murray, Lucy G. Thorne, Ann-Kathrin Reuschl, Calum Forrest, Maaroothen Ganeshalingham, Luke Muir, Mphatso D. Kalemera, Machaela Palor, Laura E. McCoy, Clare Jolly, Greg J. Towers, Matthew B. Reeves, Joe Grove
bioRxiv 2021.03.22.436468; doi: https://doi.org/10.1101/2021.03.22.436468
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Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2
Samuel J. Dicken, Matthew J. Murray, Lucy G. Thorne, Ann-Kathrin Reuschl, Calum Forrest, Maaroothen Ganeshalingham, Luke Muir, Mphatso D. Kalemera, Machaela Palor, Laura E. McCoy, Clare Jolly, Greg J. Towers, Matthew B. Reeves, Joe Grove
bioRxiv 2021.03.22.436468; doi: https://doi.org/10.1101/2021.03.22.436468

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