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Collaboration Between Host and Viral Factors Shape SARS-CoV-2 Evolution

View ORCID ProfileConnor G. G. Bamford, Lindsay Broadbent, Elihu Aranday-Cortes, Mary McCabe, James McKenna, David Courtney, Olivier Touzelet, Ahlam Ali, Grace Roberts, Guillermo Lopez Campos, David Simpson, Conall McCaughey, Derek Fairley, Ken Mills, Ultan F. Power, the Breathing Together Investigators
doi: https://doi.org/10.1101/2021.07.16.452629
Connor G. G. Bamford
1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
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  • ORCID record for Connor G. G. Bamford
  • For correspondence: c.bamford@qub.ac.uk u.power@qub.ac.uk
Lindsay Broadbent
1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
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Elihu Aranday-Cortes
2Medical Research Council-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK
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Mary McCabe
1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
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James McKenna
3Regional Virus Laboratory, Belfast Health and Social Care Trust, Belfast, UK
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David Courtney
1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
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Olivier Touzelet
1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
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Ahlam Ali
1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
4Patrick. G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK
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Grace Roberts
1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
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Guillermo Lopez Campos
1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
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David Simpson
1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
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Conall McCaughey
3Regional Virus Laboratory, Belfast Health and Social Care Trust, Belfast, UK
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Derek Fairley
3Regional Virus Laboratory, Belfast Health and Social Care Trust, Belfast, UK
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Ken Mills
4Patrick. G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK
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Ultan F. Power
1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
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  • For correspondence: c.bamford@qub.ac.uk u.power@qub.ac.uk
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Abstract

SARS-CoV-2 continues to evolve, resulting in several ‘variants of concern’ with novel properties. The factors driving SARS-CoV-2 fitness and evolution in the human respiratory tract remain poorly defined. Here, we provide evidence that both viral and host factors co-operate to shape SARS-CoV-2 genotypic and phenotypic change. Through viral whole-genome sequencing, we explored the evolution of two clinical isolates of SARS-CoV-2 during passage in unmodified Vero-derived cell lines and in parallel, in well-differentiated primary nasal epithelial cell (WD-PNEC) cultures. We identify a consistent, rich genetic diversity arising in vitro, variants of which could rapidly rise to near-fixation with 2 passages. Within isolates, SARS-CoV-2 evolution was dependent on host cells, with Vero-derived cells facilitating more profound genetic changes. However, most mutations were not shared between strains. Furthermore, comparison of both Vero-grown isolates on WD-PNECs disclosed marked growth attenuation mapping to the loss of the polybasic cleavage site (PBCS) in Spike while the strain with mutations in NSP12 (T293I), Spike (P812R) and a truncation of ORF7a remained viable in WD-PNECs. Our work highlights the significant genetic plasticity of SARS-CoV-2 while uncovering an influential role for collaboration between viral and host cell factors in shaping viral evolution and fitness in human respiratory epithelium.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵± Breathing Together investigators: Professor Andrew Bush, Professor Adnan Custovic, Professor Peter Ghazal, Dr. Mindy Gore, Professor Jonathan Grigg, Professor Clare M. Lloyd, Professor Benjamin Marsland, Professor Ultan Power, Professor Graham Roberts, Professor Sejal Saglani, Professor Jurgen Schwarze, Professor Mike Shields, and Professor Steve Turner.

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 July 16, 2021.
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Collaboration Between Host and Viral Factors Shape SARS-CoV-2 Evolution
Connor G. G. Bamford, Lindsay Broadbent, Elihu Aranday-Cortes, Mary McCabe, James McKenna, David Courtney, Olivier Touzelet, Ahlam Ali, Grace Roberts, Guillermo Lopez Campos, David Simpson, Conall McCaughey, Derek Fairley, Ken Mills, Ultan F. Power, the Breathing Together Investigators
bioRxiv 2021.07.16.452629; doi: https://doi.org/10.1101/2021.07.16.452629
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Collaboration Between Host and Viral Factors Shape SARS-CoV-2 Evolution
Connor G. G. Bamford, Lindsay Broadbent, Elihu Aranday-Cortes, Mary McCabe, James McKenna, David Courtney, Olivier Touzelet, Ahlam Ali, Grace Roberts, Guillermo Lopez Campos, David Simpson, Conall McCaughey, Derek Fairley, Ken Mills, Ultan F. Power, the Breathing Together Investigators
bioRxiv 2021.07.16.452629; doi: https://doi.org/10.1101/2021.07.16.452629

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