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Rapid SARS-CoV-2 Adaptation to Available Cellular Proteases

View ORCID ProfileM. Zeeshan Chaudhry, Kathrin Eschke, Markus Hoffmann, Martina Grashoff, Leila Abassi, Yeonsu Kim, View ORCID ProfileLinda Brunotte, View ORCID ProfileStephan Ludwig, View ORCID ProfileAndrea Kröger, View ORCID ProfileFrank Klawonn, Stefan Pöhlmann, View ORCID ProfileLuka Cicin-Sain
doi: https://doi.org/10.1101/2020.08.10.241414
M. Zeeshan Chaudhry
1Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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  • ORCID record for M. Zeeshan Chaudhry
  • For correspondence: zeeshan.chaudhry@helmholtz-hzi.de luka.cicin-sain@helmholtz-hzi.de
Kathrin Eschke
1Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Markus Hoffmann
2Infection Biology Unit, German Primate Center, Göttingen, Germany
3Faculty of Biology and Psychology, Georg-August-University Göttingen, Göttingen, Germany
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Martina Grashoff
4Research Group Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Leila Abassi
1Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Yeonsu Kim
1Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Linda Brunotte
5Institut für Virologie (IVM), Westfälische Wilhelms-Universität Münster, Münster, Germany
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  • ORCID record for Linda Brunotte
Stephan Ludwig
5Institut für Virologie (IVM), Westfälische Wilhelms-Universität Münster, Münster, Germany
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Andrea Kröger
4Research Group Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany
6Institute of Medical Microbiology and Hospital Hygiene, Otto von Guericke University, Magdeburg, Germany
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Frank Klawonn
7Biostatistics Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
8Department of Computer Science, Ostfalia University, Wolfenbüttel, Germany
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Stefan Pöhlmann
2Infection Biology Unit, German Primate Center, Göttingen, Germany
3Faculty of Biology and Psychology, Georg-August-University Göttingen, Göttingen, Germany
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Luka Cicin-Sain
1Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
9Centre for Individualized Infection Medicine (CIIM), Hannover, Germany
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  • For correspondence: zeeshan.chaudhry@helmholtz-hzi.de luka.cicin-sain@helmholtz-hzi.de
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ABSTRACT

Since the pandemic spread of SARS-CoV-2, the virus has exhibited remarkable genome stability, but recent emergence of novel variants show virus evolution potential. Here we show that SARS-CoV-2 rapidly adapts to Vero E6 cells that leads to loss of furin cleavage motif in spike protein. The adaptation is achieved by asymptotic expansion of minor virus subpopulations to dominant genotype, but wildtype sequence is maintained at low percentage in the virus swarm, and mediate reverse adaptation once the virus is passaged on human lung cells. The Vero E6-adapted virus show defected cell entry in human lung cells and the mutated spike variants cannot be processed by furin or TMPRSS2. However, the mutated S1/S2 site is cleaved by cathepsins with higher efficiency. Our data show that SARS-CoV-2 can rapidly adapt spike protein to available proteases and advocate for deep sequence surveillance to identify virus adaptation potential and novel variant emergence.

Significance Statement Recently emerging SARS-CoV-2 variants B1.1.1.7 (UK), B.1.351 (South Africa) and B.1.1.248 (Brazil) harbor spike mutation and have been linked to increased virus pathogenesis. The emergence of these novel variants highlight coronavirus adaptation and evolution potential, despite the stable consensus genotype of clinical isolates. We show that subdominant variants maintained in the virus population enable the virus to rapidly adapt upon selection pressure. Although these adaptations lead to genotype change, the change is not absolute and genome with original genotype are maintained in virus swarm. Thus, our results imply that the relative stability of SARS-CoV-2 in numerous independent clinical isolates belies its potential for rapid adaptation to new conditions.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Classification Biological Sciences, Microbiology

  • Further experiments showed that although HS antagonists have an influence on the growth of low-passage SARS-CoV-2 strain on Vero E6 cells, these antagonist fail to inhibit S1/S2 site adaptation. Furthermore, new peptide cleavage data suggest that S1/S2 site adaptation in the Vero E6 cells is largely to optimize the cleavage by available proteases.

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 March 26, 2021.
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Rapid SARS-CoV-2 Adaptation to Available Cellular Proteases
M. Zeeshan Chaudhry, Kathrin Eschke, Markus Hoffmann, Martina Grashoff, Leila Abassi, Yeonsu Kim, Linda Brunotte, Stephan Ludwig, Andrea Kröger, Frank Klawonn, Stefan Pöhlmann, Luka Cicin-Sain
bioRxiv 2020.08.10.241414; doi: https://doi.org/10.1101/2020.08.10.241414
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Rapid SARS-CoV-2 Adaptation to Available Cellular Proteases
M. Zeeshan Chaudhry, Kathrin Eschke, Markus Hoffmann, Martina Grashoff, Leila Abassi, Yeonsu Kim, Linda Brunotte, Stephan Ludwig, Andrea Kröger, Frank Klawonn, Stefan Pöhlmann, Luka Cicin-Sain
bioRxiv 2020.08.10.241414; doi: https://doi.org/10.1101/2020.08.10.241414

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