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Spike protein cleavage-activation mediated by the SARS-CoV-2 P681R mutation: a case-study from its first appearance in variant of interest (VOI) A.23.1 identified in Uganda

Bailey Lubinski, Laura E. Frazier, My V.T. Phan, Daniel L. Bugembe, Tiffany Tang, Susan Daniel, View ORCID ProfileMatthew Cotten, View ORCID ProfileJavier A. Jaimes, Gary R. Whittaker
doi: https://doi.org/10.1101/2021.06.30.450632
Bailey Lubinski
1Graduate Program in Biological & Biomedical Sciences, Cornell University, Ithaca, NY, 14853, USA
2Department of Microbiology & Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
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Laura E. Frazier
1Graduate Program in Biological & Biomedical Sciences, Cornell University, Ithaca, NY, 14853, USA
2Department of Microbiology & Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
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My V.T. Phan
3MRC/UVRI & London School of Hygiene and Tropical Medicine – Uganda Research Unit, Entebbe, Uganda
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Daniel L. Bugembe
3MRC/UVRI & London School of Hygiene and Tropical Medicine – Uganda Research Unit, Entebbe, Uganda
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Tiffany Tang
4Robert Frederick Smith School of Chemical & Biomolecular Engineering, Cornell University, Ithaca, NY, 14853, USA
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Susan Daniel
4Robert Frederick Smith School of Chemical & Biomolecular Engineering, Cornell University, Ithaca, NY, 14853, USA
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Matthew Cotten
3MRC/UVRI & London School of Hygiene and Tropical Medicine – Uganda Research Unit, Entebbe, Uganda
5MRC Centre of Virus Research, University of Glasgow, Glasgow, United Kingdom
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  • ORCID record for Matthew Cotten
Javier A. Jaimes
2Department of Microbiology & Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
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  • For correspondence: grw7@cornell.edu jaj246@cornell.edu
Gary R. Whittaker
2Department of Microbiology & Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
6Master of Public Health Program, Cornell University, Ithaca, NY, 14853, USA
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  • For correspondence: grw7@cornell.edu jaj246@cornell.edu
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Abstract

The African continent like all other parts of the world with high infection/low vaccination rates can, and will, be a source of novel SARS-CoV-2 variants. The A.23 viral lineage, characterized by three spike mutations F157L, V367F and Q613H, was first identified in COVID-19 cases from a Ugandan prison in July 2020, and then was identified in the general population with additional spike mutations (R102I, L141F, E484K and P681R) to comprise lineage A.23.1 by September 2020—with this virus being designated a variant of interest (VOI) in Africa and with subsequent spread to 26 other countries. The P681R spike substitution of the A.23.1 VOI is of note as it increases the number of basic residues in the sub-optimal SARS-CoV-2 spike protein furin cleavage site; as such, this substitution may affect viral replication, transmissibility or pathogenic properties. The same P681R substitution has also appeared in B.1.617 variants, including B.1.617.2 (Delta). Here, we performed assays using fluorogenic peptides mimicking the S1/S2 sequence from A.23.1 and B.1.617.2 and observed significantly increased cleavability with furin, compared to sequences derived from the original Wuhan-Hu1 S1/S2. We performed functional infectivity assays using pseudotyped MLV particles harboring SARS-CoV-2 spike proteins and observed an increase in transduction for A.23.1-pseudotyped particles compared to Wuhan-Hu-1 in Vero-TMPRSS2 and Calu-3 cells (with a presumed “early” entry pathway), although lowered infection in Vero E6 cells (with a presumed “late” entry pathway). However, these changes in infectivity were not reproduced in the original Wuhan-Hu-1 spike bearing only the P681R substitution. Our findings suggest that while A.23.1 has increased furin-mediated cleavage linked to the P681R substitution—which may affect viral infection and transmissibility—this substitution alone is not sufficient and needs to occur on the background of other spike protein changes to enable its full functional consequences.

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-ND 4.0 International license.
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Posted July 27, 2021.
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Spike protein cleavage-activation mediated by the SARS-CoV-2 P681R mutation: a case-study from its first appearance in variant of interest (VOI) A.23.1 identified in Uganda
Bailey Lubinski, Laura E. Frazier, My V.T. Phan, Daniel L. Bugembe, Tiffany Tang, Susan Daniel, Matthew Cotten, Javier A. Jaimes, Gary R. Whittaker
bioRxiv 2021.06.30.450632; doi: https://doi.org/10.1101/2021.06.30.450632
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Spike protein cleavage-activation mediated by the SARS-CoV-2 P681R mutation: a case-study from its first appearance in variant of interest (VOI) A.23.1 identified in Uganda
Bailey Lubinski, Laura E. Frazier, My V.T. Phan, Daniel L. Bugembe, Tiffany Tang, Susan Daniel, Matthew Cotten, Javier A. Jaimes, Gary R. Whittaker
bioRxiv 2021.06.30.450632; doi: https://doi.org/10.1101/2021.06.30.450632

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