RT Journal Article
SR Electronic
T1 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
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.30.450632
DO 10.1101/2021.06.30.450632
A1 Bailey Lubinski
A1 Laura E. Frazier
A1 My V.T. Phan
A1 Daniel L. Bugembe
A1 Tiffany Tang
A1 Susan Daniel
A1 Matthew Cotten
A1 Javier A. Jaimes
A1 Gary R. Whittaker
YR 2021
UL http://biorxiv.org/content/early/2021/11/11/2021.06.30.450632.abstract
AB 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 the additional spike mutation P681R at the S1/S2 cleavage site to comprise lineage A.23.1 by September 2020 with subsequent spread to 26 other countries. The P681R spike substitution of A.23.1 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 subsequently appeared in B.1.617 variants, including B.1.617.2 (Delta). Here, we performed assays using fluorogenic peptides mimicking the S1/S2 from A.23.1 and B.1.617 and observed significantly increased cleavability with furin, compared to sequences derived from the original Wuhan-Hu1 S1/S2. We performed cell-cell fusion and functional infectivity assays using pseudotyped particles harboring SARS-CoV-2 spike proteins and observed an increase in transduction for A.23.1-pseudotyped particles compared to Wuhan-Hu-1. However, these changes in activity 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 needs to occur on the background of other spike protein changes to enable its full functional consequences.Competing Interest StatementThe authors have declared no competing interest.