Mary Wilson
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Accepted: May 30, 2022; Published: June 21, 2022
https://doi.org/10.1371/journal.ppat.1010627
Bryan A. Johnson,Yiyang Zhou,Kumari G. Lokugamage,Michelle N. VuNathen Bopp,Patricia A. Crocquet-Valdes,Birte Kalveram,Craig Schindewolf,Yang Liu,Dionna SchartonJessica A. Plante,Xuping Xie,Patricia Aguilar, [ ... ],Vineet D. Menachery [ view all ]
Abstract
While SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored. This study investigates a highly variable region at residues 203–205 in the SARS-CoV-2 nucleocapsid protein. Recreating a mutation found in the alpha and omicron variants in an early pandemic (WA-1) background, we find that the R203K+G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2. The R203K+G204R mutant corresponds with increased viral RNA and protein both in vitro and in vivo. Importantly, the R203K+G204R mutation increases nucleocapsid phosphorylation and confers resistance to inhibition of the GSK-3 kinase, providing a molecular basis for increased virus replication. Notably, analogous alanine substitutions at positions 203+204 also increase SARS-CoV-2 replication and augment phosphorylation, suggesting that infection is enhanced through ablation of the ancestral ‘RG’ motif. Overall, these results demonstrate that variant mutations outside spike are key components in SARS-CoV-2’s continued adaptation to human infection.
https://journals.plos.org/plospathog...l.ppat.1010627
Accepted: May 30, 2022; Published: June 21, 2022
https://doi.org/10.1371/journal.ppat.1010627
Bryan A. Johnson,Yiyang Zhou,Kumari G. Lokugamage,Michelle N. VuNathen Bopp,Patricia A. Crocquet-Valdes,Birte Kalveram,Craig Schindewolf,Yang Liu,Dionna SchartonJessica A. Plante,Xuping Xie,Patricia Aguilar, [ ... ],Vineet D. Menachery [ view all ]
Abstract
While SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored. This study investigates a highly variable region at residues 203–205 in the SARS-CoV-2 nucleocapsid protein. Recreating a mutation found in the alpha and omicron variants in an early pandemic (WA-1) background, we find that the R203K+G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2. The R203K+G204R mutant corresponds with increased viral RNA and protein both in vitro and in vivo. Importantly, the R203K+G204R mutation increases nucleocapsid phosphorylation and confers resistance to inhibition of the GSK-3 kinase, providing a molecular basis for increased virus replication. Notably, analogous alanine substitutions at positions 203+204 also increase SARS-CoV-2 replication and augment phosphorylation, suggesting that infection is enhanced through ablation of the ancestral ‘RG’ motif. Overall, these results demonstrate that variant mutations outside spike are key components in SARS-CoV-2’s continued adaptation to human infection.
https://journals.plos.org/plospathog...l.ppat.1010627