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.
【초록키워드】 SARS-CoV-2, pandemic, Mutation, Pathogenesis, variant, Infection, Transmission, in vitro, Omicron variants, nucleocapsid protein, Replication, Protein, Viral, spike gene, nucleocapsid, Genetic variation, Phosphorylation, Alpha, virus replication, Omicron variant, GSK-3, Viral RNA, fitness, mutant, in vivo, SARS-CoV-2 replication, Ablation, variable region, residue, human infection, Alanine, molecular basis, residues, component, motif, while, pathogenesis of SARS-CoV-2, ENhance, increase, alanine substitution, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2,