Details

Autor(en) / Beteiligte

• Johnson, Bryan A
• Zhou, Yiyang
• Lokugamage, Kumari G
• Vu, Michelle N
• Bopp, Nathen
• Crocquet-Valdes, Patricia A
• Kalveram, Birte
• Schindewolf, Craig
• Liu, Yang
• Scharton, Dionna
• Plante, Jessica A
• Xie, Xuping
• Aguilar, Patricia
• Weaver, Scott C
• Shi, Pei-Yong
• Walker, David H
• Routh, Andrew L
• Plante, Kenneth S
• Menachery, Vineet D
• Shih, Shin-Ru

Titel

Nucleocapsid mutations in SARS-CoV-2 augment replication and pathogenesis

Ist Teil von

• PLoS pathogens, 2022-06, Vol.18 (6), p.e1010627

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.