SARS-CoV-2 genomes from Saudi Arabia implicate nucleocapsid mutations in host response and increased viral load

Monitoring SARS-CoV-2 spread and evolution through genome sequencing is essential in handling the COVID-19 pandemic. Here, we sequenced 892 SARS-CoV-2 genomes collected from patients in Saudi Arabia from March to August 2020. We show that two consecutive mutations (R203K/G204R) in the nucleocapsid (N) protein are associated with higher viral loads in COVID-19 patients. Our comparative biochemical analysis reveals that the mutant N protein displays enhanced viral RNA binding and differential interaction with key host proteins. We found increased interaction of GSK3A kinase simultaneously with hyper-phosphorylation of the adjacent serine site (S206) in the mutant N protein. Furthermore, the host cell transcriptome analysis suggests that the mutant N protein produces dysregulated interferon response genes. Here, we provide crucial information in linking the R203K/G204R mutations in the N protein to modulations of host-virus interactions and underline the potential of the nucleocapsid protein as a drug target during infection. In this study, the authors sequence 892 SARS-CoV-2 genomes from Saudi Arabia and describe population dynamics and importations into the country. They identify a nucleocapsid protein mutation associated with increased viral load and host interactions and characterise its role through biochemical analyses.

Automated summary

Monitoring the spread and evolution of SARS-CoV-2 through genome sequencing is crucial in managing the COVID-19 pandemic. In this study, the authors sequenced 892 SARS-CoV-2 genomes collected from patients in Saudi Arabia and identified two consecutive mutations in the nucleocapsid protein that were associated with higher viral loads in COVID-19 patients. Through biochemical analysis, they found that the mutant protein displayed enhanced viral RNA binding and differential interaction with key host proteins. The study also revealed dysregulated interferon response genes in host cells expressing the mutant protein. These findings provide important insights into the modulation of host-virus interactions and highlight the potential of the nucleocapsid protein as a target for drug development during infection.