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

• Published in: Nature communications Vol. 13; no. 1; pp. 601 - 14
• Main Authors: Mourier, Tobias, Shuaib, Muhammad, Hala, Sharif, Mfarrej, Sara, Alofi, Fadwa, Naeem, Raeece, Alsomali, Afrah, Jorgensen, David, Subudhi, Amit Kumar, Ben Rached, Fathia, Guan, Qingtian, Salunke, Rahul P., Ooi, Amanda, Esau, Luke, Douvropoulou, Olga, Nugmanova, Raushan, Perumal, Sadhasivam, Zhang, Huoming, Rajan, Issaac, Al-Omari, Awad, Salih, Samer, Shamsan, Abbas, Al Mutair, Abbas, Taha, Jumana, Alahmadi, Abdulaziz, Khotani, Nashwa, Alhamss, Abdelrahman, Mahmoud, Ahmed, Alquthami, Khaled, Dageeg, Abdullah, Khogeer, Asim, Hashem, Anwar M., Moraga, Paula, Volz, Eric, Almontashiri, Naif, Pain, Arnab
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 38/109; 38/77; 38/88; 38/90; 38/91; 42/44; 45/43; 45/70; 631/208/325/2483; 631/326/596/4130; 692/699/255/2514; 82/1; 82/29; 82/58; 82/80; 82/83; Biochemical analysis; Coronavirus Nucleocapsid Proteins - genetics; Coronavirus Nucleocapsid Proteins - metabolism; Coronaviruses; COVID-19; COVID-19 - enzymology; COVID-19 - genetics; COVID-19 - virology; Gene sequencing; Genome, Viral; Genomes; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Interferon; Kinases; multidisciplinary; Mutants; Mutation; Mutation, Missense; N protein; Nucleocapsid - genetics; Nucleocapsid - metabolism; Nucleocapsids; Pandemics; Phosphorylation; Phylogeny; Population dynamics; Protein Binding; Proteins; SARS-CoV-2 - classification; SARS-CoV-2 - genetics; SARS-CoV-2 - physiology; Saudi Arabia; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Therapeutic targets; Transcriptomes; Viral diseases; Viral Load; Virus Replication; Whole genome sequencing; Saudi Arabia
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28287-8

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.