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Abstract
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.
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1 King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE), Thuwal-Jeddah, Saudi Arabia (GRID:grid.45672.32) (ISNI:0000 0001 1926 5090)
2 Infectious Disease Research Department, King Abdullah International Medical Research Centre, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia (GRID:grid.452607.2) (ISNI:0000 0004 0580 0891); King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia (GRID:grid.452607.2)
3 King Fahad Hospital, Infectious Diseases Department, Madinah, Saudi Arabia (GRID:grid.45672.32)
4 King Abdullah Medical Complex, Infectious Diseases Department, Jeddah, Saudi Arabia (GRID:grid.45672.32)
5 Imperial College, Norfolk Place, St Mary’s Campus, School of Public Health, Faculty of Medicine, London, United Kingdom (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111)
6 Dr. Suliman Al-Habib Medical Group, Riyadh, Saudi Arabia (GRID:grid.45672.32)
7 King Faisal Specialist Hospital and Research Center, Department of Neuroscience, Riyadh, Saudi Arabia (GRID:grid.415310.2) (ISNI:0000 0001 2191 4301)
8 Ministry of National Guard - Health Affairs, Department of Preventive Medicine, Riyadh, Saudi Arabia (GRID:grid.416641.0) (ISNI:0000 0004 0607 2419)
9 Al Noor Specialist Hospital Makkah, Infectious Diseases Medical Department, Makkah, Saudi Arabia (GRID:grid.416641.0)
10 King Abdul Aziz Hospital Makkah, Gastroenterology Department, Makkah, Saudi Arabia (GRID:grid.415252.5)
11 College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia (GRID:grid.412892.4) (ISNI:0000 0004 1754 9358)
12 Al Noor Specialist Hospital Makkah, Infectious Diseases Medical Department, Makkah, Saudi Arabia (GRID:grid.412892.4)
13 King Abdulaziz University Jeddah, Department of Medicine, Jeddah, Saudi Arabia (GRID:grid.412125.1) (ISNI:0000 0001 0619 1117)
14 General Directorate of Health Affairs Makkah Region, Plan and Research Department, Makkah, Saudi Arabia (GRID:grid.412125.1)
15 Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia (GRID:grid.412125.1) (ISNI:0000 0001 0619 1117); King Abdulaziz University, Department of Medical Microbiology and Parasitology, Faculty of Medicine, Jeddah, Saudi Arabia (GRID:grid.412125.1) (ISNI:0000 0001 0619 1117)
16 King Abdullah University of Science and Technology (KAUST), Computer, Electrical and Mathematical Science and Engineering Division (CEMSE), Thuwal-Jeddah, Saudi Arabia (GRID:grid.45672.32) (ISNI:0000 0001 1926 5090)
17 College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia (GRID:grid.412892.4) (ISNI:0000 0004 1754 9358); Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia (GRID:grid.412892.4) (ISNI:0000 0004 1754 9358)
18 King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE), Thuwal-Jeddah, Saudi Arabia (GRID:grid.45672.32) (ISNI:0000 0001 1926 5090); Research Center for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691)