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

Tobias Mourier, Muhammad Shuaib, Sharif Hala, Sara Mfarrej, Fadwa Alofi, Raeece Naeem, Afrah Alsomali, David Jorgensen, Amit Kumar Subudhi, Fathia Ben Rached, Qingtian Guan, Rahul P. Salunke, Amanda Ooi, Luke Esau, Olga Douvropoulou, Raushan Nugmanova, Sadhasivam Perumal, Huoming Zhang, Issaac Rajan, Awad Al-Omari, Samer Salih, Abbas Shamsan, Abbas Al Mutair, Jumana Taha, Abdulaziz Alahmadi, Nashwa Khotani, Abdelrahman Alhamss, Ahmed Mahmoud, Khaled Alquthami, Abdullah Dageeg, Asim Khogeer, Anwar M. Hashem, Paula Moraga, Eric Volz, Naif Almontashiri and Arnab Pain ()
Additional contact information
Tobias Mourier: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Muhammad Shuaib: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Sharif Hala: Infectious Disease Research Department, King Abdullah International Medical Research Centre, Ministry of National Guard Health Affairs
Sara Mfarrej: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Fadwa Alofi: King Fahad Hospital
Raeece Naeem: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Afrah Alsomali: King Abdullah Medical Complex
David Jorgensen: Imperial College, Norfolk Place, St Mary’s Campus
Amit Kumar Subudhi: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Fathia Ben Rached: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Qingtian Guan: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Rahul P. Salunke: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Amanda Ooi: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Luke Esau: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Olga Douvropoulou: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Raushan Nugmanova: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Sadhasivam Perumal: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Huoming Zhang: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Issaac Rajan: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)
Awad Al-Omari: Dr. Suliman Al-Habib Medical Group
Samer Salih: Dr. Suliman Al-Habib Medical Group
Abbas Shamsan: Dr. Suliman Al-Habib Medical Group
Abbas Al Mutair: Dr. Suliman Al-Habib Medical Group
Jumana Taha: King Faisal Specialist Hospital and Research Center
Abdulaziz Alahmadi: Ministry of National Guard - Health Affairs
Nashwa Khotani: Al Noor Specialist Hospital Makkah
Abdelrahman Alhamss: King Abdul Aziz Hospital Makkah
Ahmed Mahmoud: College of Applied Medical Sciences, Taibah University
Khaled Alquthami: Al Noor Specialist Hospital Makkah
Abdullah Dageeg: King Abdulaziz University Jeddah
Asim Khogeer: General Directorate of Health Affairs Makkah Region
Anwar M. Hashem: Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University
Paula Moraga: King Abdullah University of Science and Technology (KAUST), Computer, Electrical and Mathematical Science and Engineering Division (CEMSE)
Eric Volz: Imperial College, Norfolk Place, St Mary’s Campus
Naif Almontashiri: College of Applied Medical Sciences, Taibah University
Arnab Pain: King Abdullah University of Science and Technology (KAUST), Pathogen Genomics Laboratory, Biological and Environmental Science and Engineering (BESE)

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28287-8

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