Saudi Arabian SARS-CoV-2 genomes implicate a mutant Nucleocapsid protein in modulating host interactions and increased viral load in COVID-19 patients
Ben Rached, Fathia
Salunke, Rahul Pandurang
Ooi, Amanda Siok Lee
Al Mutair, Abbas
Hashem, Anwar M
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
NGS and qPCR
Proteomics, protein expression & cytomet
KAUST Grant NumberBAS/1/1020-01-01
Permanent link to this recordhttp://hdl.handle.net/10754/669344
MetadataShow full item record
AbstractMonitoring SARS-CoV-2 spread and evolution through genome sequencing is essential in handling the COVID-19 pandemic. The availability of patient hospital records is crucial for linking the genomic sequence information to virus function during the course of infections. Here, we sequenced 892 SARS-CoV-2 genomes collected from patients in Saudi Arabia from March to August 2020. From the assembled sequences, we estimate the SARS-CoV-2 effective population size and infection rate and outline the epidemiological dynamics of import and transmission events during this period in Saudi Arabia. We show that two consecutive mutations (R203K/G204R) in the SARS-CoV-2 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 hyper-phosphorylation of the adjacent serine site (S206) in the mutant N protein by mass-spectrometry analysis. Furthermore, analysis of the host cell transcriptome suggests that the mutant N protein results in dysregulated interferon response genes. We provide crucial information in linking the R203K/G204R mutations in the N protein as a major modulator of host-virus interactions and increased viral load and underline the potential of the nucleocapsid protein as a drug target during infection.
CitationMourier, T., Shuaib, M., Hala, S., Mfarrej, S., Alofi, F., Naeem, R., … Pain, A. (2021). Saudi Arabian SARS-CoV-2 genomes implicate a mutant Nucleocapsid protein in modulating host interactions and increased viral load in COVID-19 patients. doi:10.1101/2021.05.06.21256706
SponsorsWe are sincerely grateful to all hospital members for providing samples and collating metadata in such an unprecedented pandemic, along with the MOH and ethical committee, which rendered it permissible. We thank the KAUST Rapid Research Response Team (R3T) under the Vice President – Research (VPR) office in KAUST for generous financial support. We also thank Erik Talley from KAUST Health Safety and Environment (HSE) and Hani Bukhari from KAUST Security for providing timely logistical support for samples transport during COVID-19 Curfew restrictions in the Kingdom. We extend our thanks and appreciation to GDRS director, PH. Athari Alotaibi (General Director for Research and Studies, MOH) for her vigorous facilitation of the research project, and Mohammad Fawzi (General Directorate of Health Affairs) for his help with the metadata collection. We also deeply thank Dr. Wael Hamzah Motair, Dr. Nader Hamzah Motair, Dr.Hatim Khogeer and the General Directorate of Health Affairs of Makkah Region (GDHAMR), MOH for all their help and assistance to our study. We gratefully acknowledge all of the authors from the originating laboratories responsible for obtaining the specimens and the submitting laboratories where genetic sequence data were generated and publicly shared via the GISAID Initiative, on which was partially used for additional support for some of the conclusions drawn in this study.
Grants: KAUST Rapid Research Response Team (R3T) by Vice President – Research (VPR) office in KAUST. KAUST faculty baseline fund (BAS/1/1020-01-01) to AP. KACST Grants, Proposal number: 5-20-01-002-0008 MOH COVID-19 project grants number 341 MOH COVID-19 project grants number 754 The deputyship for Research and Innovation, Ministry of Education in Saudi Arabia, project number (436) to AMH. IRBs: This project was conducted under the IRB approvals of the MOH (H-02-K-076-0420-285), KAUST (20IBEC14) and at the Dr. Suliman Al-Habib Medical group (HAP-01-R-082) in KSA.
PublisherCold Spring Harbor Laboratory