Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity

Genome Medicine

Research

Huoming Zhang¹  Luke Esau¹  Naif A. M. Almontashiri²  Abbas Shamsan³  Afrah Alsomali⁴  Fadwa S Alofi⁵  Adeel Nazir Ahmad⁶  Sara Mfarrej⁷  Muhammad Shuaib⁷  Tobias Mourier⁷  Sabir Adroub⁷  Sharif Hala⁸  Arnab Pain⁹  Asim Khogeer^1,10  Anwar M. Hashem^1,11 

[1] Bioscience Core Laboratory, King Abdullah University of Science and Technology (KAUST), 23955-6900, Thuwal, Saudi Arabia;College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia;Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia;Dr. Suliman Al-Habib Medical Group, Riyadh, Saudi Arabia;Infectious Diseases Department, King Abdullah Medical Complex, Jeddah, MOH, Saudi Arabia;Infectious Diseases Department, King Fahad Hospital, Madinah, MOH, Saudi Arabia;KAUST Health - Fakeeh Care, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia;Pathogen Genomics Laboratory, Bioscience Program, Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), 23955-6900, Thuwal, Saudi Arabia;Pathogen Genomics Laboratory, Bioscience Program, Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), 23955-6900, Thuwal, Saudi Arabia;Infectious Disease Research Department, King Abdullah International Medical Research Centre, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia;King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia;Pathogen Genomics Laboratory, Bioscience Program, Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), 23955-6900, Thuwal, Saudi Arabia;International Institute for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, 001-0020, Sapporo, Japan;Plan and Research Department, General Directorate of Health Affairs Makkah Region, Makkah, MOH, Saudi Arabia;Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia;Department of Clinical Microbiology and Immunology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia;

关键词: COVID-19;    SARS-CoV-2;    Variant of concern;    Nucleocapsid (N) R203K/G204R (KR) mutations;    Virus-like particle (VLP);    Transcriptomics;    Proteomics;    Host immune response;    Interferon-stimulated genes (ISGs);    Cytokine storm;   

DOI  :  10.1186/s13073-023-01208-0

 received in 2023-02-01, accepted in 2023-07-04,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe excessive inflammatory responses provoked by SARS-CoV-2 infection are critical factors affecting the severity and mortality of COVID-19. Previous work found that two adjacent co-occurring mutations R203K and G204R (KR) on the nucleocapsid (N) protein correlate with increased disease severity in COVID-19 patients. However, links with the host immune response remain unclear.MethodsHere, we grouped nasopharyngeal swab samples of COVID-19 patients into two cohorts based on the presence and absence of SARS-CoV-2 nucleocapsid KR mutations. We performed nasopharyngeal transcriptome analysis of age, gender, and ethnicity-matched COVID-19 patients infected with either SARS-CoV-2 with KR mutations in the N protein (KR patients n = 39) or with the wild-type N protein (RG patients n = 39) and compared to healthy controls (n = 34). The impact of KR mutation on immune response was further characterized experimentally by transcriptomic and proteomic profiling of virus-like-particle (VLP) incubated cells.ResultsWe observed markedly elevated expression of proinflammatory cytokines, chemokines, and interferon-stimulated (ISGs) genes in the KR patients compared to RG patients. Using nasopharyngeal transcriptome data, we found significantly higher levels of neutrophils and neutrophil-to-lymphocyte (NLR) ratio in KR patients than in the RG patients. Furthermore, transcriptomic and proteomic profiling of VLP incubated cells confirmed a similar hyper-inflammatory response mediated by the KR variant.ConclusionsOur data demonstrate an unforeseen connection between nucleocapsid KR mutations and augmented inflammatory immune response in severe COVID-19 patients. These findings provide insights into how mutations in SARS-CoV-2 modulate host immune output and pathogenesis and may contribute to more efficient therapeutics and vaccine development.

【 授权许可】

CC BY   
© The Author(s) 2023

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