Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity
Abstract Background The 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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-023-01208-0 |
| _version_ | 1797774040246517760 |
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| author | Muhammad Shuaib Sabir Adroub Tobias Mourier Sara Mfarrej Huoming Zhang Luke Esau Afrah Alsomali Fadwa S Alofi Adeel Nazir Ahmad Abbas Shamsan Asim Khogeer Anwar M. Hashem Naif A. M. Almontashiri Sharif Hala Arnab Pain |
| author_facet | Muhammad Shuaib Sabir Adroub Tobias Mourier Sara Mfarrej Huoming Zhang Luke Esau Afrah Alsomali Fadwa S Alofi Adeel Nazir Ahmad Abbas Shamsan Asim Khogeer Anwar M. Hashem Naif A. M. Almontashiri Sharif Hala Arnab Pain |
| author_sort | Muhammad Shuaib |
| collection | DOAJ |
| description | Abstract Background The 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. Methods Here, 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. Results We 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. Conclusions Our 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. |
| first_indexed | 2024-03-12T22:15:09Z |
| format | Article |
| id | doaj.art-a4d0f2c9f1e8463a8e98ac60176315bd |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-03-12T22:15:09Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-a4d0f2c9f1e8463a8e98ac60176315bd2023-07-23T11:21:41ZengBMCGenome Medicine1756-994X2023-07-0115111610.1186/s13073-023-01208-0Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severityMuhammad Shuaib0Sabir Adroub1Tobias Mourier2Sara Mfarrej3Huoming Zhang4Luke Esau5Afrah Alsomali6Fadwa S Alofi7Adeel Nazir Ahmad8Abbas Shamsan9Asim Khogeer10Anwar M. Hashem11Naif A. M. Almontashiri12Sharif Hala13Arnab Pain14Pathogen Genomics Laboratory, Bioscience Program, Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST)Pathogen Genomics Laboratory, Bioscience Program, Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST)Pathogen Genomics Laboratory, Bioscience Program, Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST)Pathogen Genomics Laboratory, Bioscience Program, Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST)Bioscience Core Laboratory, King Abdullah University of Science and Technology (KAUST)Bioscience Core Laboratory, King Abdullah University of Science and Technology (KAUST)Infectious Diseases Department, King Abdullah Medical ComplexInfectious Diseases Department, King Fahad HospitalKAUST Health - Fakeeh Care, King Abdullah University of Science and TechnologyDr. Suliman Al-Habib Medical GroupPlan and Research Department, General Directorate of Health Affairs Makkah RegionVaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz UniversityCollege of Applied Medical Sciences, Taibah UniversityPathogen Genomics Laboratory, Bioscience Program, Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST)Pathogen Genomics Laboratory, Bioscience Program, Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST)Abstract Background The 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. Methods Here, 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. Results We 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. Conclusions Our 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.https://doi.org/10.1186/s13073-023-01208-0COVID-19SARS-CoV-2Variant of concernNucleocapsid (N) R203K/G204R (KR) mutationsVirus-like particle (VLP)Transcriptomics |
| spellingShingle | Muhammad Shuaib Sabir Adroub Tobias Mourier Sara Mfarrej Huoming Zhang Luke Esau Afrah Alsomali Fadwa S Alofi Adeel Nazir Ahmad Abbas Shamsan Asim Khogeer Anwar M. Hashem Naif A. M. Almontashiri Sharif Hala Arnab Pain Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity Genome Medicine COVID-19 SARS-CoV-2 Variant of concern Nucleocapsid (N) R203K/G204R (KR) mutations Virus-like particle (VLP) Transcriptomics |
| title | Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity |
| title_full | Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity |
| title_fullStr | Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity |
| title_full_unstemmed | Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity |
| title_short | Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity |
| title_sort | impact of the sars cov 2 nucleocapsid 203k 204r mutations on the inflammatory immune response in covid 19 severity |
| topic | COVID-19 SARS-CoV-2 Variant of concern Nucleocapsid (N) R203K/G204R (KR) mutations Virus-like particle (VLP) Transcriptomics |
| url | https://doi.org/10.1186/s13073-023-01208-0 |
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