Principal Investigator: Prof. Arnab Pain

Poster Presenter: Muhammad Shuaib

Lab: Pathogen Genomics


Impact of the SARS-CoV-2 nucleocapsid mutations on the inflammatory immune response in COVID-19 severity




Impact of the SARS-CoV-2 nucleocapsid mutations on the inflammatory immune response in COVID-19 severity Muhammad Shuaib*, Sabir Adroub, Tobias Mourier, Sara Mfarrej, Huoming Zhang, Luke Esau, Afrah Alsomali, Fadwa Alofi, Adeel Nazir Ahmad, Abbas Shamsan, Asim Khogeer, Anwar M. Hashem, Naif Almontashiri, Sharif Hala, Arnab Pain* Abstract Excessive inflammatory responses provoked by SARS-CoV-2 infection are critical for the severity and mortality of COVID-19. We recently found that two consecutive amino acid mutations R203K and G204R (the mutant is called KR and wildtype RG) in the nucleocapsid (N) protein, are linked with increased viral load and severity in a diverse population of COVID-19 patients. The identified association of KR mutation with increased disease severity suggests a potential link with host immune response, which is so far unexplored. In this work, by employing a combination of omics approaches using patient samples and cell culture models, we provide evidence for an unexpected connection of KR mutation with augmented host immune response in COVID-19 patients. We performed nasopharyngeal transcriptome analysis of matched COVID-19 patients infected with either KR mutant SARS-CoV-2 (KR patients) or wildtype SARS-CoV-2 (RG patients) and compared to healthy controls. 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 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-infected cells further confirmed a similar hyper-inflammatory response mediated by the KR variant. These findings provide insight into how mutations in SARS-CoV-2 modulate host immune output and pathogenesis and may contribute to efficient therapeutics and vaccine development.