Metabolic dysregulation accompanying SARS-CoV-2 infection is a key determinant of disease severity. In this study, we performed extensive data mining of multiple existing single-cell RNA seq datasets of COVID-19 BALFs, in combination with high-dimensional immune cell profiling of PBMCs from COVID-19-infected patients, to get a comprehensive, systemic profile of the immunometabolic regulation of adaptive immunity during severe COVID-19. Hypoxia, a hallmark of COVID-19 ARDS, was found to elicit a global metabolic reprogramming in effector lymphocytes. In response to oxygen and nutrient-deprived microenvironments, these cells shift from aerobic respiration to increase their dependence on anaerobic processes including glycolysis, mitophagy, and glutaminolysis to fulfill their bioenergetic demands. We find that these metabolically reprogrammed CD8 and NK cells, under persistent antigen stimulation, become exhausted, displaying impaired cytotoxic function and anti-viral efficacy. We demonstrate that dysregulated metabolism significantly impairs memory lymphocyte differentiation, including the formation of memory NK and tissue resident CD8 memory cells. Unsupervised clustering techniques revealed multiple distinct, differentially abundant CD8 and NK memory cell states that are marked by high glycolytic flux, mitochondrial dysfunction, and cellular exhaustion, further highlighting the connection between disrupted metabolism and impaired memory cell function in COVID-19. Overall, our findings provide novel insight on how SARS-CoV-2 infection affects host immunometabolism and anti-viral response during COVID-19.
Bachelor of Science (B.S.)
College of Medicine
Burnett School of Biomedical Sciences
Length of Campus-only Access
Gurshaney, Sanjeev, "Metabolic Dysregulation Induces Impaired Memory Lymphocyte Formation During Severe SARS-COV-2 Infection" (2022). Honors Undergraduate Theses. 1258.