Mitochondrial induced T cell apoptosis and aberrant myeloid metabolic programs define distinct immune cell subsets during acute and recovered SARS-CoV-2 infection

AbstractBy interrogating metabolic programs in the peripheral blood mononuclear cells (PBMC) of acutely infected COVID-19 patients, we identified novel and distinct immune cell subsets Our studies identified a non-clonal population of T cells expressing high H3K27me3 and voltage-dependent anion channel (VDAC) with mitochondrial dysfunction and increased susceptibility to cell death. Characterized by dysmorphic mitochondria and increased cytoplasmic cytochromec, apoptosis of these cells was inhibited by preventing VDAC aggregation or blocking caspase activation. Further, we observed a marked increase in Hexokinase II+polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC). While PMN-MDSC were also found in the PBMC of patients with other viral infections, the Hexokinase II+PMN-MDSC were found exclusively in the acute COVID-19 patients with moderate or severe disease. Finally, we identified a population of monocytic MDSC (M-MDSC) expressing high carnitine palmitoyltransferase I (CPT1a) and VDAC, which were present in the PBMC of the acute COVID-19 patients, but not recovered COVID-19 patients and whose presence correlated with severity of disease. Overall, these unique populations of immune cells provide insight into the pathogenesis of SARS-CoV-2 infection and provide a means to predict and track disease severity as well as an opportunity to design and evaluate novel therapeutic regimens.One Sentence SummaryMetabolic programs define unique immune cells among COVID-19 patients with severe diease.