Critical role of immune metabolism in Staphylococcus aureus infection-driven myeloid-derived suppressor cells and disease tolerance

Myeloid-derived suppressor cells (MDSC) are a compendium of immature myeloid cells with potent T cell suppressive capacity that expand during pathological conditions such as chronic infections and cancer. While the physiology of MDSC in cancer is well-characterized, less is known about the biology of these cells in the context of infection, where they may represent an important mechanism of disease tolerance. Here, we used scRNA-seq to decipher the heterogeneity of MDSC expanding during experimental Staphylococcus aureus infection at a single cell level. We demonstrated that infection-driven MDSC originated from both bone marrow and in situ from extramedullary hematopoiesis. Metabolic flux analysis indicated that MDSC engaged aerobic glycolysis and mitochondrial respiration for energy production and consumed high levels of glucose that was required for undergoing terminal maturation. Limiting glucose availability by infection-induced anorexia creates a bottleneck in the maturation process that can explain the accumulation of MDSC in an immature stage.