Glycolysis and HIF-1α signaling are important for granulocytic myeloid-derived suppressor cell activity during Staphylococcus aureus biofilm infection

Abstract

Abstract Prosthetic joint infection (PJI) is a severe complication following hip and knee arthroplasty and is reported to affect 1-2% of total arthroplasties. Staphylococcus aureus (S. aureus) contributes to most PJIs, with a higher treatment failure rate partly due to biofilm formation. Granulocytic myeloid-derived suppressor cell (G-MDSC) expansion and IL-10 secretion are critical for inducing an immunosuppressive environment that supports S. aureus persistence during PJI. Recently, S. aureus-derived lactate was shown to promote IL-10 production by G-MDSCs. However, the importance of G-MDSC metabolism in programming their anti-inflammatory activity is unknown. Single-cell RNA sequencing (scRNA-seq) of infected tissues from a mouse model of S. aureus PJI revealed enrichment of glycolysis and hypoxia pathway genes in G-MDSCs. Increased glycolytic activity in G-MDSCs was confirmed following S. aureus biofilm co-culture and attenuating glycolysis with either 2-deoxyglucose or granulocyte-specific HIF-1a deletion reduced bacterial growth during S. aureus PJI. These changes coincided with less G-MDSC suppressive activity and a transformation towards a proinflammatory phenotype. scRNA-seq of samples from PJI patients revealed heightened glycolysis and hypoxia signatures, supporting findings with the mouse PJI model. Together, these results suggest that glycolysis and HIF-1a pathways are critical for the anti-inflammatory activity of G-MDSCs during S. aureus biofilm infection.