Granulocytic myeloid-derived suppressor cell activity during biofilm infection is regulated by a glycolysis-HIF-1a axis
Staphylococcus aureus is a leading cause of biofilm-associated prosthetic joint infection (PJI). A primary contributor to infection chronicity is an expansion of granulocytic myeloid-derived suppressor cells (G-MDSCs) that are critical for orchestrating the anti-inflammatory biofilm milieu. Single-cell sequencing and bioinformatic metabolic algorithms were used to explore the link between G-MDSC metabolism and S. aureus PJI outcome. Glycolysis and the hypoxic response through hypoxia-inducible factor-1 alpha (HIF-1a) were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2-deoxyglucose nanopreparation and granulocyte-targeted HIF-1a conditional knockout mice, respectively, attenuated G-MDSC-mediated immunosuppression and reduced bacterial burden in a mouse model of S. aureus PJI. In addition, scRNA-seq analysis of granulocytes from PJI patients also showed an enrichment in glycolysis and hypoxic response genes. These findings support the importance of a glycolysis/HIF-1a axis in promoting G-MDSC anti-inflammatory activity and biofilm persistence during PJI. Overall design: C57BL/6J mice received 2-DG-containing or empty nanoparticles at day 3 post-infection, whereupon live Ly6G+ cells were collected from the soft tissue adjacent to the knee joint 4 days later (i.e. day 7 post-infection) by FACS and RNA isolated for bulk RNA-sequencing.