Granulocytic myeloid-derived suppressor cell activity during biofilm infection is regulated by a glycolysis/HIF1a axis

• Published in: The Journal of clinical investigation Vol. 134; no. 8; pp. 1 - 18
• Main Authors: Horn, Christopher M, Arumugam, Prabhakar, Van Roy, Zachary, Heim, Cortney E, Fallet, Rachel W, Bertrand, Blake P, Shinde, Dhananjay, Thomas, Vinai C, Romanova, Svetlana G, Bronich, Tatiana K, Hartman, Curtis W, Garvin, Kevin L, Kielian, Tammy
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.04.2024
• Subjects: Analysis; Animals; Anti-inflammatory agents; Antibiotics; Artificial joints; Biofilms; Complications and side effects; Deoxyglucose; Development and progression; Fatty acids; Flow cytometry; Gene expression; Genes; Glycolysis; Granulocytes; Health aspects; Humans; Hypoxia; Immunosuppression; Immunotherapy; Infection; Joint diseases; Joint surgery; Leukocytes; Leukocytes (granulocytic); Metabolism; Mice; Myeloid-Derived Suppressor Cells - physiology; Oxidation; Patient outcomes; Physiological aspects; Prostheses; Risk factors; RNA sequencing; Staphylococcus aureus; Staphylococcus aureus infections; Staphylococcus infections; Suppressor cells; Transcription factors; United States; Infectious disease; Innate immunity; Bacterial infections; Immunology; Orthopedics
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI174051

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), which are critical for orchestrating the antiinflammatory 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 hypoxia response through HIF1a were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2-deoxyglucose nanopreparation and granulocyte-targeted Hif1a conditional KO mice, respectively, attenuated G-MDSC-mediated immunosuppression and reduced bacterial burden in a mouse model of S. aureus PJI. In addition, single-cell RNA-Seq (scRNA-Seq) analysis of granulocytes from PJI patients also showed an enrichment in glycolysis and hypoxia-response genes. These findings support the importance of a glycolysis/HIF1a axis in promoting G-MDSC antiinflammatory activity and biofilm persistence during PJI.