Granulocytic myeloid-derived suppressor cell activity during biofilm infection is regulated by a glycolysis/HIF1a
Christopher M Horn1, Prabhakar Arumugam1, Zachary Van Roy1
1Department of Pathology, Microbiology, and Immunology and.
Abstract:
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.
Insights
Staphylococcus aureus prosthetic joint infections (PJI) involve myeloid-derived suppressor cells (MDSCs) that promote inflammation. Targeting their metabolism, specifically glycolysis and hypoxia response, reduced bacterial burden in a PJI mouse model.
Area of Science:
- Immunology
- Microbiology
- Metabolic Engineering
Background:
- Staphylococcus aureus is a major cause of prosthetic joint infections (PJI), often becoming chronic.
- Granulocytic myeloid-derived suppressor cells (G-MDSCs) are key players in chronic PJI, fostering an anti-inflammatory environment that supports biofilm persistence.
Purpose of the Study:
- To investigate the metabolic pathways within G-MDSCs that contribute to the chronicity of Staphylococcus aureus PJI.
- To explore the potential of targeting G-MDSC metabolism to treat S. aureus PJI.
Main Methods:
- Single-cell RNA sequencing (scRNA-Seq) and bioinformatic metabolic algorithms were employed to analyze G-MDSC metabolism in a mouse model of S. aureus PJI.
- Pharmacological inhibition of glycolysis (using 2-deoxyglucose) and genetic targeting of the hypoxia-inducible factor 1-alpha (HIF1a) pathway in granulocytes were utilized in vivo.
- scRNA-Seq was also performed on granulocytes from human PJI patients.
Main Results:
- G-MDSCs in S. aureus PJI exhibited significantly enriched glycolysis and hypoxia response pathways.
- Interfering with glycolysis and HIF1a in vivo attenuated G-MDSC immunosuppression and reduced bacterial load in the PJI mouse model.
- Analysis of human PJI patient granulocytes confirmed enrichment of glycolysis and hypoxia-response genes.
Conclusions:
- The glycolysis/HIF1a axis is crucial for G-MDSC-mediated immunosuppression and biofilm persistence in S. aureus PJI.
- Targeting this metabolic axis presents a potential therapeutic strategy for managing chronic S. aureus prosthetic joint infections.
Related Concept Videos
01:01Regulation of Hematopoietic Stem Cells
01:15Differentiation of Common Myeloid Progenitor Cells
01:24Regulation of Angiogenesis and Blood Supply