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Granulocytic myeloid-derived suppressor cell activity during biofilm infection is regulated by a glycolysis-HIF-1α axis

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) 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-1α) were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2-deoxyglucose nanopreparation and granulocyte-targeted HIF-1α 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-1α axis in promoting G-MDSC anti-inflammatory activity and biofilm persistence during PJI.

ORGANISM(S): Mus musculus

PROVIDER: GSE248055 | GEO | 2024/02/08

REPOSITORIES: GEO

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Granulocytic myeloid-derived suppressor cell activity during biofilm infection is regulated by a glycolysis-HIF-1α axis (scRNA-Seq)

Project description: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-1α) were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2-deoxyglucose nanopreparation and granulocyte-targeted HIF-1α 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-1α axis in promoting G-MDSC anti-inflammatory activity and biofilm persistence during PJI.

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