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

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): Homo sapiens

PROVIDER: GSE241739 | 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

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.

2024-02-08 | GSE248055 | GEO

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

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Project description:Myeloid-derived suppressor cells (MDSCs) are pathologically activated immature myeloid cells with immunosuppressive activity that expand during chronic inflammation, such as cancer and prosthetic joint infection (PJI). MDSCs can be broadly separated into two populations based on surface marker expression and function, namely monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs). In cancer models, M-MDSCs have been reported to transition into tumor-associated macrophages and/or dendritic cells, whereas G-MDSCs are considered terminally differentiated with short half-lives. G-MDSCs are the most abundant leukocyte infiltrate during PJI; however, how this population is maintained in vivo and cellular heterogeneity is currently unknown. In this study, we identified a population of Ly6G+Ly6C+F4/80+MHCII+ MDSCs during PJI that displayed immunosuppressive properties ex vivo. We leveraged F4/80 and MHCII expression by these cells for further characterization using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), which revealed a distinct transcriptomic signature of this population. F4/80+MHCII+ MDSCs displayed gene signatures resembling G-MDSCs, neutrophils, and monocytes, but had increased expression of genes involved in cytokine response/production, inflammatory cell death, and mononuclear cell differentiation. To determine whether F4/80+MHCII+ MDSCs represented an alternative differentiation state of G-MDSCs, Ly6G+Ly6C+F4/80-MHCII- G-MDSCs from CD45.1 mice were adoptively transferred into CD45.2 recipients using a mouse model of PJI. A small percentage of transferred G-MDSCs acquired F4/80 and MHCII expression in vivo, suggesting some degree of plasticity in this population. Collectively, these results demonstrate a previously unappreciated phenotype of G-MDSCs during PJI, which suggests a novel granulocytic-to-monocytic transition of MDSC infiltrates.

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Project description:Background: Tibetan chicken, a unique plateau breed, has a suite of adaptive features that enable it to tolerate the high-altitude hypoxic environment. HIF‐1α (hypoxia inducible factor 1 subunit alpha) is a crucial mediator of the cellular response to hypoxia. HIF‐1α maintains oxygen homeostasis by inducing glycolysis, erythropoiesis, and angiogenesis; however, the target genes involved in adaptive responses to hypoxia in animals and birds of plateaus are still unclear. Results: We used ChIP-seq to map HIF‐1α binding regions in chorioallantoic membrane (CAM) tissue of chicken embryos, and identified 752 HIF-1α target genes (TG), of which 112 were differentially expressed target genes (DTGs) between the two breeds. We found that eight genes (PTK2, GPNMB, CALD1, SLC25A1, SPRY2, NUPL2, RANBPL, and CBWD1) play important roles in hypoxic adaption by regulating blood vessel development, energy metabolism through angiogenesis, vascular smooth muscle contraction, and various hypoxia-related signaling pathways (including VEGF and MAPK) in Tibetan chickens during embryonic development. Conclusions: This study enhances our understanding of the molecular mechanisms of hypoxic adaptation in Tibetan chickens and provides new insights into adaptation to hypoxia in humans and other species living at high altitude.

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Effect of NDRG3 expression on cell response to hypoxia

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Staphylococcus aureus gene expression during infection and antibiotic treatment with moxifloxacin in a guinea pig biofilm infection model

Project description:Staphylococcus aureus is a major agent in device related infections. Upon infection, it upregulates virulence factors and adapts to host environment. We investigated the gene expression profile of S. aureus in a guinea pig infection model. Four Teflon® cages were placed subcutaneously in each of 12 animals prior to inoculation of a S. aureus strain from a patient with prosthetic joint infection (PJI). The animals were divided into two groups of six, one treated with moxifloxacin after three days of infection and for four days, and the other untreated. Cage fluid and cages were collected for RNA sequencing analysis and metabolomics. The gene expression profiles in untreated controls on day 7 and 9 were not differentiable and resemble the profile reported for the PJI case from where the strain originated. Compared to the profiles from day 3, we found upregulation of ammonia production through urea degradation, arginine deiminase and acetoin biosynthesis pathways on day 7 and 9, while several virulence genes were downregulated. Interestingly, the transcriptome seven day after termination of moxifloxacin treatment resembled infection day 3. Overall, the gene expression profiles showed adaptation to hypoxic and acidic environment during infection development. We deem the model to be suitable for pathogenesis studies.

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