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Identification of Discriminating Metabolic Pathways and Metabolites in Human PBMCs Stimulated by Various Pathogenic Agents.

ABSTRACT: Immunity and cellular metabolism are tightly interconnected but it is not clear whether different pathogens elicit specific metabolic responses. To address this issue, we studied differential metabolic regulation in peripheral blood mononuclear cells (PBMCs) of healthy volunteers challenged by Candida albicans, Borrelia burgdorferi, lipopolysaccharide, and Mycobacterium tuberculosis in vitro. By integrating gene expression data of stimulated PBMCs of healthy individuals with the KEGG pathways, we identified both common and pathogen-specific regulated pathways depending on the time of incubation. At 4 h of incubation, pathogenic agents inhibited expression of genes involved in both the glycolysis and oxidative phosphorylation pathways. In contrast, at 24 h of incubation, particularly glycolysis was enhanced while genes involved in oxidative phosphorylation remained unaltered in the PBMCs. In general, differential gene expression was less pronounced at 4 h compared to 24 h of incubation. KEGG pathway analysis allowed differentiation between effects induced by Candida and bacterial stimuli. Application of genome-scale metabolic model further generated a Candida-specific set of 103 reporter metabolites (e.g., desmosterol) that might serve as biomarkers discriminating Candida-stimulated PBMCs from bacteria-stimuated PBMCs. Our analysis also identified a set of 49 metabolites that allowed discrimination between the effects of Borrelia burgdorferi, lipopolysaccharide and Mycobacterium tuberculosis. We conclude that analysis of pathogen-induced effects on PBMCs by a combination of KEGG pathways and genome-scale metabolic model provides deep insight in the metabolic changes coupled to host defense.

SUBMITTER: Zhang X

PROVIDER: S-EPMC5835230 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Identification of Discriminating Metabolic Pathways and Metabolites in Human PBMCs Stimulated by Various Pathogenic Agents.

Zhang Xiang X Mardinoglu Adil A Joosten Leo A B LAB Kuivenhoven Jan A JA Li Yang Y Netea Mihai G MG Groen Albert K AK

Frontiers in physiology 20180227

Immunity and cellular metabolism are tightly interconnected but it is not clear whether different pathogens elicit specific metabolic responses. To address this issue, we studied differential metabolic regulation in peripheral blood mononuclear cells (PBMCs) of healthy volunteers challenged by <i>Candida albicans, Borrelia burgdorferi</i>, lipopolysaccharide, and <i>Mycobacterium tuberculosis in vitro</i>. By integrating gene expression data of stimulated PBMCs of healthy individuals with the KE ...[more]

PMID: 29535640

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Project description:Glucocorticoid resistance (GR) is associated with exposure to chronic stress and an increased risk of metabolic and inflammatory disorders in both animal and human populations. Studies on ethnic disparities highlight the African-American (AA) population as having a high propensity to both GR and chronic stress exposure. Glucocorticoids and inflammation play a very important role in pregnancy outcome and fetal development. To date, however, the metabolites and metabolic pathways associated with GR during pregnancy have not been identified, obscuring the mechanisms by which adverse health consequences arise, and thus impeding targeted therapeutic intervention. The objective of this study was to perform untargeted high-resolution metabolomics (HRM) profiling on 273 pregnant AA women, to identify metabolites and metabolic pathways associated with GR during the first trimester of pregnancy and to evaluate their cross-sectional association with birth outcomes and psychosocial variables related to chronic stress exposure. For this study, GR was determined by the concentration of dexamethasone required for 50% inhibition (Dex IC50) of the cytokine tumor-necrosis factor alpha (TNF-alpha) release in vitro in response to a standard dose of lipopolysaccharide. The results for Metabolome-Wide Association Studies (MWAS) and pathway enrichment analysis for serum metabolic associations with Dex IC50, showed energy (nicotinamide and TCA cycle), amino acid, and glycosphingolipid metabolism as top altered pathways. Bioinformatic analysis showed that GR, as indicated by elevated Dex IC50 in the pregnant women, was associated with increased inflammatory metabolites, oxidative stress related metabolites, increased demand for functional amino acids to support growth and development, and disruption in energy-related metabolites. If confirmed in future studies, targeting these physiologically significant metabolites and metabolic pathways may lead to future assessment and intervention strategies to prevent inflammatory and metabolic complications observed in pregnant populations.

Dataset Information

Identification of Discriminating Metabolic Pathways and Metabolites in Human PBMCs Stimulated by Various Pathogenic Agents.

Publications

Identification of Discriminating Metabolic Pathways and Metabolites in Human PBMCs Stimulated by Various Pathogenic Agents.

Similar Datasets

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