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Front. Physiol. | doi: 10.3389/fphys.2018.00139

Identification of discriminating metabolic pathways and metabolites in human PBMCs stimulated by various pathogenic agents

 Xiang Zhang1*,  Adil Mardinoglu2, 3,  Leo A. Joosten4, Jan A. Kuivenhoven5, Yang Li6,  Mihai Netea4, 7 and Albert K. Groen1, 8
  • 1Department of Experimental Vascular Medicine, Academic Medical Center (AMC), Netherlands
  • 2Department of Chemical and Biological Engineering, Chalmers University of Technology, Sweden
  • 3Science for Life Laboratory, Royal Institute of Technology, Sweden
  • 4Department of Internal Medicine, Medical Center, Radboud University Nijmegen, Netherlands
  • 5Department of Pediatrics, University Medical Center Groningen, Netherlands
  • 6Department of Genetics, University Medical Center Groningen, Netherlands
  • 7Department for Genomics & Immunoregulation Life and Medical Sciences Institute (LIMES), University of Bonn, Germany
  • 8Department of Laboratory Medicine, University Medical Center Groningen, Netherlands

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 burgdorfer i, 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-sspecific regulated pathways depending on the time of incubation. At 4 hour of incubation, pathogenic agents inhibited expression of genes involved in both the glycolysis and oxidative phosphorylation pathways. In contrast, at 24 hour 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 hour compared to 24 hour 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.

Keywords: innate immunity, Genome scale metabolic model, Candida albicans, Borrelia burgdorferi, Mycobacterium tuberculosis (MTB), Metabolism, peripheral blood mononuclear cell (PBMCs), Lipopolysaccharides

Received: 11 Dec 2017; Accepted: 12 Feb 2018.

Edited by:

Xiaogang Wu, Institute for Systems Biology, United States

Reviewed by:

Alessandro Giuliani, Istituto Superiore di Sanità, Italy
Syed Aun Muhammad, Institute of Molecular Biology and Biotechnology, BZ University, Pakistan  

Copyright: © 2018 Zhang, Mardinoglu, Joosten, Kuivenhoven, Li, Netea and Groen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mr. Xiang Zhang, Academic Medical Center (AMC), Department of Experimental Vascular Medicine, Amsterdam, Netherlands, xiang.zhang@amc.uva.nl