title: The pyruvate-tricarboxylic acid cycle node: a focal point of virulence control in the enteric pathogen Yersinia pseudotuberculosis.
abstract: Despite our increasing knowledge of the specific pathogenicity factors in bacteria, the contribution of metabolic processes to virulence is largely unknown. Here, we elucidate a tight connection between pathogenicity and core metabolism in the enteric pathogen Yersinia pseudotuberculosis by integrated transcriptome and [(13)C]fluxome analysis of the wild type and virulence-regulator mutants. During aerobic growth on glucose, Y. pseudotuberculosis reveals an unusual flux distribution with a high level of secreted pyruvate. The absence of the transcriptional and post-transcriptional regulators RovA, CsrA, and Crp strongly perturbs the fluxes of carbon core metabolism at the level of pyruvate metabolism and the tricarboxylic acid (TCA) cycle, and these perturbations are accompanied by transcriptional changes in the corresponding enzymes. Knock-outs of regulators of this metabolic branch point and of its central enzyme, pyruvate kinase (ΔpykF), result in mutants with significantly reduced virulence in an oral mouse infection model. In summary, our work identifies the pyruvate-TCA cycle node as a focal point for controlling the host colonization and virulence of Yersinia.
authors.affiliation: From the Institute of Systems Biotechnology, Saarland University, 66123 Saarbrücken, the Institute of Biochemical Engineering, Technische Universität, Braunschweig and.
authors.forename: René
authors.initials: R
authors.lastname: Bücker
authors.affiliation: the Department of Molecular Infection Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Ann Kathrin
authors.initials: AK
authors.lastname: Heroven
authors.affiliation: From the Institute of Systems Biotechnology, Saarland University, 66123 Saarbrücken.
authors.forename: Judith
authors.initials: J
authors.lastname: Becker
authors.affiliation: the Department of Molecular Infection Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Dersch
authors.affiliation: From the Institute of Systems Biotechnology, Saarland University, 66123 Saarbrücken, christoph.wittmann@uni-saarland.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wittmann
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D018533:Biomass; D002952:Citric Acid Cycle / Q000187:drug effects / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D053263:Gene Regulatory Networks; D005947:Glucose / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D064688:Metabolic Flux Analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics; D011773:Pyruvates / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014774:Virulence / Q000187:drug effects / Q000235:genetics; D015011:Yersinia pseudotuberculosis / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity*; D015012:Yersinia pseudotuberculosis Infections / Q000382:microbiology / Q000473:pathology
chemical_list: D001426:Bacterial Proteins; D011773:Pyruvates; D007501:Iron; D005947:Glucose
keywords: Bacteria; Bacterial Metabolism; Bacterial Pathogenesis; Gene Expression; Metabolic Flux Analysis; Pyruvate; Systems Biology; Tricarboxylic Acid Cycle (TCA Cycle) (Krebs Cycle); Yersinia