title: Shigella reroutes host cell central metabolism to obtain high-flux nutrient supply for vigorous intracellular growth.
abstract: Shigella flexneri proliferate in infected human epithelial cells at exceptionally high rates. This vigorous growth has important consequences for rapid progression to life-threatening bloody diarrhea, but the underlying metabolic mechanisms remain poorly understood. Here, we used metabolomics, proteomics, and genetic experiments to determine host and Shigella metabolism during infection in a cell culture model. The data suggest that infected host cells maintain largely normal fluxes through glycolytic pathways, but the entire output of these pathways is captured by Shigella, most likely in the form of pyruvate. This striking strategy provides Shigella with an abundant favorable energy source, while preserving host cell ATP generation, energy charge maintenance, and survival, despite ongoing vigorous exploitation. Shigella uses a simple three-step pathway to metabolize pyruvate at high rates with acetate as an excreted waste product. The crucial role of this pathway for Shigella intracellular growth suggests targets for antimicrobial chemotherapy of this devastating disease.
authors: Biozentrum, University of Basel, 4056 Basel, Switzerland; david.kentner@gmx.de dirk.bumann@unibas.ch.
authors: David
authors: D
authors: Kentner
authors: Institute of Microbiology, Eidgenössiche Technische Hochschule Zürich, 8093 Zürich, Switzerland; and.
authors: Giuseppe
authors: G
authors: Martano
authors: Biozentrum, University of Basel, 4056 Basel, Switzerland;
authors: Morgane
authors: M
authors: Callon
authors: Biozentrum, University of Basel, 4056 Basel, Switzerland;
authors: Petra
authors: P
authors: Chiquet
authors: Biozentrum, University of Basel, 4056 Basel, Switzerland;
authors: Maj
authors: M
authors: Brodmann
authors: Biozentrum, University of Basel, 4056 Basel, Switzerland;
authors: Olga
authors: O
authors: Burton
authors: Functional Genomics Center Zurich, 8057 Zürich, Switzerland.
authors: Asa
authors: A
authors: Wahlander
authors: Functional Genomics Center Zurich, 8057 Zürich, Switzerland.
authors: Paolo
authors: P
authors: Nanni
authors: Institute of Microbiology, Eidgenössiche Technische Hochschule Zürich, 8093 Zürich, Switzerland; and.
authors: Nathanaël
authors: N
authors: Delmotte
authors: Functional Genomics Center Zurich, 8057 Zürich, Switzerland.
authors: Jonas
authors: J
authors: Grossmann
authors: Biozentrum, University of Basel, 4056 Basel, Switzerland;
authors: Julien
authors: J
authors: Limenitakis
authors: Functional Genomics Center Zurich, 8057 Zürich, Switzerland.
authors: Ralph
authors: R
authors: Schlapbach
authors: Institute of Microbiology, Eidgenössiche Technische Hochschule Zürich, 8093 Zürich, Switzerland; and.
authors: Patrick
authors: P
authors: Kiefer
authors: Institute of Microbiology, Eidgenössiche Technische Hochschule Zürich, 8093 Zürich, Switzerland; and.
authors: Julia A
authors: JA
authors: Vorholt
authors: Biozentrum, University of Basel, 4056 Basel, Switzerland;
authors: Sebastian
authors: http://orcid.org/0000-0002-6709-4684
authors: S
authors: Hiller
authors: Biozentrum, University of Basel, 4056 Basel, Switzerland; david.kentner@gmx.de dirk.bumann@unibas.ch.
authors: Dirk
authors: D
authors: Bumann
mesh_terms: D000085:Acetates / Q000378:metabolism; D002244:Carbon / Q000378:metabolism; D002455:Cell Division; D003600:Cytosol / Q000378:metabolism; D016680:Genome, Bacterial; D006367:HeLa Cells; D006801:Humans; D055432:Metabolomics; D019906:Nuclear Magnetic Resonance, Biomolecular; D010100:Oxygen / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D012760:Shigella / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D000085:Acetates; D002244:Carbon; D019289:Pyruvic Acid; D010100:Oxygen
keywords: host–pathogen interactions; infectious diseases