Open AccessGlutamate Utilization Couples Oxidative Stress Defense and the Tricarboxylic Acid Cycle in Francisella Phagosomal Escape
Author(s) -
Elodie Ramond,
Gaël Gesbert,
Rigard Mélanie,
Julien Dairou,
Marion Dupuis,
Iharilalao Dubail,
Karin Lederballe Meibom,
Thomas Henry,
Monique Barel,
Alain Charbit
Publication year - 2014
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1003893
Subject(s) - francisella , biology , microbiology and biotechnology , intracellular , citric acid cycle , intracellular parasite , phagosome , cytosol , oxidative stress , francisella tularensis , innate immune system , virulence , biochemistry , metabolism , gene , enzyme , receptor
Intracellular bacterial pathogens have developed a variety of strategies to avoid degradation by the host innate immune defense mechanisms triggered upon phagocytocis. Upon infection of mammalian host cells, the intracellular pathogen Francisella replicates exclusively in the cytosolic compartment. Hence, its ability to escape rapidly from the phagosomal compartment is critical for its pathogenicity. Here, we show for the first time that a glutamate transporter of Francisella (here designated GadC) is critical for oxidative stress defense in the phagosome, thus impairing intra-macrophage multiplication and virulence in the mouse model. The gadC mutant failed to efficiently neutralize the production of reactive oxygen species. Remarkably, virulence of the gadC mutant was partially restored in mice defective in NADPH oxidase activity. The data presented highlight links between glutamate uptake, oxidative stress defense, the tricarboxylic acid cycle and phagosomal escape. This is the first report establishing the role of an amino acid transporter in the early stage of the Francisella intracellular lifecycle.