Glutamate utilization couples oxidative stress defense and the tricarboxylic acid cycle in Francisella phagosomal escape.

Elodie Ramond (1) , Gael Gesbert (1) , Mélanie Rigard (2, 3) , Julien Dairou (4) , Marion Dupuis (1) , Iharilalao Dubail (1) , Karin Meibom (1) , Thomas Henry (3, 2) , Monique Barel (1) , Alain Charbit (1)

1 Inserm U1002 - Pathogénie des infections systémiques
2 CIRI - Centre International de Recherche en Infectiologie
3 I2V - Immunité infection vaccination
4 UPD7 - Université Paris Diderot - Paris 7

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.

Domains: Bacteriology; Innate immunity

Elodie Ramond, Gael Gesbert, Mélanie Rigard, Julien Dairou, Marion Dupuis, et al.. Glutamate utilization couples oxidative stress defense and the tricarboxylic acid cycle in Francisella phagosomal escape.. PLoS Pathogens, 2014, 10 (1), pp.e1003893. ⟨10.1371/journal.ppat.1003893⟩. ⟨hal-00972072⟩