Glutamate utilization couples oxidative stress defense and the tricarboxylic acid cycle in Francisella phagosomal escape.
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.
Université Paris Descartes, Sorbonne Paris Cité, Bâtiment Leriche, Paris, France ; INSERM, U1002, Unité de Pathogénie des Infections Systémiques, Paris, France.
Elodie
E
Ramond
Université Paris Descartes, Sorbonne Paris Cité, Bâtiment Leriche, Paris, France ; INSERM, U1002, Unité de Pathogénie des Infections Systémiques, Paris, France.
Gael
G
Gesbert
Centre international de recherche en infectiologie, Université de Lyon, Lyon, France ; Bacterial Pathogenesis and Innate Immunity Laboratory, INSERM U851 "Immunity, Infection and Vaccination", Lyon, France.
Mélanie
M
Rigard
Platform "Bioprofiler" Université Paris Diderot, Paris, France.
Julien
J
Dairou
Université Paris Descartes, Sorbonne Paris Cité, Bâtiment Leriche, Paris, France ; INSERM, U1002, Unité de Pathogénie des Infections Systémiques, Paris, France.
Marion
M
Dupuis
Université Paris Descartes, Sorbonne Paris Cité, Bâtiment Leriche, Paris, France ; INSERM, U1002, Unité de Pathogénie des Infections Systémiques, Paris, France.
Iharilalao
I
Dubail
Université Paris Descartes, Sorbonne Paris Cité, Bâtiment Leriche, Paris, France ; INSERM, U1002, Unité de Pathogénie des Infections Systémiques, Paris, France.
Karin
K
Meibom
Centre international de recherche en infectiologie, Université de Lyon, Lyon, France ; Bacterial Pathogenesis and Innate Immunity Laboratory, INSERM U851 "Immunity, Infection and Vaccination", Lyon, France.
Thomas
T
Henry
Université Paris Descartes, Sorbonne Paris Cité, Bâtiment Leriche, Paris, France ; INSERM, U1002, Unité de Pathogénie des Infections Systémiques, Paris, France.
Monique
M
Barel
Université Paris Descartes, Sorbonne Paris Cité, Bâtiment Leriche, Paris, France ; INSERM, U1002, Unité de Pathogénie des Infections Systémiques, Paris, France.
Alain
A
Charbit
D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002952:Citric Acid Cycle; D005260:Female; D005604:Francisella tularensis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D014406:Tularemia / Q000235:genetics / Q000378:metabolism*
D027322:Amino Acid Transport System X-AG; D001426:Bacterial Proteins; C103589:GadC protein, bacteria; D008565:Membrane Proteins; D018698:Glutamic Acid; D019255:NADPH Oxidases