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1.
Infect Immun ; 88(2)2020 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-31740527

RESUMEN

The mechanisms by which interferon gamma (IFN-γ) controls the replication of cytosolic pathogens independent of responses, such as the generation of reactive oxygen species/reactive nitrogen species (ROS/RNS), have not been fully elucidated. In the current study, we developed a model using Francisella tularensis, the causative agent of tularemia, in which pathways triggered by IFN-γ commonly associated with bacterial control were not required. Using this model, we demonstrated that IFN-γ-mediated production of itaconate and its ability to impair host mitochondrial function, independent of activity on the pathogen, were central for the restriction of bacterial replication in vitro and in vivo We then demonstrate that IFN-γ-driven itaconate production was dispensable, as directly targeting complex II using cell membrane-permeable metabolites also controlled infection. Together, these findings show that while reprogramming of mitochondrial metabolism is a key factor in IFN-γ control of intracellular bacteria, the development of antimicrobial strategies based on targeting host mitochondrial metabolism independent of this cytokine may be an effective therapeutic approach.


Asunto(s)
Francisella tularensis/efectos de los fármacos , Interferón gamma/farmacología , Mitocondrias/efectos de los fármacos , Animales , Membrana Celular/metabolismo , Membrana Celular/microbiología , Citosol/metabolismo , Citosol/microbiología , Humanos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias/microbiología , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Succinatos/farmacología , Tularemia/tratamiento farmacológico , Tularemia/metabolismo , Tularemia/microbiología
2.
Infect Immun ; 86(8)2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29760217

RESUMEN

Francisella tularensis subsp. tularensis is a highly pathogenic intracellular bacterium that suppresses host inflammation by impairing the metabolic shift from oxidative phosphorylation to glycolysis. Decreased mitochondrial metabolism is central to initiating a metabolic shift to glycolysis and regulating inflammation, but F. tularensis subsp. tularensis manipulation of host mitochondrial function has not been explored. We demonstrate, using extracellular flux analysis, that F. tularensis subsp. tularensis infection initially improves host macrophage mitochondrial bioenergetics in a capsule-dependent manner. Enhancement of mitochondrial function by F. tularensis subsp. tularensis allowed for modest replication and inhibition of apoptosis early after infection. However, using live cell imaging, we found that F. tularensis subsp. tularensis facilitated the loss of mitochondrial function at later time points during infection in a capsule-independent fashion. This loss of function was paired with oncosis and rapid bacterial replication. Inhibition of oncosis reduced intracellular bacterial numbers, underscoring the requirement for this process during F. tularensis subsp. tularensis infection. These findings establish that temporal mitochondrial manipulation by F. tularensis subsp. tularensis is critical for maintenance of a noninflammatory environment and subsequently aids in optimal replication and dissemination of this pathogenic organism.


Asunto(s)
Cápsulas Bacterianas/metabolismo , Muerte Celular , Metabolismo Energético , Francisella tularensis/patogenicidad , Interacciones Huésped-Patógeno , Mitocondrias/metabolismo , Mitocondrias/microbiología , Animales , Carga Bacteriana , Células Cultivadas , Citoplasma/microbiología , Femenino , Francisella tularensis/crecimiento & desarrollo , Evasión Inmune , Inflamación/patología , Microscopía Intravital , Macrófagos/microbiología , Macrófagos/fisiología , Ratones Endogámicos C57BL
3.
Int J Toxicol ; 36(5): 395-402, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28820005

RESUMEN

Repeated developmental exposure to the organophosphate (OP) insecticide chlorpyrifos (CPF) inhibits brain fatty acid amide hydrolase (FAAH) activity at low levels, whereas at higher levels, it inhibits brain monoacylglycerol lipase (MAGL) activity. FAAH and MAGL hydrolyze the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG), respectively. Peripherally, AEA and 2-AG have physiological roles in the regulation of lipid metabolism and immune function, and altering the normal levels of these lipid mediators can negatively affect these processes. Exposure to CPF alters brain endocannabinoid hydrolysis activity, but it is unclear whether low-level exposure alters this activity in peripheral tissues important in metabolic and immune function. Therefore, rat pups were exposed orally from day 10 to 16 to 0.5, 0.75, or 1.0 mg/kg CPF or 0.02 mg/kg PF-04457845 (a specific FAAH inhibitor). At 12 hours postexposure, FAAH, MAGL, and cholinesterase (ChE) activities were determined. All treatments inhibited FAAH activity in brain, spleen, and liver. CPF inhibited ChE activity in spleen and liver (all dosages) and in brain (highest dosage only). CPF inhibited total 2-AG hydrolysis and MAGL-specific activity in brain and spleen (high dosage only). In liver, total 2-AG hydrolysis was inhibited by all treatments and could be attributed to inhibition of non-MAGL-mediated 2-AG hydrolysis, indicating involvement of other enzymes. MAGL-specific activity in liver was inhibited only by the high CPF dosage, whereas PF-04457845 slightly increased this activity. Overall, exposure to low levels of CPF and to PF-04457845 can alter endocannabinoid metabolism in peripheral tissues, thus potentially affecting physiological processes.


Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Ácidos Araquidónicos/metabolismo , Cloropirifos/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Endocannabinoides/metabolismo , Glicéridos/metabolismo , Insecticidas/toxicidad , Alcamidas Poliinsaturadas/metabolismo , Piridazinas/toxicidad , Urea/análogos & derivados , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Colinesterasas/metabolismo , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Bazo/efectos de los fármacos , Bazo/metabolismo , Urea/toxicidad
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