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1.
STAR Protoc ; 4(2): 102175, 2023 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-36933221

RESUMEN

Regulation of bioenergetics and cell death are pivotal mitochondrial functions determining the responses of macrophages to infection. Here, we provide a protocol to investigate mitochondrial functions during infection of macrophages by intracellular bacteria. We describe steps for quantifying mitochondrial polarization, cell death, and bacterial infection in infected, living, human primary macrophages at the single-cell level. We also detail the use of the pathogen Legionella pneumophila as model. This protocol can be adapted to investigate mitochondrial functions in other settings. For complete details on the use and execution of this protocol, please refer to Escoll et al. (2021).1.

2.
Elife ; 102021 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-34882089

RESUMEN

Legionella pneumophila, the causative agent of Legionnaires' disease, a severe pneumonia, injects via a type 4 secretion system (T4SS) more than 300 proteins into macrophages, its main host cell in humans. Certain of these proteins are implicated in reprogramming the metabolism of infected cells by reducing mitochondrial oxidative phosphorylation (OXPHOS) early after infection. Here. we show that despite reduced OXPHOS, the mitochondrial membrane potential (Δψm) is maintained during infection of primary human monocyte-derived macrophages (hMDMs). We reveal that L. pneumophila reverses the ATP-synthase activity of the mitochondrial FOF1-ATPase to ATP-hydrolase activity in a T4SS-dependent manner, which leads to a conservation of the Δψm, preserves mitochondrial polarization, and prevents macrophage cell death. Analyses of T4SS effectors known to target mitochondrial functions revealed that LpSpl is partially involved in conserving the Δψm, but not LncP and MitF. The inhibition of the L. pneumophila-induced 'reverse mode' of the FOF1-ATPase collapsed the Δψm and caused cell death in infected cells. Single-cell analyses suggested that bacterial replication occurs preferentially in hMDMs that conserved the Δψm and showed delayed cell death. This direct manipulation of the mode of activity of the FOF1-ATPase is a newly identified feature of L. pneumophila allowing to delay host cell death and thereby to preserve the bacterial replication niche during infection.


Asunto(s)
Adenosina Trifosfato/metabolismo , Proteínas Bacterianas/genética , Legionella pneumophila/metabolismo , Mitocondrias/metabolismo , ATPasas de Translocación de Protón/deficiencia , Adenosina Trifosfato/genética , Proteínas Bacterianas/metabolismo , Legionella pneumophila/genética , Mitocondrias/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , ATPasas de Translocación de Protón/metabolismo , Sistemas de Secreción Tipo IV/metabolismo
3.
Int Immunol ; 32(7): 475-483, 2020 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-32441740

RESUMEN

In this review, we propose that certain modifications in cellular metabolism might function as danger signals triggering inflammasome-mediated immune responses. We propose to call them danger-associated metabolic modifications (DAMMs). As intracellular bacteria can actively modulate macrophage metabolism for their benefit, infected host cells might sense bacteria-induced metabolic alterations and activate immune reactions. Here we report the known metabolic interactions that occur during infection of macrophages by intracellular bacteria and discuss the possible emergence of DAMMs upon bacteria-induced alterations of cellular metabolism.


Asunto(s)
Infecciones Bacterianas/metabolismo , Macrófagos/metabolismo , Animales , Infecciones Bacterianas/inmunología , Humanos , Macrófagos/inmunología
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