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© Carmen Buchrieser, Marie-Christine Prevost
Legionella pneumophila et son flagelle, bactérie responsable de pneumopathie aigue grave. Bactérie de l'environnement , l'émergence récente de cette maladie s'explique par son affinité pour les systèmes modernes d'alimentation en eau comme les tours de refroidissement. Image colorisée.
Project

Metabolic Host-Pathogen Interactions: Revealing how Intracellular Bacteria hijack Mitochondrial OXPHOS during Infection (ANR JCJC 2021)

Scientific Fields
Diseases
Organisms
Applications
Technique
Starting Date
01
Feb 2022
Ending Date
31
Jan 2026
Status
Ongoing
Members
3
Structures
3

About

Mitochondria are critical players in cellular metabolism. Mitochondrial respiration generates ATP by a process known as oxidative phosphorylation (OXPHOS), which involves the coordinated action of several complexes and accessory proteins in the electron transport chain (ETC) at the mitochondrial inner membrane. The ETC is composed of five complexes (CI to CV) that assemble into supercomplexes to generate the mitochondrial membrane potential (mΔψ). This mΔψ allows the utilization of the proton-motive force to perform OXPHOS and thus to synthesize ATP trough the activity of complex V, the FO-F1-ATPase.

Besides bioenergetics, mitochondria have also functions in the regulation of cell death and innate immunity. Mitochondrial functions are key during the activation and subsequent responses of immune cells and specifically of macrophages, which are innate immune cells at the forefront of host defense against bacterial pathogens. In macrophages, immune responses and metabolic parameters such as oxygen consumption or ATP production depending on mitochondrial activity and fitness are connected. Considering the important functions of mitochondria, intracellular bacteria have evolved mechanisms to target these organelles during infection to exploit the key roles they play in the cell. Several intracellular bacteria target mitochondria during infection to modulate their functions to the bacterial advantage. However, the mechanisms used by intracellular bacteria to hijack mitochondrial functions during infection of human cells remain poorly understood. Learning how human pathogens subvert mitochondrial functions will not only provide fundamental knowledge about novel virulence strategies, but may also open new avenues for host-directed therapies to fight bacterial infection.

Legionella pneumophila, the causative agent of Legionnaires’ disease, injects via a type-IV- secretion-system (T4SS) more than 300 bacterial proteins into macrophages, its main host cell in humans. Certain of these proteins are implicated in reprogramming the metabolism of infected cells by reducing OXPHOS early after infection. One of these bacterial effectors is MitF, which targets mitochondrial dynamics during infection of primary human macrophages (hMDMs) via the recruitment of the host fission protein DNM1L to the mitochondrial surface. The fragmentation of mitochondrial networks provokes a T4SS-dependent reduction of OXPHOS in Legionella-infected human macrophages, evidencing a functional connection between mitochondrial dynamics and mitochondrial respiration. In addition to L. pneumophila, the intracellular bacteria Mycobacterium tuberculosis, Chlamydia trachomatis, S. Typhimurium, Brucella abortus or Listeria monocytogenes are also reported to regulate OXPHOS during infection of human cells. However, the exact mechanisms how these pathogens target the OXPHOS machinery of the host cells and whether these are similar or different is currently not known. This project aims to determine the precise mechanisms by which intracellular bacteria regulate OXPHOS activity during infection.

Fundings