Reverting the mode of action of the mitochondrial FOF1-ATPase by Legionella pneumophila preserves its replication niche

Abstract

Legionella pneumophila, the causative agent of Legionnaires'; disease, a severe pneumonia, injects via a type-IV-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.

Data availability

All data generated or analysed during this study are included in the manuscript. Source data files are uploaded to Github: https://github.com/bbi-ip/Legionella_and_mitochondrial_ATPase.git

The following data sets were generated

Article and author information

Author details

  1. Pedro Escoll

    Biologie des Bactéries Intracellulaires, Institut Pasteur, Paris, France
    For correspondence
    pescoll@pasteur.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5933-094X
  2. Lucien Platon

    Biologie des Bactéries Intracellulaires, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7894-5977
  3. Mariatou Dramé

    Biologie des Bactéries Intracellulaires, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Tobias Sahr

    Biologie des Bactéries Intracellulaires, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Silke Schmidt

    Biologie des Bactéries Intracellulaires, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Christophe Rusniok

    Biologie des Bactéries Intracellulaires, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Carmen Buchrieser

    Biologie des Bactéries Intracellulaires, Institut Pasteur, Paris, France
    For correspondence
    cbuch@pasteur.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3477-9190

Funding

Agence Nationale de la Recherche (ANR-10-LABX-62-IBEID)

  • Carmen Buchrieser

Fondation de la Recherche Medicale (EQU201903007847)

  • Carmen Buchrieser

Institut Carnot MIE (INNOV-SP10-19)

  • Pedro Escoll

Agence Nationale de la Recherche (ANR-21-CE15-0038-01)

  • Pedro Escoll

Ecole Doctorate FIRE (Programme Bettencourt)

  • Mariatou Dramé

Pasteur Paris-University (International PhD Program)

  • Silke Schmidt

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Melanie Blokesch, Ecole Polytechnique Fédérale de Lausanne, Switzerland

Publication history

  1. Received: July 7, 2021
  2. Accepted: December 6, 2021
  3. Accepted Manuscript published: December 9, 2021 (version 1)
  4. Accepted Manuscript updated: December 15, 2021 (version 2)
  5. Version of Record published: December 30, 2021 (version 3)

Copyright

© 2021, Escoll et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Pedro Escoll
  2. Lucien Platon
  3. Mariatou Dramé
  4. Tobias Sahr
  5. Silke Schmidt
  6. Christophe Rusniok
  7. Carmen Buchrieser
(2021)
Reverting the mode of action of the mitochondrial FOF1-ATPase by Legionella pneumophila preserves its replication niche
eLife 10:e71978.
https://doi.org/10.7554/eLife.71978
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