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.
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
Reverting the mode of action of the mitochondrial FOF1-ATPase by Legionella pneumophila preserves its replication nichePublicly available at Github (https://github.com).
- Carmen Buchrieser
- Carmen Buchrieser
- Pedro Escoll
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Melanie Blokesch, Ecole Polytechnique Fédérale de Lausanne, Switzerland
© 2021, Escoll et al.
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