Metabolic adaption of Legionella pneumophila during intracellular growth in Acanthamoeba castellanii

Kunze, Mareike; Steiner, Thomas; Chen, Fan; Huber, Claudia; Rydzewski, Kerstin; Stammler, M.; Heuner, Klaus; Eisenreich, Wolfgang

doi:10.1016/j.ijmm.2021.151504

Cited by 8 publications

(2 citation statements)

References 70 publications

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“…Metabolic reprogramming upon infection may be pathogen-specific, with each pathogen impacting specific metabolic pathways that better fit its respective metabolic needs [7]. This was shown for infections of various tissues with Chlamydia pneumonia, Legionella pneumophila, Mycobacterium tuberculosis, and Salmonella [62][63][64][65] and, by our group, for PA infections [17,18,24]. It would be interesting, however, to test whether 2-AA affects the killing efficacy of macrophages against other pathogens, as emerging evidence shows that synergistic or antagonistic interactions between clinically relevant microorganisms and host have important implications for polymicrobial infectious diseases [66].…”

Section: Discussionmentioning

confidence: 99%

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection

Chakraborty,

Bandyopadhaya,

Singh

et al. 2024

Preprint

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How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in macrophages mitochondrial respiration and bioenergetics. We found that the 2-AA tolerization impairs oxidative phosphorylation (OXPHOS), leading to decreased generation of the crucial energy metabolite ATP and histone acetylation acetyl-CoA. We provide evidence that these effects result from reduced pyruvate flux into mitochondria due to the decreased expression of the mitochondrial pyruvate carrier (MPC1) mediated via the reduced expression and nuclear presence of its transcriptional regulator estrogen-related nuclear receptor (ERRα), leading to the weaker binding of ERRα to MPC1 promoter. This is the outcome of the hampered interaction of ERRα with the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) that ultimately leads to reduced pyruvate flux into mitochondria and ATP production in tolerized macrophages. Exogenously added ATP in 2-AA exposed macrophages restores the transcript levels of MPC1 and ERR-α and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic impairment and PA persistence. These findings unveil 2-AA as a negative modulator of cellular immunometabolism implicating the PGC-1α/ERRα axis in its influence on MPC1/OXPHOS-dependent energy production and PA clearance. These findings shed light on the underlying mechanisms of host tolerance and on potential therapeutic strategies to combat persistent PA infections.

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Section: Discussionmentioning

confidence: 99%

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection

Chakraborty,

Bandyopadhaya,

Singh

et al. 2024

Preprint

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“…Some OMIC approaches have been used to study how the bacterium hijacks A. castellanii metabolism. Metabolomics approaches have shown that L. pneumophila was able to uptake A. castellanii amino acids into the LCV and to use serine preferentially during the postexponential phase of intracellular growth (Schunder et al 2014;Kunze et al 2021). At the transcriptomics level, in response to L. pneumophila infection, A. castellanii transcriptome was modified with LegAS4 that promotes rDNA transcription by targeting specific rDNA chromatin regions and upregulating genes linked to hydrolase activity, catalytic activity, and DNA binding while downregulating genes associated with oxidoreductase activity (Li et al 2020;Moon et al 2021).…”

mentioning

confidence: 99%

Proteomic analysis of Acanthamoeba castellanii response to Legionella pneumophila infection

Hay,

Rolland,

Bernard

et al. 2023

FEMS Microbiology Letters

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Legionella pneumophila is an opportunistic pathogen responsible for Legionnaires' disease or Legionellosis. This bacterium is found in the environment interacting with free-living amoebae such as Acanthamoeba castellanii. Until now, proteomic analyses have been done in amoebae infected with L. pneumophila but focused on the Legionella-containing vacuole. In this study, we propose a global proteomic analysis of the A. castellanii proteome following infection with L. pneumophila wild-type (WT) or with an isogenic ΔdotA mutant strain, which is unable to replicate intracellularly. We found that infection with L. pneumophila WT leads to reduced levels of A. castellanii proteins associated with lipid homeostasis/metabolism, GTPase regulation and kinase. The levels of organelle-associated proteins were also decreased during infection. L. pneumophila WT infection leads to increase levels of proteins associated with proteins polyubiquitination, folding or degradation and antioxidant activities. This study reinforces our knowledge of this too-little-explored but so fundamental interaction between L. pneumophila and A. castellanii, to understand how the bacterium could resist amoeba digestion.

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Isotopologue Profiling of Infectious Disease

Steiner

Eisenreich

2022

Encyclopedia of Infection and Immunity

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Metabolic adaption of Legionella pneumophila during intracellular growth in Acanthamoeba castellanii

Cited by 8 publications

References 70 publications

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection

Proteomic analysis of Acanthamoeba castellanii response to Legionella pneumophila infection

Isotopologue Profiling of Infectious Disease

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