Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Modulates Immune Cell Metabolism and Promotes Tolerance to Pseudomonas aeruginosa Infection

Core Concepts

The bacterial quorum-sensing molecule 2-aminoacetophenone (2-AA) from Pseudomonas aeruginosa impairs the PGC-1α/ERRα axis, leading to decreased mitochondrial pyruvate import, ATP, and acetyl-CoA production in macrophages, which contributes to immune tolerance and persistent bacterial infection.

Abstract

The content explores how the bacterial quorum-sensing (QS) signal 2-aminoacetophenone (2-AA) from Pseudomonas aeruginosa (PA) modulates the metabolism and bioenergetics of immune cells, particularly macrophages, to promote immune tolerance and persistence of the pathogen. Key highlights: 2-AA tolerization of macrophages decreases the levels of crucial energy metabolites ATP and acetyl-CoA, as well as mitochondrial respiration and OXPHOS. The decreased mitochondrial pyruvate import and metabolism is attributed to the 2-AA-mediated impairment of the PGC-1α/ERRα transcriptional axis, which regulates the expression of the mitochondrial pyruvate carrier (MPC1). 2-AA disrupts the interaction between PGC-1α and ERRα, leading to reduced binding of ERRα to the MPC1 promoter and decreased MPC1 expression. The metabolic alterations, including reduced ATP and acetyl-CoA levels, are associated with the persistence of PA in infected host tissues. Exogenous addition of ATP restores MPC1 and ERRα expression and enhances cytokine production and intracellular bacterial clearance in infected macrophages. In vivo studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA levels and their association with PA persistence. These findings reveal an unprecedented mechanism by which a bacterial QS molecule modulates the host's cellular immunometabolism through the PGC-1α/ERRα axis, contributing to immune tolerance and pathogen persistence.

Stats

Macrophages exposed to 2-AA for 1 or 6 h showed significantly higher concentrations of cytosolic and mitochondrial pyruvate compared to control cells. Tolerized macrophages exposed to 2-AA for 48 h exhibited significantly decreased levels of cytosolic and mitochondrial pyruvate. 2-AA tolerization led to a significant decrease in the abundance of the mitochondrial pyruvate carrier (MPC1) protein over time. 2-AA tolerization caused a significant decrease in the abundance of the transcription factor ERRα protein over time. In tolerized macrophages, ERRα binding to the MPC1 promoter was reduced by approximately 4-fold compared to control cells. Exogenous addition of ATP in PA14-infected macrophages reduced the intracellular bacterial burden. Infection with PA14 or injection of 2-AA in mice led to a significant decrease in ATP and acetyl-CoA concentrations in spleen tissues compared to infection with the 2-AA-deficient ΔmvfR mutant.

Quotes

"2-AA tolerization decreases crucial metabolites of cellular energy and affects mitochondrial respiration in mouse BMDM." "2-AA perturbs the mitochondrial MPC1-mediated import and metabolism of pyruvate." "2-AA-mediated macrophage tolerization deranges PGC-1α/ERRα-dependent metabolic programing." "Increased intracellular burden in macrophages is associated with decreased expression of MPC1, ERR-α, and TNF-α genes."

Key Insights Distilled From

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

by Chakraborty,... at www.biorxiv.org 02-29-2024

https://www.biorxiv.org/content/10.1101/2024.02.26.582124v2

Deeper Inquiries

How might the 2-AA-mediated metabolic alterations in macrophages impact other immune cell types and their interactions during infection?

The 2-AA-mediated metabolic alterations in macrophages could have significant implications for other immune cell types and their interactions during infection. Macrophages play a crucial role in the immune response by phagocytosing pathogens and initiating inflammatory responses. The metabolic reprogramming induced by 2-AA, leading to decreased ATP and acetyl-CoA levels, could impact the overall energy metabolism of immune cells. This could affect the ability of immune cells to mount an effective response against pathogens, as ATP is essential for various cellular functions, including phagocytosis and cytokine production. Furthermore, the dysregulation of the PGC-1α/ERRα axis by 2-AA could have broader effects on immune cell metabolism. PGC-1α is a key regulator of mitochondrial biogenesis and function, and its interaction with ERRα is crucial for the expression of genes involved in mitochondrial metabolism. Therefore, the impairment of this axis by 2-AA could lead to altered mitochondrial function in other immune cell types, impacting their ability to generate energy and respond to infection. In addition, the reduced pyruvate transport into mitochondria in tolerized macrophages could affect the TCA cycle and oxidative phosphorylation in other immune cells. This could lead to a shift in cellular metabolism towards glycolysis, which is less efficient in generating ATP but can support rapid energy production during immune responses. Overall, the 2-AA-mediated metabolic alterations in macrophages could have cascading effects on the metabolic and functional properties of other immune cell types, potentially influencing their interactions and overall immune response during infection.

What other cellular pathways or signaling mechanisms could be involved in the 2-AA-induced immune tolerance beyond the PGC-1α/ERRα axis?

While the PGC-1α/ERRα axis plays a central role in the 2-AA-induced immune tolerance by regulating mitochondrial metabolism, other cellular pathways and signaling mechanisms could also be involved in this process. One potential pathway that could be implicated in 2-AA-induced immune tolerance is the NF-κB signaling pathway. NF-κB is a key regulator of inflammatory responses and immune cell activation, and its dysregulation has been linked to immune tolerance and impaired host defense mechanisms. 2-AA has been shown to modulate the NF-κB signaling pathway by altering the acetylation status of histones and affecting the expression of pro-inflammatory genes. Moreover, the mTOR signaling pathway, which is a central regulator of cellular metabolism and immune responses, could also be involved in 2-AA-induced immune tolerance. mTOR integrates signals from nutrients, energy levels, and growth factors to regulate cell growth, proliferation, and metabolism. Dysregulation of the mTOR pathway has been associated with immune dysfunction and tolerance to pathogens. 2-AA may impact mTOR signaling, leading to altered immune cell metabolism and function during infection. Additionally, the crosstalk between metabolic pathways, such as glycolysis, fatty acid metabolism, and amino acid metabolism, could contribute to the 2-AA-induced immune tolerance. Changes in nutrient availability and metabolic fluxes can influence immune cell function and responsiveness to infection. Therefore, exploring the interplay between different cellular pathways and signaling mechanisms beyond the PGC-1α/ERRα axis could provide a more comprehensive understanding of the mechanisms underlying 2-AA-induced immune tolerance.

Could targeting the PGC-1α/ERRα axis or mitochondrial metabolism be a potential therapeutic strategy to enhance host resilience against persistent Pseudomonas infections?

Targeting the PGC-1α/ERRα axis or mitochondrial metabolism could indeed be a promising therapeutic strategy to enhance host resilience against persistent Pseudomonas infections. The PGC-1α/ERRα axis plays a critical role in regulating mitochondrial biogenesis, metabolism, and energy production, which are essential for immune cell function and host defense mechanisms. By modulating this axis, it may be possible to restore mitochondrial function, improve energy metabolism, and enhance the immune response against Pseudomonas infections. One approach could involve the development of small molecule agonists or activators that target PGC-1α or ERRα to promote mitochondrial biogenesis and function in immune cells. By enhancing mitochondrial metabolism, these compounds could potentially boost the energy production capacity of immune cells, improving their ability to clear pathogens and mount an effective immune response. Furthermore, targeting specific metabolic pathways involved in mitochondrial function, such as the TCA cycle and oxidative phosphorylation, could also be explored as a therapeutic strategy. Inhibitors or activators of key enzymes or transporters involved in these pathways could be used to modulate cellular metabolism and enhance immune cell function during infection. Overall, targeting the PGC-1α/ERRα axis or mitochondrial metabolism represents a promising avenue for developing novel therapeutic interventions to bolster host resilience against persistent Pseudomonas infections. Further research in this area is warranted to explore the potential of these strategies in combating recalcitrant bacterial pathogens.