improving-zero-shot-classification-by-adjusting-pretrained-model-predictions-via-optimal-transport

ein-rückwärts-differenzierender-deep-learning-basierter-algorithmus-zum-lösen-hochdimensionaler-nichtlinearer-rückwärts-stochastischer-differentialgleichungen

ゼロショット分類の精度向上のためのオプティマル-トランスポートを用いた手法

제로샷-분류-성능-향상을-위한-최적-전송-기반-접근법

verbesserung-der-nullklassen-klassifizierung-durch-optimalen-transport

efficient-riemannian-optimization-on-the-symplectic-stiefel-manifold-using-second-order-information

リーマン多様体上の最適化手法を用いた共形シュテーフェル多様体の最適化

실제-정보를-숨기지-않는-정보성-있는-제목-두-번째-차수-정보를-이용한-심플렉틱-스티펠-다양체에서의-리만-최적화


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.


coremsg

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 present evidence indicating that these effects stem from a decrease in pyruvate transport into mitochondria. This reduction is attributed to decreased expression of the mitochondrial pyruvate carrier (MPC1), which is mediated by diminished expression and nuclear presence of its transcriptional regulator, estrogen-related nuclear receptor alpha (ERRα). Consequently, ERRα exhibits weakened binding to the MPC1 promoter. This outcome arises from the impaired interaction between ERRα and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and consequently reduced ATP production in tolerized macrophages. Exogenously added ATP in infected 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 alterations and PA persistence. These findings unveil 2-AA as a modulator of cellular immunometabolism and reveal an unprecedent mechanism of host tolerance to infection involving the PGC-1α/ERRα axis in its influence on MPC1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings paving the way for developing treatments to bolster resilience to pathogen-induced damage. Given that QS is a common characteristic of prokaryotes, it is likely that 2-AA-like molecules with similar functions may be present in other pathogens.

### Competing Interest Statement

L.G.R. has a financial interest in Spero Therapeutics, a company developing therapies to treat bacterial infections. L.G.R. financial interests are reviewed and managed by Massachusetts General Hospital and Partners Health Care in accordance with their conflict-of-interest policies. No funding was received from Spero Therapeutics, and it had no role in study design, data collection, analysis, interpretation, or the decision to submit the work for publication. The remaining authors declare no competing interests.

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

bacterial-quorum-sensing-signal-2-aminoacetophenone-modulates-immune-cell-metabolism-and-promotes-tolerance-to-pseudomonas-aeruginosa-infection


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


title_rewrite

Immunometabolic Reprogramming by Bacterial Quorum-Sensing Molecule