Pseudomonas Bacteria Escape Immunity by Disrupting Energy Production in Macrophages

Good news! Human ingenuity will defeat antimicrobial resistance!

"... Often a hospital-acquired pathogen, it tends to infect people with burns or weakened immunity, and it has evolved to resist multiple antibiotics and counteract the immune system, rendering it difficult to treat. ...

In a recent publication ... molecular microbiologists ... found that these bacteria release a chemical that inhibits energy generation in the mitochondria of macrophages, thus dampening the immune response.

This work identified a new tactic that P. aeruginosa uses to subvert host immunity, and it intimated a new approach for treating the recalcitrant infection.  ..."

From the eLife assessment and abstract:

"eLife assessment

This important study demonstrates that the Pseudomonas aeruginosa-derived quorum sensing signal, 2-aminoacetophenone, induces immune tolerization in macrophages by perturbing metabolism, particularly in the context of mitochondrial respiration and bioenergetics. The authors present convincing evidence for 2-aminoacetophenone-mediated reduction of pyruvate transport into mitochondria, with downstream effects that result in reduced ATP production in tolerized macrophages. The work will be of interest to those studying host-pathogen interactions.

Abstract

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 murine macrophages’ mitochondrial respiration and bioenergetics. We present evidence indicating that these effects stem from decreased 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 (Esrra). Consequently, Esrra exhibits weakened binding to the Mpc1 promoter. This outcome arises from the impaired interaction between Esrra and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and, consequently reduced ATP production in tolerized murine and human macrophages. Exogenously added ATP in infected macrophages restores the transcript levels of Mpc1 and Esrra 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 unprecedented mechanism of host tolerance to infection involving the Ppargc1a/Esrra axis in its influence on Mpc1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings pave the way for developing treatments to bolster host 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."

Pseudomonas Bacteria Escape Immunity by Disrupting Energy Production in Macrophages | The Scientist Magazine® "Pseudomonas infections are tough to treat, but a new study reveals a chemical they use to subdue macrophages, suggesting new therapeutic avenues."

The bacterial quorum sensing signal 2’-aminoacetophenone rewires immune cell bioenergetics through the Ppargc1a/Esrra axis to mediate tolerance to infection (open access)