Post Doctoral Fellow Massachusetts Gen. Hosp., Harvard Med. Sch. Boston, Massachusetts, United States
Disclosure(s):
Arijit Chakraborty, MS-PhD: No financial relationships to disclose
Introduction/Rationale: Pseudomonas aeruginosa (PA) uses its quorum-sensing molecule 2′-aminoacetophenone (2-AA) to modulate host mitochondrial activity. This study investigates how 2-AA–driven host metabolic reprogramming contributes to macrophage dysfunction and supports bacterial persistence.
Methods: We used biochemical and molecular assays to show that 2-AA induced host lactate augmentation. Immunoprecipitation identified proteins involved in histone lactylation (Kla), while CUT&RUN and transcriptomics studies deciphered gene regulation and molecular anergy.
Results: Mechanistically, 2-AA disrupts the ESRRA–PPARGC1α regulatory axis, leading to the downregulation of the mitochondrial pyruvate carrier (MPC1). This impairment affects pyruvate transport into mitochondria, rewiring cellular metabolism to a glycolytic state, leading to increased lactate dehydrogenase A (LDHA) activity, elevated and sustained lactate levels in PA-infected immune cells and host tissues, and Kla. Genome-wide profiling of H3 lysine 18 lactylation (H3K18la) demonstrated distinct chromatin modification at regulatory regions, indicating novel epigenetic regulation by lactylation. The 2-AA-mediated H3K18la involves the GTP-specific succinyl-CoA synthetase (GTPSCS) and its interaction with histone lactyl-transferases CREB-binding protein (CBP) and p300. In agreement with H3k18la signatures, transcriptomic profiling of wild-type PA and its 2-AA-deficient mutant revealed regulatory pathways modulating immune and metabolic responses. Functionally, enhanced H3K18la favors a tolerogenic macrophage phenotype that supports intracellular bacterial survival. Conversely, inhibiting lactate accumulation or blocking 2-AA synthesis diminishes H3K18la and enhances bacterial clearance.
Conclusion: Collectively, these findings uncover a previously unrecognized QS-regulated metabolic–epigenetic axis through which PA manipulates host immunity, highlighting lactate metabolism as a potential therapeutic target for combating chronic Pseudomonas infections.
