Histone lactylation during host–pathogen interaction: An intimate and persistent affair between Pseudomonas aeruginosa quorum-sensing signaling and host lactate

Bacteria can stimulate host lactate production, aiding their colonization and virulence. However, the role of pathogen-driven host lactate remains underexplored. We show that Pseudomonas aeruginosa (PA)-secreted quorum-sensing (QS) signaling molecule 2'-aminoacetophenone (2-AA) elevates and sustains lactate in PA-infected immune-cells and animal tissues. In support, 2-AA increases the protein abundance of the lactate transporter, MCT4, and lactyl-coenzyme A synthetase (guanosine triphosphate (GTP)-specific SCS (GTPSCS)), and GTPSCS's interaction with the transcriptional coactivators CREB-binding protein (CBP) and p300. Lactate augmentation drives histone H3 lysine 18 lactylation (H3K18la) enrichment at the regulatory regions of key immune and metabolic genes. H3K18la and consequent transcriptional changes promote PA survival in macrophages. Inhibition of lactate or 2-AA synthesis impedes lactate augmentation and H3K18la and reduces PA survival in macrophages. The uncovered QS-driven H3K18la represents a seminal interplay during host-pathogen interaction. Targeting this QS-epigenetic axis may offer a viable therapeutic approach for chronic PA infection. Overall design: RNA sequencing of RAW 267.4 cells infected with Pseudomonas aeurginosa UCBPP-PA14, and the quorum sensing regulator isogenic deletion mutant strain mvfR and mvfR mutant supplemented with 200 µM of 2'-AA (2-aminoacetophenone).Uninfected cells served as controls.