Enterococcus faecalis -derived lactic acid suppresses macrophage activation to facilitate persistent and polymicrobial wound infections

Macrophage activation is essential for innate immunity, and its suppression enables pathogen persistence. We show that Enterococcus faecalis suppresses macrophage activation through lactic acid-mediated extracellular acidification. Mutants lacking lactate dehydrogenase ( ldh ), and thus unable to acidify the environment, fail to inhibit NF-κB. E. faecalis- derived lactic acid acts via MCT-1 and GPR81 through two distinct but complementary mechanisms that culminate in the reduction of NF-κB activity. Lactic acid acts through MCT-1 to inhibit ERK and STAT3 phosphorylation, leading to reduced STAT3 binding to the Myd88 promoter, and reduced MyD88 protein levels. Lactic acid signaling to GPR81 mediates the phosphorylation of the transcriptional factor YAP, ultimately attenuating NF-κB signaling. In a murine wound infection model, this lactic acid-driven immunosuppressive niche enables prolonged E. faecalis persistence and enhances the fitness of co-infecting bacteria such as Escherichia coli. These findings reveal how bacterial lactic acid subverts innate immunity to support chronic and polymicrobial infections.