Enterococcus faecalis-derived lactic acid facilitates persistent and polymicrobial wound infections by suppressing macrophage activation

Abstract

Macrophage activation is critical for the innate immune response, and its suppression by pathogens represents a significant barrier to immune clearance. Here we identify E. faecalis-derived lactic acid as a key factor in suppressing macrophage activation via extracellular acidification. We demonstrate that E. faecalis mutants lacking lactate dehydrogenase (ldh), essential for lactic acid production and extracellular pH reduction, fail to suppress NF-B. Mechanistically, E. faecalis-derived lactic acid acts via MCT-1 and GPR81, to impair ERK and STAT3 phosphorylation, leading to reduced STAT3 binding to the Myd88 promoter and reduced MyD88 protein levels, and ultimately to reduced NF-kB activity in macrophages. Consequently, in a wound infection model, the immunosuppressive microenvironment created by E. faecalis promotes long-term virulence and the virulence of co-infecting bacteria such as Escherichia coli. These findings highlight that bacterial-derived lactic acid contributes to the subversion of host immunity to promote persistent and polymicrobial infections.

Competing Interest Statement

The authors have declared no competing interest.