Enterococcus faecalis-derived lactic acid suppresses macrophage activation to facilitate persistent and polymicrobial wound infections
Abstract
Macrophage activation is essential for innate immunity and antimicrobial defense. We show that Enterococcus faecalis suppresses macrophage activation through lactic-acid-mediated acidification of the extracellular environment, enabling pathogen persistence. E. faecalis- derived lactic acid acts via the lactate transporter monocarboxylate transporter 1 (MCT-1) and the sensor GPR81 to initiate complementary mechanisms that collaboratively reduce nuclear factor κB (NF-κB) activity. Lactic acid acts through MCT-1 to inhibit extracellular signal-regulated kinase and STAT3 phosphorylation, leading to reduced levels of the adaptor MyD88 involved in NF-κB activation. Lactic acid signaling to GPR81 induces phosphorylation of the transcription factor YAP, ultimately attenuating NF-κB signaling. A bacterial mutant lacking lactate dehydrogenase is unable to acidify the environment and thus fails to inhibit NF-κB. In a murine wound infection model, lactic-acid-driven immunosuppression 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. • E. faecalis suppresses macrophage activation via lactic acid release • Lactic acid signals through MCT-1 and GPR81 to inhibit NF-κB • Lactic-acid-driven immunosuppression promotes persistence and polymicrobial infection da Silva et al. show that Enterococcus faecalis -derived lactic acid suppresses macrophage NF-κB activation via MCT-1 and GPR81 signaling. This lactic-acid-driven immunosuppression promotes bacterial persistence and enhances polymicrobial infection in vivo .
Related
- Oleic acid suppresses NLRP3 inflammasome activation to prevent dermal macrophage death and limit imiquimod-induced psoriasis
- Polymicrobial catheter biofilms sustain susceptible Enterococcus faecalis and Escherichia coli during β-lactam treatment
- Targeting Macrophage Connexin 43 Hemichannels Suppresses Synovial Inflammation and Osteoarthritis
- The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation
- Macrophage-mediated bystander T cell activation in varicose veins
BibTeX
@article{silva2026enterococcus,
title = {{Enterococcus faecalis-derived lactic acid suppresses macrophage activation to facilitate persistent and polymicrobial wound infections}},
author = {Ronni A.G. da Silva and Brenda Yin Qi Tien and Patrick Hsien Neng Kao and Haris Antypas and Cenk Celik and Ai Zhu Casandra Tan and Muhammad Hafiz Ismail and Guangan Hu and Kelvin Kian Long Chong and Guillaume Thibault and Jianzhu Chen and Kimberly A. Kline},
journal = {Cell Host and Microbe},
year = {2026},
month = sep,
doi = {10.1016/j.chom.2026.01.002},
url = {https://hal.science/hal-05770379v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Enterococcus faecalis-derived lactic acid suppresses macrophage activation to facilitate persistent and polymicrobial wound infections
AU - Ronni A.G. da Silva
AU - Brenda Yin Qi Tien
AU - Patrick Hsien Neng Kao
AU - Haris Antypas
AU - Cenk Celik
AU - Ai Zhu Casandra Tan
AU - Muhammad Hafiz Ismail
AU - Guangan Hu
AU - Kelvin Kian Long Chong
AU - Guillaume Thibault
AU - Jianzhu Chen
AU - Kimberly A. Kline
PY - 2026
DA - 2026/09/30
JO - Cell Host and Microbe
DO - 10.1016/j.chom.2026.01.002
UR - https://hal.science/hal-05770379v1
AB - Macrophage activation is essential for innate immunity and antimicrobial defense. We show that Enterococcus faecalis suppresses macrophage activation through lactic-acid-mediated acidification of the extracellular environment, enabling pathogen persistence. E. faecalis- derived lactic acid acts via the lactate transporter monocarboxylate transporter 1 (MCT-1) and the sensor GPR81 to initiate complementary mechanisms that collaboratively reduce nuclear factor κB (NF-κB) activity. Lactic acid acts through MCT-1 to inhibit extracellular signal-regulated kinase and STAT3 phosphorylation, leading to reduced levels of the adaptor MyD88 involved in NF-κB activation. Lactic acid signaling to GPR81 induces phosphorylation of the transcription factor YAP, ultimately attenuating NF-κB signaling. A bacterial mutant lacking lactate dehydrogenase is unable to acidify the environment and thus fails to inhibit NF-κB. In a murine wound infection model, lactic-acid-driven immunosuppression 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. • E. faecalis suppresses macrophage activation via lactic acid release • Lactic acid signals through MCT-1 and GPR81 to inhibit NF-κB • Lactic-acid-driven immunosuppression promotes persistence and polymicrobial infection da Silva et al. show that Enterococcus faecalis -derived lactic acid suppresses macrophage NF-κB activation via MCT-1 and GPR81 signaling. This lactic-acid-driven immunosuppression promotes bacterial persistence and enhances polymicrobial infection in vivo .
SN - 1931-3128
ER -