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

  • Cell Host Microbe. 2026 Feb 11;34(2):245-262.e8. doi: 10.1016/j.chom.2026.01.002.
Ronni A G da Silva  1 ,  Brenda Yin Qi Tien  2 ,  Patrick Hsien Neng Kao  2 ,  Haris Antypas  2 ,  Cenk Celik  3 ,  Ai Zhu Casandra Tan  2 ,  Muhammad Hafiz Ismail  2 ,  Guangan Hu  4 ,  Kelvin Kian Long Chong  2 ,  Guillaume Thibault  5 ,  Jianzhu Chen  6 ,  Kimberly A Kline  7
Affiliations
  • 1. Singapore-MIT Alliance for Research and Technology Centre, Antimicrobial Resistance Interdisciplinary Research Group, Singapore, Singapore; Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
  • 2. Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
  • 3. School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
  • 4. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 5. School of Biological Sciences, Nanyang Technological University, Singapore, Singapore; Mechanobiology Institute, National University of Singapore, Singapore, Singapore.
  • 6. Singapore-MIT Alliance for Research and Technology Centre, Antimicrobial Resistance Interdisciplinary Research Group, Singapore, Singapore; Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 7. Singapore-MIT Alliance for Research and Technology Centre, Antimicrobial Resistance Interdisciplinary Research Group, Singapore, Singapore; Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore; Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Electronic address: [email protected].
PMID: 41605216 DOI: 10.1016/j.chom.2026.01.002
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.

Keywords
E. faecalis; NF-κB inhibition; lactic acid; lactic acid signaling; lactic-acid-mediated immune evasion; macrophage immunosuppression; macrophages; polymicrobial wound infections; recalcitrant wound infections.
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