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

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

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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