Bacteria silence immune defenses

SUMMARY

Macrophage activation is essential for innate immunity and antimicrobial defense. The authors of this article 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.

Full article: https://doi.org/10.1016/j.chom.2026.01.002

WHY IS IT IMPORTANT?

Effective wound healing depends on a strong immune response, particularly from macrophages. This study shows that Enterococcus faecalis can interfere with this process by releasing lactic acid into the wound. The lactic acid lowers the local pH and disrupts immune signaling inside macrophages, preventing them from activating genes needed to fight infection. This immune suppression allows E. faecalis to persist and also helps other bacteria survive, leading to polymicrobial infections. This is especially relevant in hospital settings, where chronic wounds and antibiotic-resistant infections are common. The findings highlight that bacteria do not just evade antibiotics, they can actively shut down immune defenses. Understanding this mechanism may help develop new treatments that boost immunity and reduce persistent infections.

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