<i>Enterococcus faecalis</i> redox metabolism activates the unfolded protein response to impair wound healing.

Abstract

<i>Enterococcus faecalis</i> is an opportunistic pathogen that thrives in biofilm-associated infections and delays wound healing, yet how it impairs host tissue responses is unclear. Here, we identified extracellular electron transport (EET) as a previously unrecognized source of reactive oxygen species (ROS) in <i>E. faecalis</i> and showed that this activity directly triggers the unfolded protein response (UPR) in epithelial cells and delays epithelial cell migration. ROS detoxification with catalase suppressed <i>E. faecalis</i>-induced UPR and rescued epithelial cell migration, while exogenous hydrogen peroxide was sufficient to restore UPR activation in EET-deficient strains. UPR disruption by pharmacological inhibition also impaired cell migration, highlighting a critical role for UPR homeostasis in wound repair. Our findings establish EET as a virulence mechanism that links bacterial redox metabolism to host cell stress and impaired repair, offering previously unidentified avenues for therapeutic intervention in chronic infections.