Enterococcus faecalis redox metabolism activates the unfolded protein response to impair wound healing

TL;DR

This study shows how a bacteria called Enterococcus faecalis delays wound healing by producing harmful molecules that stress out skin cells.

Contribution

The study reveals extracellular electron transport as a new source of harmful molecules in E. faecalis that impairs wound healing.

Findings

E. faecalis extracellular electron transport generates reactive oxygen species that activate the unfolded protein response in epithelial cells.

Detoxifying reactive oxygen species with catalase rescues epithelial cell migration and suppresses the unfolded protein response.

Disrupting the unfolded protein response impairs epithelial cell migration, showing its importance in wound repair.

Abstract

Enterococcus faecalis 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 E. faecalis 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 E. faecalis–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.

E. faecalis EET generates ROS, which induces the UPR in keratinocytes, inhibiting in vitro migration.

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