Staphylococcus aureus accessory gene regulator quorum-sensing system inhibits keratinocyte lipid enzymes and delays wound repair
Michelle D. Bagood, … , Alexander R. Horswill, Richard L. Gallo
Michelle D. Bagood, … , Alexander R. Horswill, Richard L. Gallo
Published October 15, 2025
Citation Information: J Clin Invest. 2025;135(20):e190411. https://doi.org/10.1172/JCI190411.
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Research Article Dermatology Infectious disease

Staphylococcus aureus accessory gene regulator quorum-sensing system inhibits keratinocyte lipid enzymes and delays wound repair

Abstract

Mechanisms responsible for delayed wound repair are poorly understood despite the common impact of this disorder on health. To study how Staphylococcus aureus disrupts healing, mouse and human wound repair models were evaluated after exposure to S. aureus or commensal Staphylococcus. Quorum sensing by S. aureus, but not S. hominis, delayed repair and inhibited the expression of genes responsible for lipid metabolism in keratinocytes. S. aureus with inactive accessory gene regulator (agr) did not delay healing, and the inhibition of lipid metabolism was recapitulated in vitro by synthetic phenol soluble modulin α1 (psmα1) and psmα4, genes that are under agr control. However, S. aureus strains with single deletion of psmA, psmB, alpha-hemolysin (hla), or hld gene continued to delay repair, suggesting that S. aureus used multiple agr-dependent virulence factors to disrupt healing. These observations provide insight into mechanisms for delayed wound healing, identify quorum sensing as a critical event, and highlight the role of lipid biosynthesis in wound reepithelialization.

Authors

Michelle D. Bagood, Jelena Marjanovic, Nina Jiang, Hung Chan, Tatsuya Dokoshi, Kellen J. Cavagnero, Fengwu Li, Andrea Roso-Mares, Samia Almoughrabie, Edward Liu, Irena Pastar, Marjana Tomic-Canic, Alexander R. Horswill, Richard L. Gallo

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Figure 1

S. aureus, not S. hominis, delays cutaneous wound healing.

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S. aureus, not S. hominis, delays cutaneous wound healing. (A) Schema o...
(A) Schema of mouse infected wound model. (B) Representative images of murine wounds on day 7 after inoculation with vehicle, S. aureus, or S. hominis (1 × 107 CFU/wound in 10 μL gel). (C) Quantification of wound closure based on analysis of wound images on days after wounding 0, 3, 5, and 7. (D) Quantification of live bacteria cultured from wounds on day 7. (E) Representative H&E-stained histology images of S. aureus– and S. hominis–inoculated wounds on day 7 (black arrows: original wound edge; yellow arrows: end of neo-epithelial tongue). (F) Quantification of reepithelialization of vehicle-, S. aureus–, and S. hominis–inoculated wounds on day 7 based on analysis of H&E histology images. (G) Unbiased clustering of Visium spatial RNA-Seq data from intact and wounded murine skin 1 day after treatment with vehicle, S. aureus, or S. hominis. UMAP, uniform manifold approximation and projection. (H) Representative images of H&E, spatial location of all Visium clusters, and either cluster 4 or 11 highlighted (wound area highlighted by box). Experiments were performed at least twice unless otherwise indicated. One-way ANOVA followed by Dunnett’s multiple-comparison adjustment for more than 2 groups (C, D, and F). Data represent mean ± SEM. **P < 0.01, ****P < 0.0001.