Staphylococcus aureus accessory gene regulator quorum-sensing system inhibits keratinocyte lipid enzymes and delays wound repair
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
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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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 7

S. aureus agr system influences keratinocyte function and gene expression.

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S. aureus agr system influences keratinocyte function and gene expressi...
(A) Quantification of in vitro NHEK scratch-wound closure 24 hours after treatment with S. aureus or S. aureusΔagr CM (3 × 107 CFU/mL equivalent), or media control. (B) qPCR for lipid metabolic/synthesis enzyme genes of scratch-wounded in vitro NHEKs treated for 24 hours with S. aureus or S. aureusΔagr CM (3 × 107 CFU/mL equivalent), or media control (control and S. aureus groups shown previously in Figure 3E). (C) Protein immunoblot of ELOVL4 and GAPDH protein extracted from scratch-injured NHEKs exposed to S. aureus, S. hominis, or S. aureusΔagr CM (3 × 107 CFU/mL equivalent), or media control for 24 hours. (D) Representative images of murine wounds infected with vehicle, S. aureus, or S. aureusΔagr immunofluorescence-stained for ELOVL4 (scale bar: 300 μm). (E) MTT proliferation assay of in vitro NHEKs after 24 hours of treatment with S. aureus or S. aureusΔagr CM (3 × 107 CFU/mL equivalent), or media control. (F) KI67 gene expression of proliferating NHEKs after 24 hours of treatment with S. aureus or S. aureusΔagr CM (3 × 107 CFU/mL equivalent), or media control. (G) Expression of cell cycle genes by in vitro NHEKs after 24 hours of treatment with S. aureus or S. aureusΔagr CM (3 × 107 CFU/mL equivalent), or media control. Experiments were performed at least twice. One-way ANOVA followed by Bonferroni’s multiple-comparison adjustment for more than 2 groups. Data represent mean ± SEM. **P < 0.01, ***P < 0.001, ****P < 0.0001.