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 5

Activation of agr quorum sensing in S. aureus inhibits wound healing.

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Activation of agr quorum sensing in S. aureus inhibits wound healing. (A...
(A) Quantification of murine wound closure over time (days 0, 1, 3, 5, 7) inoculated with low (1 × 104 CFU/wound in 10 μL gel) or high dose (1 × 107 CFU/wound in 10 μL gel) of S. aureus or vehicle control (10 μL). (B) Quantification of reepithelialization based on H&E histology image analysis of wounds on day 7 after exposure to vehicle control or low or high dose of S. aureus. (C) Quantification of IVIS images confirming activation of agr by S. aureus in vivo. (D) IVIS imaging of control and S. aureus agr reporter strain infected mouse wounds. ROI, region of interest. (E) Live bacteria cultured from infected murine wounds on days 1, 3, and 7. (F) Quantification of murine wound closure after infection with S. aureus or S. aureusΔagr (days 0, 1, 3, 5, and 7). (G) Representative images of WT S. aureus and agr mutant (S. aureusΔagr) infected wounds (days 1, 3, 5, and 7). Experiments were performed at least twice. Student’s t test for comparison of 2 groups (C, E, and F), 1-way ANOVA followed by Bonferroni’s multiple-comparison adjustment for more than 2 groups (A, B, and D). Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.