Abstract

Secreted factors of Staphylococcus aureus can activate host signaling from the epidermal growth factor receptor (EGFR). The superantigen toxic shock syndrome toxin-1 (TSST-1) contributes to mucosal cytokine production through a disintegrin and metalloproteinase (ADAM)-mediated shedding of EGFR ligands and subsequent EGFR activation. The secreted hemolysin, α-toxin, can also induce EGFR signaling and directly interacts with ADAM10, a sheddase of EGFR ligands. The current work explores the role of EGFR signaling in menstrual toxic shock syndrome (mTSS), a disease mediated by TSST-1. The data presented show that TSST-1 and α-toxin induce ADAM- and EGFR-dependent cytokine production from human vaginal epithelial cells. TSST-1 and α-toxin also induce cytokine production from an ex vivo porcine vaginal mucosa (PVM) model. EGFR signaling is responsible for the majority of IL-8 production from PVM in response to secreted toxins and live S. aureus. Finally, data are presented demonstrating that inhibition of EGFR signaling with the EGFR-specific tyrosine kinase inhibitor AG1478 significantly increases survival in a rabbit model of mTSS. These data indicate that EGFR signaling is critical for progression of an S. aureus exotoxin-mediated disease and may represent an attractive host target for therapeutics.

Highlights

  • The epidermal growth factor receptor (EGFR) is a single-pass receptor tyrosine kinase

  • Analysis of EGFR ligand shedding was performed to investigate the potential role of a disintegrin and metalloproteinase (ADAM) and the EGFR in the human vaginal epithelial cells (HVECs) inflammatory response to α-toxin

  • The fact that there are already many EGFR inhibitors approved by the Food and Drug Administration for use in humans may ease the road to clinical development and implementation of EGFR inhibition for staphylococcal diseases

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Summary

Introduction

The epidermal growth factor receptor (EGFR) is a single-pass receptor tyrosine kinase. Important EGFR ligands shed by ADAMs include transforming growth factor-α (TGF-α), amphiregulin. Upon activation by shed ligands, EGFRs dimerize and auto- and trans-phosphorylate one another, forming docking sites for downstream intracellular effectors [2]. These effectors go on to regulate a number of critical cellular processes such as differentiation, survival, proliferation, adhesion, and migration. EGFR signaling is essential for proper epidermal barrier homeostasis and wound healing [3, 4]. During the inflammatory response to injury, EGFR signaling induces expression of toll-like receptors, antimicrobial peptides, cytokines, and chemokines from keratinocytes, contributing to the innate immune response to minimize the potential for infection and promote healing [5]

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