title: Local Epidermal Growth Factor Receptor Signaling Mediates the Systemic Pathogenic Effects of Staphylococcus aureus Toxic Shock Syndrome.
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.
authors.affiliation: University of Minnesota, College of Pharmacy, Department of Experimental and Clinical Pharmacology, Minneapolis, Minnesota, United States of America.
authors.forename: Laura M
authors.identifier: http://orcid.org/0000-0002-0997-1140
authors.initials: LM
authors.lastname: Breshears
authors.affiliation: University of Minnesota, College of Pharmacy, Department of Experimental and Clinical Pharmacology, Minneapolis, Minnesota, United States of America.
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Gillman
authors.affiliation: University of Minnesota, College of Biological Sciences, Biotechnology Institute, Minneapolis, Minnesota, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stach
authors.affiliation: University of Iowa, Carver College of Medicine, Department of Microbiology, Iowa City, Iowa, United States of America.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Schlievert
authors.affiliation: University of Minnesota, College of Pharmacy, Department of Experimental and Clinical Pharmacology, Minneapolis, Minnesota, United States of America.
authors.forename: Marnie L
authors.initials: ML
authors.lastname: Peterson
mesh_terms: D051722:ADAM Proteins / Q000502:physiology; D000818:Animals; D004847:Epithelial Cells / Q000502:physiology; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology; D011817:Rabbits; D012772:Shock, Septic / Q000382:microbiology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D013203:Staphylococcal Infections / Q000382:microbiology / Q000503:physiopathology*; D014621:Vagina / Q000166:cytology / Q000503:physiopathology
chemical_list: D016209:Interleukin-8; D066246:ErbB Receptors; D051722:ADAM Proteins