Journal article
Epidermal Growth Factor Receptor Signaling Enhances the Proinflammatory Effects of Staphylococcus aureus Gamma-Toxin on the Mucosa
Toxins, Vol.9(7), p.202
06/28/2017
DOI: 10.3390/toxins9070202
PMCID: PMC5535149
PMID: 28657583
Abstract
(
) produces many different exotoxins including the gamma-toxins, HlgAB and HlgCB. Gamma-toxins form pores in both leukocyte and erythrocyte membranes, resulting in cell lysis. The genes encoding gamma-toxins are present in most strains of
and are commonly expressed in clinical isolates recovered from menstrual Toxic Shock Syndrome (mTSS) patients. This study set out to investigate the cytotoxic and proinflammatory effects of gamma-toxins on vaginal epithelial surfaces. We found that both HlgAB and HlgCB were cytotoxic to cultured human vaginal epithelial cells (HVECs) and induced cytokine production at sub-cytotoxic doses. Cytokine production induced by gamma-toxin treatment of HVECs was found to involve epidermal growth factor receptor (EGFR) signaling and mediated by shedding of EGFR ligands from the cell surface. The gamma-toxin subunits displayed differential binding to HVECs (HlgA 93%, HlgB 97% and HlgC 28%) with both components (HlgAB or HlgCB) required for maximum detectable binding and significant stimulation of cytokine production. In studies using full thickness ex vivo porcine vaginal mucosa, HlgAB or HlgCB stimulated a dose-dependent cytokine response, which was reduced significantly by inhibition of EGFR signaling. The effects of gamma-toxins on porcine vaginal tissue and cultured HVECs were validated using ex vivo human ectocervical tissue. Collectively, these studies have identified the EGFR-signaling pathway as a key component in gamma-toxin-induced proinflammatory changes at epithelial surfaces and highlight a potential therapeutic target to diminish toxigenic effects of
infections.
Details
- Title: Subtitle
- Epidermal Growth Factor Receptor Signaling Enhances the Proinflammatory Effects of Staphylococcus aureus Gamma-Toxin on the Mucosa
- Creators
- Aaron N Gillman - Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA. aaron.gillman@uit.noLaura M Breshears - Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA. bresh006@umn.eduCharles K Kistler - Extherid Biosciences, LLC., Jackson, WY 83001, USA. charles@extherid.comPatrick M Finnegan - School of Pharmacy, University of Wyoming, Laramie, WY 82071, USA. Patrick.Finnegan@uwyo.eduVictor J Torres - Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA. victor.torres@nyumc.orgPatrick M Schlievert - Department of Microbiology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. patrick-schlievert@uiowa.eduMarnie L Peterson - School of Pharmacy, University of Wyoming, Laramie, WY 82071, USA. mpeter68@uwyo.edu
- Resource Type
- Journal article
- Publication Details
- Toxins, Vol.9(7), p.202
- DOI
- 10.3390/toxins9070202
- PMID
- 28657583
- PMCID
- PMC5535149
- NLM abbreviation
- Toxins (Basel)
- ISSN
- 2072-6651
- eISSN
- 2072-6651
- Publisher
- Switzerland
- Grant note
- DOI: 10.13039/100006492, name: National Institute of Allergy and Infectious Diseases, award: AI-73366, AI-74283
- Language
- English
- Date published
- 06/28/2017
- Academic Unit
- Microbiology and Immunology; Internal Medicine
- Record Identifier
- 9984001214402771
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