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dc.contributor.authorGillman, Aaron N.
dc.contributor.authorBreshears, Laura M.
dc.contributor.authorKistler, Charles K.
dc.contributor.authorFinnegan, Patrick M.
dc.contributor.authorTorres, Victor J.
dc.contributor.authorSchlievert, Patrick M.
dc.contributor.authorPeterson, Marnie L.
dc.date.accessioned2018-05-16T12:00:11Z
dc.date.available2018-05-16T12:00:11Z
dc.date.issued2017-06-28
dc.description.abstractStaphylococcus aureus (S. aureus) 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 S. aureus, 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 S. aureus infections.en_US
dc.descriptionSource at <a href=https://doi.org/10.3390/toxins9070202>https://doi.org/10.3390/toxins9070202</a>.en_US
dc.identifier.citationGillman, A. N., Breshears, L. M., Kistler, C. K., Finnegan, P. M., Torres, V. J., Schlievert, P. M.& Peterson, M. L. (2017). Epidermal growth factor receptor signaling enhances the proinflammatory effects of staphylococcus aureus gamma-toxin on the mucosa. Toxins, 9(7), 1-17. https://doi.org/10.3390/toxins9070202en_US
dc.identifier.cristinIDFRIDAID 1544527
dc.identifier.doi10.3390/toxins9070202
dc.identifier.issn2072-6651
dc.identifier.urihttps://hdl.handle.net/10037/12723
dc.language.isoengen_US
dc.publisherMDPIen_US
dc.relation.journalToxins
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk mikrobiologi: 715en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical microbiology: 715en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Klinisk farmakologi: 739en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Clinical pharmacology: 739en_US
dc.subjectStaphylococcus aureusen_US
dc.subjectGamma-toxinen_US
dc.subjectEpidermal growth factor receptoren_US
dc.subjectMenstrual toxic shock syndromeen_US
dc.subjectTyrosine kinase inhibitorsen_US
dc.subjectMucosal immune responseen_US
dc.titleEpidermal growth factor receptor signaling enhances the proinflammatory effects of staphylococcus aureus gamma-toxin on the mucosaen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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