Abstract
Staphylococcus 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.
Highlights
Staphylococcus aureus is a diverse pathogen that is capable of infecting many human tissues and organs causing a wide range of illnesses including skin and soft tissue infections, pneumonia, necrotizing fasciitis and endocarditis [1]
We found that HlgAB and HlgCB were cytotoxic to immortalized human vaginal epithelial cells (HVECs) and induced production of proinflammatory cytokines at sub-cytolytic doses
As HlgAB and HlgCB stimulation of proinflammatory cytokines is enhanced through an epidermal growth factor receptor (EGFR)-dependent mechanism in HVECs, we investigated the requirement for EGFR signaling in gamma-toxin-induced IL-8 production by Porcine vaginal mucosa (PVM)
Summary
Staphylococcus aureus is a diverse pathogen that is capable of infecting many human tissues and organs causing a wide range of illnesses including skin and soft tissue infections, pneumonia, necrotizing fasciitis and endocarditis [1]. S. aureus contributes to disease through production of an arsenal of virulence factors including secreted toxins, which disrupt the host immune response. These secreted toxins include superantigens (SAgs) such as toxic shock syndrome toxin-1 (TSST-1), and cytolysins, such as alpha-toxin and gamma-toxins. S. aureus causes the systemic disease, toxic shock syndrome (TSS) through the activity of SAgs. About half of TSS cases are associated with menstruation (menstrual, mTSS) and occur in the absence of significant bacteremia [2,3]. There is evidence that they may contribute to mTSS progression through enhancement of local inflammation and disruption of the epithelial barrier, increasing SAg penetration into the mucosa [10,11]
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