The Innate Immune System Is Activated by Stimulation of Vaginal Epithelial Cells withStaphylococcus aureusand Toxic Shock Syndrome Toxin 1

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Abstract
Despite knowledge of the effects of toxic shock syndrome (TSS) toxin 1 (TSST-1) on the adaptive immune system, little is known about stimulation of the innate immune system, particularly epithelial cells. This study investigated the interactions of TSSStaphylococcus aureusand TSST-1 with human vaginal epithelial cells (HVECs) and porcine mucosal surfaces. When cocultured with HVECs for 6 h, TSSS. aureusMN8 proliferated, formed aggregates on the HVEC surfaces, and produced exotoxins. Receptor binding studies showed that35S-TSST-1 bound to 5 × 104receptors per HVEC, with saturation at 15 min. Affymetrix Human GeneChip U133A microarray analysis determinedS. aureusMNSM (100 bacteria/HVEC) caused at least twofold up- or down-regulation of 410 HVEC genes by 6 h; these data were also confirmed withS. aureusMN8. TSST-1 (100 μg/ml) caused up- or down-regulation of 2,386 HVEC genes by 6 h. In response toS. aureus, the HVEC genes most up-regulated compared to those in controls were those coding for chemokines or cytokines—MIP-3α, 478-fold; GRO-α, 26-fold; GRO-β, 14-fold; and GRO-γ, 30-fold—suggesting activation of innate immunity. TSST-1 also caused up-regulation of chemokine/cytokine genes. Chemokine/cytokine gene up-regulation was confirmed by enzyme-linked immunosorbent assays measuring the corresponding proteins induced byS. aureusand TSST-1.S. aureusMN8, when incubated with porcine vaginal tissue, increased the flux of35S-TSST-1 across the mucosal surface. This was accompanied by influx of lymphocytes into the upper layers of the tissue. These data suggest innate immune system activation through epithelial cells, reflected in chemokine/cytokine production and influx of lymphocytes, may cause changes in vaginal mucosa permeability, facilitating TSST-1 penetration.

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