| Staphylococcus aureus is an important gram positive pathogen that causes a multitude of human diseases. Many of these diseases are associated with the production of staphylococcal exotoxins. Superantigens are a family of staphylococcal exotoxins associated with many of these illnesses. Superantigens may be also be involved in staphylococcal pulmonary infections. I hypothesize that superantigens are involved with the severity and fatality associated with these infections (likely by causing TSS). This dissertation represents one of the most comprehensive investigation into superantigens associated with S. aureus strains from patients with atopic dermatitis.;Additional research has demonstrated the potential for using glycerol monolaurate (GML) for inhibiting staphylococcal toxin production in vitro. GML has also been shown to inhibit the growth of several vaginal pathogens such as Gardnerella vaginalis, and Candida albicans, without inhibiting the grown of Lactobacillus crispatus, which is a predominant member of the vaginal normal flora. This finding suggests that GML may be useful as a treatment for vaginal infections such as bacterial vaginosis and vulvovaginal candidiasis.;S. aureus isolates collected from steroid-resistant atopic dermatitis patients had significantly different superantigen profiles than other isolates. Strains from patients with steroid-resistant atopic dermatitis carried the genes for a greater number of superantigens, were more likely to produce the three major TSS-associated superantigens (TSST-1, SEB, and SEC), and were also more likely to have uncommon combinations of superantigens, compared to isolates from steroid-sensitive patients and vaginal isolates from healthy women. These findings suggest that S. aureus isolates from patients with steroid-resistant atopic dermatitis are selected for on the basis of greater superantigen production.;From my studies that focused on the role of superantigens in severe pulmonary diseases, I found that rabbits challenged with viable bacteria developed fatal pulmonary infections. Rabbits previously immunized against purified SEC and then challenged with viable bacteria did not develop fatal disease. Rabbits treated with soluble high affinity Vbeta-TCRs for SEB, and then challenged with purified SEB, also did not develop fatal pulmonary disease. In these studies, immunity to superantigens prevents lethality associated with the pulmonary bacterial exposure. Administration of a soluble high-affinity Vbeta-TCR to non-immune animals also protected rabbits.;Results from in vivo investigations of the effects of tampons containing GML, on both staphylococcal exotoxin production and vaginal inflammation, revealed that lower amounts of S. aureus and exotoxins were detected in study tampons +/- GML than the women's own tampons. I also found lower amounts of exotoxins were present in GML+ than GML- study tampons. My findings suggest adding GML to tampons may provide additional safety over other tampons relative to menstrual TSS.;My investigations into the effects of GML on additional vaginal pathogens demonstrated that in vitro GML concentrations of ≥100 mug/ml were bactericidal for C. albicans, while concentrations ≥5 mug/ml were bactericidal for G. vaginalis. Use of gels containing GML significantly reduced vaginal levels of Candida. The control gel did not significantly alter Candida levels. Use of both the control and the GML-containing gels significantly lowered the levels of G. vaginalis. These findings suggest that an intravaginal gel containing GML may be useful for treating both vulvovaginal candidiasis and bacterial vaginosis, meanwhile not inhibiting the growth of Lactobacillus.;During our studies to investigate the role of superantigens in pulmonary infections caused by USA300 S. aureus isolates, I observed that immunity to staphylococcal enterotoxin-like Q (SEl-Q) offers partial (but not statistically significant) protection from lethal pulmonary infection. Further investigation revealed the presence of a variant form of TSST-1 that contains a large deletion in the tstH gene. When tested for superantigen activity, variant TSST-1 was found to retain some superantigen activity, and is still highly lethal in rabbits. Additional experiments using soluble high affinity Vbeta-TCRs to neutralize full length TSST-1 superantigen activity revealed that full length TSST-1 exposure is still lethal; suggesting that full length TSST-1 can cause lethality through another mechanism in addition to superantigenicity. My findings suggest that lethality due to full length TSST-1 exposure may occur through multiple mechanisms, including superantigenicity, and potentially through direct interaction with the central nervous system. (Abstract shortened by UMI.)... |
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