Molecular mechanisms of immunosuppression induced by superanfigens

Mississippi State University, Mississippi State MS

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Abstract

Staphylococcus aureus is an opportunistic pathogen causing a wide range of diseases in humans and animals. S. aureus produces numerous exotoxins causing toxin-associated syndromes, surface proteins for colonization and persistence on the host organs and prosthetic devices, numerous enzymes utilized to invade and to destroy host tissues, and antibiotic resistance. Staphylococcal enterotoxins (SEs) and toxic shock syndrome toxin-1 (TSST-1) are the family of superanfigens (SAgs) and are important virulence factors of S. aureus. Although the toxic properties of SAg have been well characterized, this prediction was based on the observations using high concentrations of SAgs. Several lines of evidence in animal models indicated that low concentrations of SAg was produced in chronic S. aureus infection. Furthermore, our results in the animal models demonstrated that a low dose stimulation with SAg induced immunosuppressive regulatory and suppressor T cells and proinflammatory dendritic cells. Also, a deletion of the 9 SAg genes or a vaccination with 9 recombinant SAgs greatly attenuated staphylococcal pathogenesis. These results suggest that SAg plays an important role in staphylocccal pathogenesis. However, parallel knowledge in humans is critically limited. In this proposed study, we will characterize phenotypic and functional characteristics of human T cells and antigen presenting cells stimulated with various concentrations of SAg to elucitate the roles of these cells in the staphylococcal pathogenesis. If successful, this approach will enhance the current understanding of SAg immunopathobiology and allow the development of a novel preventive strategy against diseases associated with SAg. This will be accomplished by completing following three specific aims; Aim 1: Determine the dose-dependent effect of SAg stimulation on the phenotypic and functional characteristics of T cells; Aim 2: Determine the dose-dependent effect of SAg stimulation on the phenotypic and functional characteristics of APCs; Aim 3: Determine cellular signaling pathways and gene expression in response to dose-dependent SAg stimulation.