Recently it was discovered that several of the major integral membrane immunogens of Treponema pallidum are lipoproteins. Further analyses indicate that the 47-kDa antigen, the most immunogenic and abundant among the membrane lipoproteins, possesses an as yet unclarified novel structure. In addition to the profound immunogenicities of the lipoproteins, preliminary studies suggest that they also are stimulatory for human T cells and B cells, and perhaps endothelial cells. The working hypothesis for this study is that the lipoprotein structure of these immunogens, particularly the 47-kDa novel lipoprotein structure, is responsible for some of these important biological activities. To relate structure with function, the N-terminus and site(s) of lipid attachment in the 47-kDa lipoprotein will be determined by using both genetic and biochemical strategies. Biological activities of the 47-kDa, 34-kDa, and 15-kDa lipoproteins and their relevant lipopeptides will be examined in three key areas: 1) polyclonal activation of human B cells; 2) stimulation of specific subsets of human T cells; and, 3) activation of human vascular endothelial cells. Investigations into polyclonal B cell activation may clarify many unexplained aspects of the non-treponemal (VDRL) and specific antibody responses during syphilis. Identification of responsive human T cell subpopulations will help to explain a critical area of cell-mediated immunity in syphilis that is poorly understood. A long term goal of isolating human T cells clones will help to evaluate both stimulatory as well as possibly suppressive cellular activities operative during the progression of syphilis. Endothelial cell activation to promote T cell binding and migration will be examined to understand how T. pallidum, its lipoproteins, or other constituents induce any of the characteristic inflammatory responses of syphilis. Finally, our discovery that the major immunogens of T. pallidum are lipoproteins allows us to exploit in vaccine experiments their affinity for liposome (Iscom) incorporation. Knowledge obtained in this study will clarify the roles of the lipoproteins in several of the major events in the immunopathogenesis of syphilis, and will provide a foundation for a better understanding of cell-mediated immune mechanisms operative during syphilis. The information ultimately will be useful in conceptualizing potentially novel immunologic intervention strategies for treponemal infections.
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