Syphilis, a chronic, complex sexually transmitted disease of humans caused by the spirochetal bacterium Treponema pallidum, remains a global public health problem. Although the immunology of syphilis is complex, clinical manifestations in all stages of syphilis derive principally from cell-mediated processes that are """"""""triggered"""""""" by T. pallidum as it invades and replicates within genital skin. The actual cell type that initiates this early immune response thus far has not been identified. Over the past decade, overwhelming evidence suggests that dendritic cells (DCs) (e.g., Langerhans cells [LCs] of the epidermis and dermal dendritic cells [DDCs]) are crucial for the initiation of primary T cell responses to foreign antigens. The working hypothesis for this proposal is that the DC likely is the pivotal immune effector cell that initiates the cellular inflammatory response during syphilis. Thus far, DCs in the cellular immune responses to T. pallidum have not been studied. Accordingly, the Specific Aims of this proposal are (1) To characterize the interaction(s) of virulent T. pallidum with DCs, with emphasis on examining phagocytic processes, (2) To assess DC activation and/or maturation following exposure of immature DCs to L pallidum or its constituent proinflammatory membrane lipoproteins, and (3) To examine whether tissue migration is induced following exposure of DCs to T. pallidum or its membrane lipoproteins (longer range goal). For experiments in Specific Aims 1 and 2, we shall employ two immortalized murine DC lines, XS52 and XS106, developed by Dr. Akira Takashima. Initial results will be validated by performing parallel experiments with freshly-prepared human DCs.
In Specific Aim 3, we will utilize human skin organ cultures to examine T. pallidum- or lipoprotein-induced DC migration and activation. This study is likely to yield important new insights into the role(s) of DCs as key effector cells in the immunopathogenesis of syphilis.
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