Lyme disease, caused by infection with the tick-transmitted spirochete Borrelia burgdorferi, is a multi-system disorder involving the skin, heart, joints and nervous system. Spirochetes first establish infection in the skin before disseminating via the bloodstream to infect distant sites and cause disease. The skin therefore provides the first immune barrier to tick-transmitted B. burgdorferi infection. It has ben difficult to study the interaction of B. burgdorferi with human skin and vascular endothelial cells, which must be penetrated for dissemination to occur, due to the paucity of clinical samples and variability in onset of infection. In addition, the most widely studied animal model, the mouse model of Lyme borreliosis, does not develop skin disease. In vitro studies show that B. burgdorferi can bind to human adhesins and integrins, which may facilitate their colonization of diverse tissues. Spirochete lipoproteins also are pro-inflammatory and can activate vascular endothelium in vitro to up-regulate adhesion molecules that promote immune cell migration to extravascular sites of infection. Because mammalian-adapted spirochetes vary surface expression of lipoproteins, it is unclear whether results of in vitro analyses accurately reflect B. burgdorferi interaction with human skin and vascular endothelium in vivo. This proposal seeks to use the chimeric human skin-severe combined immunodeficient mouse model to begin to delineate in vivo the consequences of B. burgdorferi infection on human dermal vasculature and human skin. Our preliminary data show that human skin grafts become infected through spirochete dissemination in these chimeric mice and develop acute inflammation. The results of these pilot studies which utilize both cultured spirochetes as well as B. burgdorferi-infected nymphal ticks to establish infection, will set the stage for the direct evaluation of the role of B. burgdorferi adhesins and human vascular endothelial cell-derived chemokines in the pathogenesis of human Lyme disease.
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