The long-term objective of this project is to elucidate the interaction of the human patient with the tick-borne, obligately intracellular bacterium Ehrlichia chaffeensis, particularly with the ehrlichial structural and functional components which stimulate protective immunity and those that mediate the pathogenic mechanisms. Human monocytic ehrlichiosis, an emerging, life-threatening illness, was the first infectious disease caused by an Ehrlichia spp. discovered in the United States, with the first clinical report in 1987 and the first isolate reported in 1991. Despite the severe deficiencies in the ability to make a clinical or laboratory diagnosis and inadequacy of epidemiologic reporting, more that 400 cases have been confirmed by the CDC in 30 states, and hundreds of cases have been confirmed by reference laboratories. The majority of patients have required hospitalization and there is a 2-3% mortality. This competing continuation application focuses on the major immunodominant surface exposed proteins. Since immunity to obligately intracellular bacteria such as ehrlichiae depends heavily upon T- lymphocyte directed, cytokine-dependent mechanisms, emphasis is placed on understanding these mechanisms. The hypotheses to be tested are 1) that the major, immunodominant 120, 29 and 28 kDa surface proteins contain T-lymphocyte epitopes that are critical to stimulating protective immunity to E. chaffeensis, 2) that genetically determined diversity of each of these three proteins forms the basis for potential biologically important differences and 3) that the 120 kDa ehrlichial protein is an adhesin for the human monocyte. The common theme that unites these hypotheses is elucidation of the interaction of the major surface proteins with the host target cell and the host's cellular immune system.
The specific aims focus on the molecular characterization of the major surface proteins of 120, 29 and 28 kDa, expression of their recombinant polypeptides, and mapping of the T-lymphocyte epitopes with the T-cell clones derived from convalescent patients. Because a greater diversity of these little studied ehrlichiae is strongly suspected, a wider geographic and clinical representation of isolates will be collected. These isolates will be available to the scientific community and will be investigated in this project for the antigenic and genetic diversity of the 120, 29 and 28 kDa surface proteins. Toward the goal of elucidating the pathogenesis of E. chaffeensis infection, a series of studies are designed to identify the E. chaffeensis adhesin for the human and canine monocyte/macrophage.
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