The long-term goal of the project is to analyze the structural and molecular composition of spotted fever group (SFG) rickettsiae and to correlate rickettsial antigenic components with stimulation of cell- mediated immunity. The immunodominant 190 and 135 Kda major proteins of Rickettsia rickettsii, R. conorii, and other medically important SFG rickettsiae will be characterized by identification of T-lymphocyte epitopes within the proteins by utilizing T-lymphocyte clones and hybridomas. Our recent advances in the development of murine models of endothelial-target infection, characterized by vascular pathology which closely mimics the human disease, enable the design of experiments to dissect the roles of interferon-gamma, tumor necrosis factor-alpha, and T- lymphocyte subsets in protective immunity against SFG rickettsiae in vivo. Use of adoptive transfer of immune T lymphocytes in inbred mice, depletion of interferon-gamma, depletion of tumor necrosis factor-alpha, identification of T-lymphocyte subsets, and immunization with recombinant and purified proteins and synthetic peptides will address critically the essential immune effector and protection-stimulating antigens. Investigation of the tissue sites of immunity to endothelial infection will demonstrate the local quantity of T-lymphocyte subsets and the content of mRNA for interferon-gamma or tumor necrosis factor-alpha adjacent to the endothelial foci of infection. The role of cytotoxic T lymphocytes will be evaluated regarding the response to rickettsial epitopes expressed on infected endothelial cells in vitro, determining whether the cytotoxic effect occurs in vivo, and determining whether it acts in favor of the infected host. The outcome of this project will be enhanced knowledge of immunity to intracellular parasites by the correlation of the response to immunodominant T-lymphocyte epitopes with the mechanisms of protective immunity against intraendothelial infection. Rocky Mountain spotted fever (R. rickettsii), the most severe and widespread rickettsiosis in the U.S., boutonneuse fever (R. conorii) with high incidence and significant mortality in Africa, Europe, and Asia, North Asian tick typhus (R. sibirica) occurring in vast regions of the USSR, China, and Mongolia, Queensland tick typhus (R. australis), Israel tick typhus (unnamed Rickettsia sp.), and the recognized Oriental spotted fever (R. japonica) comprise scientifically and medically important diseases that offer a fertile focus of investigation.
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