MOLECULAR PARASITOLOGY AND PARASITIC DISEASE

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The long-term objective of this Program is to define antigens of Onchocerca volvulus that are related to development of ocular and skin disease and to improve our understanding of molecular pathogenesis. Onchocerciasis is one of the leading blinding diseases of humans as well as a leading cause of skin disease. The disease is believed to be immune-mediated, but the precise pathogenesis of most manifestations is unknown. Disease control by attacking the vector blackfly is not realistic for most areas of the world. Further, although ivermectin given at regular intervals may suppress disease, such a regimen is beyond the means of the health care infrastructure in much of the developing world. Thus, improved understanding of disease pathogenesis is clearly needed. This proposal is designed to establish a multidisciplinary, interactive program that capitalizes on the expertise of established investigators to apply the techniques of molecular biology and molecular immunology to human onchocerciasis. This is based upon a combined field-based clinical and basic immunology program of onchocerciasis research developed over the past 11 years in the U.S. and West Africa. Project 1 will identify individuals with ocular or skin disease and provide reagents to define antigens and epitopes associated with clinical disease at the molecular level, and test defined antigens for effect on cells from persons with disease. This basis for geographic variation in disease and the influence of ivermectin treatment on the immune response will be examined. Project 2 will identify and characterize clones encoding disease-associated antigens, and will examine the genetic basis for the difference between forest and savannah pathogenic epitopes. Project 3 will prepare T lymphocyte clones against disease-associated antigens; these clones will be utilized for T epitope mapping and functional studies of the most active antigens. Project 4 will examine recombinant antigens in the guinea pig model of keratitis and define pathogenic epitopes and MHC restriction of reactivity. Core A will serve Projects 1-4 with protein and peptide chemistry and epitope mapping expertise. Core B will provide the necessary starting materials for Projects 1, 2, 3, and 4. The goal of this multidisciplinary Program is to focus the extraordinary talent represented by this group of investigators on a disease problem that is not readily amenable to more limited approaches, with the objective of contributing to ultimate disease control.