INHIBITION OF PLASMODIUM/HEPATOCYTE INTERACTION

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Malaria is one of the most important infectious diseases in the world. The World Health Organization estimates that there are 270 million new cases of malaria every year. Although efforts at control initially met with some success, the increasing resistance of mosquitos to insecticides and of parasites to chemotherapeutic agents makes it imperative to find new solutions to the problem. The ligand on sporozoites, the infective stage of the parasite, for hepatocytes has recently been described. Phase I of the Physician Scientist Award will focus on acquiring skills in peptide chemistry and applying them to precisely determine the primary and secondary-structure of the malaria sporozoite ligand for hepatocytes. This training will be supplemented with course work in protein chemistry as well as immunology and cell biology seminars that will be useful in Phase II of this project. Phase Il will apply the results generated during Phase I in an attempt to inhibit sporozoite invasion of hepatocytes and thereby prevent malaria infection. Efforts will focus on using a phage combinatorial library to make monoclonal antibodies to the sporozoite ligand, and on the development of new and rational peptide vaccines aiming at inhibition of sporozoite infectivity of hepatocytes. The studies proposed will contribute to the understanding of the biology of malaria parasites and to disease prophylaxis. The educational and research goals of the Physician Scientist Award will provide the physician applicant with the foundation to independently continue basic research in host-parasite interactions with an emphasis on biochemistry and immunology.