Lymphatic filariasis remains a major global health problem. Little is known about parasite pathogenicity and modulation of host immune responses in human filarial infections. In particular, interactions between bloodborne microfilariae and host blood cells, including platelets, leukocytes, and endothelial cells, are largely unexplored. In mammalian cells, arachidonic acid is metabolized to eicosanoids, biologically active lipid derivatives that mediate a wide range of inflammatory and immune responses. Brugia malayi, a filarial parasite of humans, avidly incorporates arachidonic acid and cal also metabolize arachidonic acid to eicosanoids in vitro. Such parasite-derived eicosanoids could present newly recognized mediators of the in vivo interactions between microfilariae and host cells. The major training goal of this Physician Scientist Award is to provide the physician-applicant with training in concepts and methods of the basic sciences relevant to the study of metazoan parasites, in order to provide him with a solid foundation for developing an independent research career. The major research goals of this proposal are to elucidate the biosynthesis of eicosanoids in B. malayi microfilariae and their roles in mediating interactions between these parasites and host blood cells. Phase I of the Award will emphasize training in research methods as well as coursework and seminars in biochemistry, cell biology, and immunology. Studies of microfilarial eicosanoid production will be continued using sensitive techniques of HPLC, TLC, and RIA to detect parasite products of arachidonic acid metabolism. This phase will also provide intensive training in analytical biochemistry techniques, including gas chromatography - mass spectroscopy, to structurally characterize unknown and novel parasite-derived eicosanoids. In Phase II, these techniques will be applied and expanded to study the effects of microfilarial eicosanoids on human blood cells, including leukocytes, platelets, and endothelial cells. The effects of diethylcarbamazine, the major antifilarial drug, and other pharmacologic inhibitors of mammalian eicosanoid biosynthesis on the biosynthesis and actions of microfilarial eicosanoids will also be assessed. These investigations will help to define the role of parasite-derived eicosanoids in the pathogenesis and immunology of human filariasis. While these studies are focused on filarial parasites, other metazoan parasites are likely to possess similar capabilities to form bioactive lipids. Rigorous studies of parasite-derived eicosanoids may provide new insights in the molecular means by which metazoan parasites elude natural or vaccine-induced immunity. Such understanding may influence the development of useful drugs and synthetic vaccines to control important metazoan parasites. The educational and training components of this Award will provide the applicant with the scientific expertise that will enable his to successfully pursue basic studies of host-parasite interactions as an independent investigator.
