Mechanisms by which human filarial parasites cause disease and modulate the host's immune response are poorly understood. Although the pathways and products of arachidonic acid metabolism in mammalian cells have been intensely studied, the presence and function of pathways of arachidonic acid metabolism in helminthic parasites are largely undefined. Parasite elaboration of bioactive arachidonate derivatives, such as prostaglandins, thromboxanes, leukotrienes, or hydroxyeicosatetraenoic acids, with their known potent activities; including effects on platelet aggregation, vascular permeability, and inflammatory and immunological responses, would represent a novel means of regulating the microenvironment surrounding helminthic parasites. Utilizing adults and microfilariae of the human lymphatic filarial parasite Brugia malayi, this project will investigate the biochemical pathways of arachidonic acid metabolism in these filarial nematodes. The ability of adults or microfilariae to incorporate 3H-arachidonic acid in vitro into parasite neutral and phospholipids has been assessed utilizing thin layer chromatography and reverse phase high performance liquid chromatography (HPLC). Mechanisms of parasite incorporation of arachidonate will be further evaluated and compared with those for other saturated and unsaturated fatty acids. Pathways of parasite metabolism of arachidonic acid to cyclooxygenase (e.g., prostaglandins) or lipoxygenase (e.g., leukotrienes) products will be defined utilizing reverse phase HPLC and radioimmunoassays. Possible actions of the antifilarial agent, diethylcarbamazine, on the pathways of parasite arachidonic acid metabolism will be determined. The potential roles of filarial parasite-derived arachidonic acid metabolites as mediators of pathogenicity and as modulators of host immunity will be examined. The effects of filarial arachidonate derivatives on human eosinophil, neutrophil, lymphocyte and platelet functions will be assessed. These investigations may document the existence within multicellular metazoan parasites of biochemical pathways heretofore appreciated only in mammalian cells. Further, by characterizing the biological activities of any filarial arachidonate derivatives, these studies may provide insights into novel mechanisms of parasite pathogenicity and may suggest rational approaches to the development of antifilarial agents.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Unknown (R22)
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Tropical Medicine and Parasitology Study Section (TMP)
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Beth Israel Deaconess Medical Center
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Liu, L X; Buhlmann, J E; Weller, P F (1992) Release of prostaglandin E2 by microfilariae of Wuchereria bancrofti and Brugia malayi. Am J Trop Med Hyg 46:520-3
Liu, L X; Weller, P F (1992) Intravascular filarial parasites inhibit platelet aggregation. Role of parasite-derived prostanoids. J Clin Invest 89:1113-20
Liu, L X; Serhan, C N; Weller, P F (1991) Formation of cyclooxygenase-derived eicosanoids by a parasitic intravascular nematode. Adv Prostaglandin Thromboxane Leukot Res 21B:509-12
Liu, L X; Serhan, C N; Weller, P F (1990) Intravascular filarial parasites elaborate cyclooxygenase-derived eicosanoids. J Exp Med 172:993-6
Lucey, D R; Dorsky, D I; Nicholson-Weller, A et al. (1989) Human eosinophils express CD4 protein and bind human immunodeficiency virus 1 gp120. J Exp Med 169:327-32
Liu, L X; Weller, P F (1989) Brugia malayi: microfilarial polyunsaturated fatty acid composition and synthesis. Exp Parasitol 69:198-203
Lucey, D R; Nicholson-Weller, A; Weller, P F (1989) Mature human eosinophils have the capacity to express HLA-DR. Proc Natl Acad Sci U S A 86:1348-51
Weller, P F; Longworth, D L; Jaffe, J J (1989) Leukotriene C4 synthesis catalyzed by Dirofilaria immitis glutathione S-transferase. Am J Trop Med Hyg 40:171-5
Longworth, D L; Monahan-Earley, R A; Dvorak, A M et al. (1988) Brugia malayi: arachidonic acid uptake into lipid bodies of adult parasites. Exp Parasitol 65:251-7
McCrone, E L; Lucey, D R; Weller, P F (1988) Fluorescent staining for leukocyte chemotaxis. Eosinophil-specific fluorescence with aniline blue. J Immunol Methods 114:79-88

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