An important question in biology is how intracellular parasites infect phagocytic cells. Toxoplasma gondii is an obligate intracellular protozoal parasite that actively invades macrophages without triggering respiratory burst activity, prevents the fusion of the phagosome (containing the ingested parasite) with lysosomes and replicates intracellularly. The consequence of this intracellular parasitism in humans is the disease toxoplasmosis that is of increasing concern because of its high incidence in immunocompromised patients especially in those individuals with the acquired immunodeficiency syndrome (AIDS). We have recently found that resident murine peritoneal macrophages release an altered profile of arachidonic acid metabolites after infection with toxoplasma. Typically these macrophages release the potent inflammatory leukotrienes B4, C4 and D4 after soluble or particulate stimulation. Instead, after infection with T. gondii, the macrophages fail to form leukotrienes but do form monohydroxyeicosatetraenoic acids and a novel, unidentified arachidonate product termed compound X. This proposal will examine the mechanisms of this alteration of macrophage arachidonate metabolism induced by T. gondii.
The specific aims of this proposal are as follows: 1) to determine the structure and biologic properties of the novel arachidonate product produced by toxoplasma infected macrophages, 2) to determine whether arachidonic acid metabolism is altered in human phagocytic cells ingesting toxoplasma, 3) to determine the mechanism of altered 5-lipoxygenase product release in macrophages ingesting toxoplasma and 4) to determine the effect of leukotrienes on the ingestion and intracellular killing of toxoplasma by macrophages. Elucidation of the mechanisms by which toxoplasma may evade normal host defense mechanisms may suggest means for prevention of and specific treatment of infection by this and related intracellular pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023713-04
Application #
3136033
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1986-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Henderson Jr, W R; Rashed, M; Yong, E C et al. (1992) Toxoplasma gondii stimulates the release of 13- and 9-hydroxyoctadecadienoic acids by human platelets. Biochemistry 31:5356-62
Henderson, W R; Chi, E Y (1992) Cytotoxic activity of 13-hydroxyoctadecadienoic acid against Toxoplasma gondii. Parasitology 105 ( Pt 3):343-7
Henderson Jr, W R (1991) Eicosanoids and platelet-activating factor in allergic respiratory diseases. Am Rev Respir Dis 143:S86-90
Yong, E C; Chi, E Y; Fritsche, T R et al. (1991) Human platelet-mediated cytotoxicity against Toxoplasma gondii: role of thromboxane. J Exp Med 173:65-78
Michelson, M K; Henderson Jr, W R; Chi, E Y et al. (1990) Ultrastructural studies on the effect of tumor necrosis factor on the interaction of neutrophils and Naegleria fowleri. Am J Trop Med Hyg 42:225-33
Skerrett, S J; Henderson, W R; Martin, T R (1990) Alveolar macrophage function in rats with severe protein calorie malnutrition. Arachidonic acid metabolism, cytokine release, and antimicrobial activity. J Immunol 144:1052-61
Liles, W C; Meier, K E; Henderson, W R (1987) Phorbol myristate acetate and the calcium ionophore A23187 synergistically induce release of LTB4 by human neutrophils: involvement of protein kinase C activation in regulation of the 5-lipoxygenase pathway. J Immunol 138:3396-402
Henderson Jr, W R (1987) Lipid-derived and other chemical mediators of inflammation in the lung. J Allergy Clin Immunol 79:543-53
Chi, E Y; Kuo, C C; Grayston, J T (1987) Unique ultrastructure in the elementary body of Chlamydia sp. strain TWAR. J Bacteriol 169:3757-63