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.
