T. cruzi: pathogenesis modulation by eicosanoids

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Eicosanoids are important mediators of the cardiovascular system in health and disease. Chagasic cardiomyopathy is one of the most important causes of cardiovascular diseases in many endemic areas of the world. Infection with the parasite T. cruzi causes this disease which has many characteristics similar to the effects of certain eicosanoids such as thromboxane. This infection leads to activation of the inflammatory cascade. It also causes vasocontriction, platelet aggregation and and smooth muscle cell proliferation. Our preliminary data indicate that discrete signaling pathways from host thromboxane prostanoid recptor (TP) regulate the hostparasite relationship. In endothelial cells (ECs) isolated from TP knockout (KO) and WT mice we found that expression of mutated TP in TP-KO ECs can be used as an approach to dissect the molecular regulation of intracellular parasite growth. We demonstrated that G-alpha q or Galpha11 are responsible, in part, for the control of intracellular parasite growth. We will perform additional experiments to confirm that those pathways are directly responsible for the suppression of parasite growth by host TP and thus define the mechanism(s) through which second messengers affects parasite growth. The endpoints to be examined include susceptibility of these cells to this parasite, adhesion and penetration, parasite growth and down-stream signaling pathways of G alpha -q. ECs obtained from various conventional and KO mice will be used to determine important pathways in the pathogenesis of this infection. Cells other than ECs have TP but in our studies we use murine cardiac ECs because they are readily obtained, easily transfectable and maintain their phenotype. Other cell types, such as murine cardiac myocytes, are difficult to obtain in pure form and do not maintain their phenotype in culture. Therefore, ECs act as a surrogate for all cells with TP and are a model for the characterization of the effects of TP signaling. Mice in which various parts of the eicosanoid pathway have been deleted will be used to evaluate signaling pathways important in the pathogenesis of chagasic heart disease. Having identified and cloned a putative thromboxane synthase gene from this parasite we also plan to examine eicosanoid KOs and chatacterize the phenotype of these KOs. The eicosanoid pathway has already provided targets for the treatment of cardiovascular disease and our current studies are likely to provide additional targets for the treatment of this important human parasitic disease.