Chagas' disease is an incurable disease affecting at least 20 million people in Latin America and is caused by Trypanosoma cruzi. In the last few years the molecular mechanisms underlying T. cruzi- host interaction is beginning to be understood. The developmentally regulated neuraminidase of T. cruzi is one of the parasite molecules recently implicated in the pathogenesis of Chagas' disease because it may regulate infection by a negative control mechanism. Moreover, the T. cruzi neuraminidase appears to be the receptor for host lipoproteins which, in this way, may alter the infective properties of the parasite. The studies proposed here are designed to extend these observations and to gain further insight into the structure-function relationship of the enzyme. Future goals include a determination of whether neuraminidase-host lipoproteins interaction is a risk factor is determining susceptibility to Chagas' disease in humans and an analysis of the mechanism of the gene expression of the enzyme. The goals of this project are therefore to study: 1. The biological significance of the T. cruzi neuraminidase as ascertained by in vitro and in vivo experiments in which specific enzyme probes such as monoclonal and polyclonal antibodies, and high density lipoprotein will be tested for their effect on T. cruzi infection. 2. Regulation of the T. cruzi neuraminidase by host lipoproteins as assessed by determining the fate of lipoprotein bound to T. cruzi, and the influence of the type and concentration of lipoprotein in growth media. 3. Structure-functions of the T. cruzi neuraminidase as assessed by the polymorphism and processing of the enzyme in the parasite, and by ligand blotting analysis. 4. Molecular cloning of the gene encoding the T. cruzi neuraminidase to obtain mg amounts of the enzyme for future fine structural and functional analysis.
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