Acidocalcisomes in Trypanosoma cruzi

University Of Illinois Urbana-Champaign, Champaign IL

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Abstract

DESCRIPTION (provided by the applicant): In the Americas, from Mexico in the North to Argentina and Chile in the South, there are 16 to 19 million people infected with Trypanosoma cruzi, the causative agent of Chagas' disease. Estimated yearly incidence amounts to 561,000 cases not including countries like Argentina, Brazil, Chile and Uruguay where active programs of vector elimination have been in progress for years. Chemotherapy of Chagas' disease is unsatisfactory. Our long-term goal is to find targets for the treatment of Chagas' disease. A few years ago we discovered a novel organelle in trypanosomes that we named the acidocalcisome. Over the years we have found this organelle in several trypanosomatids (T. cruzi, T. brucei, Leishmania spp.) and apicomplexan parasites (T. gondii, P. falciparum). Our objective is to understand the function of this organelle. The discovery of novel enzymes in this organelle that are absent in mammalian cells led to the finding of compounds (bisphosphonates) that produced radical cures in animal models of the diseases caused by several parasites. Our preliminary data indicate the presence of a contractile vacuole system in T. cruzi and our proposal postulates that acidocalcisomes of T. cruzi are involved, through their association with this contractile vacuole apparatus, in osmoregulation. Osmoregulation is essential for T. cruzi since the parasite is in contact with a variety of osmotic stresses during its life cycle. The participation of a contractile vacuole in osmoregulation has been demonstrated in other unicellular eukaryotes, like algae and Dictyostelium, and we recently demonstrated both, the presence of acidocalcisomes, and their association with the contractile vacuole, in these unicellular eukaryotes. We propose, based on our previous record for innovative research, that further exploration of the osmo-regulatory mechanisms in T. cruzi, and the role of the acidocalcisome in this function, will lead to the identification of further targets for drug action. We will focus on studying osmoregulation, with particular emphasis on the role of acidocalcisomes, with the following specific aims: Specific aim 1, investigation of mechanisms of regulatory volume decrease in T. cruzi, especially the role of acidocalcisomes and the contractile vacuole; Specific aim 2, Investigation of the role of acidocalcisome polyP in osmoregulation.