The role of polyphosphate and acidocalcisomes in Trypanosoma brucei

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DESCRIPTION (provided by applicant): Trypanosoma brucei is the causative agent of sleeping sickness or African trypanosomiasis. According to the World Health Organization, over 60 million persons in sub-Saharan Africa are at risk of infection with an incidence of 300-500,000 cases per year resulting in 55,000 deaths. African trypanosomiasis has been reemerging since 1970, and chemotherapy remains unsatisfactory, especially for advanced cases. The acidocalcisome is a dense, acidic organelle with a high concentration of phosphorus present as pyrophosphate and polyphosphate complexed with calcium, and other cations. The acidocalcisome membrane contains a number of pumps (Ca2+- ATPase, V-H+-ATPase, H+-PPase), exchangers (Na+/H+, Ca2+/H+), and channels (aquaporins), while its matrix contains enzymes related to pyrophosphate and polyphosphate metabolism. Acidocalcisomes have been found in several pathogenic microorganisms as well as in the green alga Chlamydomonas reinhardtii, and the slime mold Dictyostelium discoideum. The identification of the acidocalcisome in bacteria and the finding that human platelet dense granules are similar to acidocalcisomes, indicate that this organelle either appeared before the divergence of bacterial and eukaryotic lineages or independently by convergent evolution. Some of the potential functions of the acidocalcisome are the storage of cations and phosphorus, and its participation in pyrophosphate and polyphosphate metabolism, calcium homeostasis, maintenance of intracellular pH homeostasis, and osmoregulation. T. brucei is an excellent model to study the acidocalcisome and our goal is to know its composition and function. In recent years we have demonstrated the presence of novel enzymes in this organelle that are absent from mammalian cells and this led to the finding of compounds (pyrophosphate analogs) that produced radical cures in animal models of diseases caused by several parasites. Further exploration of the composition and function of the acidocalcisome in T. brucei could lead to the identification of new targets for chemotherapeutic agents. We will focus on studying the composition and function of the acidocalcisome proteins of T. brucei, the targeting mechanism of transmembrane proteins to this organelle, and the roles of pyrophosphate and polyphosphate metabolism in T. brucei growth and development. PUBLIC HEALTH RELEVANCE: Our goal is to find ways of interfering with Trypanosoma brucei metabolic pathways as a strategy of controlling infections caused by this and similar parasites. The polyphosphate and acidocalcisome metabolic pathways may be good targets for new trypanocidal agents and this work is designed to test the function and significance of polyphosphate and acidocalcisomes of T. brucei.