The morbidity and mortality associated with African trypanosomiasis, Chagas disease, and leishmaniasis may exceed better-known conditions such as of HIV/AIDS, tuberculosis, or malaria. These neglected diseases affect millions of people around the world, causing thousands of deaths and affecting the ability of more people to raise cattle, and crops, or earn a living. No vaccines are available to prevent them and drug treatments have serious side effects or are not completely effective. The study of metabolic pathways in these parasites that may be essential for their survival but may not find an equivalent counterpart in their host could provide information on potential new targets that could be exploited for development of new therapeutic approaches. Channels and transporters are targets of many therapeutically useful agents and they remain significantly under-explored as therapeutic targets, even more so as antiparasitic agents. The goal of this application is to study calcium ion (Ca2+) signaling in Trypanosoma brucei. Our hypothesis is that the characterization of the pathways involving Ca2+ signaling in trypanosomes will lead to important insights into the biology of these parasites, the evolution of eukaryotic cells, and ultimately novl targets for anti-parasitic intervention. We recently discovered that the inositol 1,4,5-trisphosphate receptor (IP3R), a Ca2+ release channel, localizes to acidocalcisomes of T. brucei. This is a highly unique localization for this channel, which is usually present in the endoplasmic reticulum (ER) of vertebrate cells. The IP3R is the primary cytosolic target responsible for the initiation of intracellular Ca2+ signaling in most eukaryotic cells. The releas of Ca2+ via IP3Rs stimulates activities critical for life, but under some conditions IP3R-mediated Ca2+ signals are subverted to cause cell death. For example, flow of Ca2+ specifically from IP3Rs can cause mitochondrial permeability transition and activate the apoptotic cascade, suggesting this pathway as of potential therapeutic significance. The presence of this Ca2+ release channel in acidocalcisomes, an acidic calcium storage organelle highly rich in polyphosphate (a polymer of orthophosphate), suggests unique regulatory mechanisms and functions. Flow of Ca2+ from IP3Rs is facilitated by the close IP3R-mitochondrial calcium uniporter (MCU) connection. Several years ago, our laboratory discovered the activity of MCU in trypanosomes and this information was used to identify the molecular nature of the mammalian MCU. We recently characterized the MCU ortholog in T. brucei and found it to be essential for growth and establishment of infection. Our future goals are to characterize Ca2+ signaling through the TbIP3R and its role in growth, and its regulatory role on the metabolic activity of the mitochondria through the TbMCU.
Approximately 1 billion people suffer from neglected tropical diseases (NTDs), which include African trypanosomiasis caused by the Trypanosoma brucei group or parasites. Unlike the 'big three'infectious diseases (AIDS, tuberculosis, and malaria), NTDs receive comparatively little attention. Many of the existing drugs used to treat NTDs have serious limitations including high cost, difficulties in administration, poor safety profiles and lck of efficacy. New drugs are desperately needed against human African trypanosomiasis (HAT). Our goal is to find ways of interfering with T. brucei metabolic pathways as a strategy of controlling the infection caused by this parasite. The regulation of calcium homeostasis in T. brucei is a potential target for trypanocidal agents and this work is designed to investigate the role of acidocalcisome and mitochondrial calcium in parasite growth, development, and pathogenicity.
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