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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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Mcgugan, Glen C
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University of Georgia
Public Health & Prev Medicine
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United States
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Cruz-Bustos, Teresa; Ramakrishnan, Srinivasan; Cordeiro, Ciro D et al. (2018) A Riboswitch-based Inducible Gene Expression System for Trypanosoma brucei. J Eukaryot Microbiol 65:412-421
Huang, Guozhong; Docampo, Roberto (2018) The Mitochondrial Ca2+ Uniporter Complex (MCUC) of Trypanosoma brucei Is a Hetero-oligomer That Contains Novel Subunits Essential for Ca2+ Uptake. MBio 9:
Zhuo, You; Cordeiro, Ciro D; Hekmatyar, S Khan et al. (2017) Dynamic nuclear polarization facilitates monitoring of pyruvate metabolism in Trypanosoma brucei. J Biol Chem 292:18161-18168
Docampo, Roberto (2016) The origin and evolution of the acidocalcisome and its interactions with other organelles. Mol Biochem Parasitol 209:3-9
Lander, Noelia; Cordeiro, Ciro; Huang, Guozhong et al. (2016) Polyphosphate and acidocalcisomes. Biochem Soc Trans 44:1-6
Docampo, Roberto; Huang, Guozhong (2016) Acidocalcisomes of eukaryotes. Curr Opin Cell Biol 41:66-72
King-Keller, Sharon; Moore, Christina A; Docampo, Roberto et al. (2015) Ca2+ Regulation of Trypanosoma brucei Phosphoinositide Phospholipase C. Eukaryot Cell 14:486-94
Docampo, Roberto; Huang, Guozhong (2015) Calcium signaling in trypanosomatid parasites. Cell Calcium 57:194-202
Docampo, Roberto; Vercesi, Anibal E; Huang, Guozhong (2014) Mitochondrial calcium transport in trypanosomes. Mol Biochem Parasitol 196:108-16