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. The goal of this application is to continue our studies of the roles of acidocalcisomes and polyphosphate in Trypanosoma brucei. Our hypothesis is that the characterization of the acidocalcisome and polyphosphate functions in trypanosomes will lead to important insights into the biology of these parasites, and ultimately novel targets for anti-parasitic intervention. We have identified a novel metabolic pathway in trypanosomes involving the synthesis of inositol pyrophosphates, and found a number of polyphosphate-binding proteins. These findings, together with the recent discoveries of the roles of polyphosphate in inflammatory reactions and as a primordial chaperone greatly enhance our chances to discover novel metabolic pathways and targets for anti- parasitic drugs. We will investigate the link between inositol pyrophosphates (InsPPs), polyphosphate (polyP) synthesis, and acidocalcisomes, the function of InsPPs, and the role of polyphosphate as a chaperone in trypanosomes.

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 polyphosphate and acidocalcisome homeostasis in T. brucei is a potential target for trypanocidal agents and this work is designed to investigate the role of acidocalcisome and polyphosphate in parasite growth, development, and pathogenicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077538-10
Application #
9600016
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcgugan, Glen C
Project Start
2009-07-01
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Georgia
Department
Public Health & Prev Medicine
Type
Organized Research Units
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Potapenko, Evgeniy; Cordeiro, Ciro D; Huang, Guozhong et al. (2018) 5-Diphosphoinositol pentakisphosphate (5-IP7) regulates phosphate release from acidocalcisomes and yeast vacuoles. J Biol Chem 293:19101-19112
Negreiros, Raquel S; Lander, Noelia; Huang, Guozhong et al. (2018) Inorganic polyphosphate interacts with nucleolar and glycosomal proteins in trypanosomatids. Mol Microbiol 110:973-994
Cordeiro, Ciro D; Saiardi, Adolfo; Docampo, Roberto (2017) The inositol pyrophosphate synthesis pathway in Trypanosoma brucei is linked to polyphosphate synthesis in acidocalcisomes. Mol Microbiol 106:319-333
Docampo, Roberto (2016) The origin and evolution of the acidocalcisome and its interactions with other organelles. Mol Biochem Parasitol 209:3-9
Yang, Yunyun; Ko, Tzu-Ping; Chen, Chun-Chi et al. (2016) Structures of Trypanosome Vacuolar Soluble Pyrophosphatases: Antiparasitic Drug Targets. ACS Chem Biol 11:1362-71
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
Huang, Guozhong; Ulrich, Paul N; Storey, Melissa et al. (2014) Proteomic analysis of the acidocalcisome, an organelle conserved from bacteria to human cells. PLoS Pathog 10:e1004555
Docampo, Roberto; Vercesi, Anibal E; Huang, Guozhong (2014) Mitochondrial calcium transport in trypanosomes. Mol Biochem Parasitol 196:108-16

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