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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077538-05
Application #
8485516
Study Section
Special Emphasis Panel (ZRG1-IDM-B (02))
Program Officer
Mcgugan, Glen C
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$362,337
Indirect Cost
$118,339
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
Docampo, Roberto; Vercesi, Anibal E; Huang, Guozhong (2014) Mitochondrial calcium transport in trypanosomes. Mol Biochem Parasitol 196:108-16
Ulrich, Paul N; Lander, Noelia; Kurup, Samarchith P et al. (2014) The acidocalcisome vacuolar transporter chaperone 4 catalyzes the synthesis of polyphosphate in insect-stages of Trypanosoma brucei and T. cruzi. J Eukaryot Microbiol 61:155-65
Huang, Guozhong; Vercesi, Anibal E; Docampo, Roberto (2013) Essential regulation of cell bioenergetics in Trypanosoma brucei by the mitochondrial calcium uniporter. Nat Commun 4:2865
Huang, Guozhong; Bartlett, Paula J; Thomas, Andrew P et al. (2013) Acidocalcisomes of Trypanosoma brucei have an inositol 1,4,5-trisphosphate receptor that is required for growth and infectivity. Proc Natl Acad Sci U S A 110:1887-92
Moreno, Silvia N J; Docampo, Roberto (2013) Polyphosphate and its diverse functions in host cells and pathogens. PLoS Pathog 9:e1003230
Docampo, Roberto; Lukes, Julius (2012) Trypanosomes and the solution to a 50-year mitochondrial calcium mystery. Trends Parasitol 28:31-7
Docampo, Roberto; Moreno, Silvia N J (2011) Acidocalcisomes. Cell Calcium 50:113-9
Docampo, Roberto; Jimenez, Veronica; King-Keller, Sharon et al. (2011) The role of acidocalcisomes in the stress response of Trypanosoma cruzi. Adv Parasitol 75:307-24
Huang, Guozhong; Fang, Jianmin; Sant'Anna, Celso et al. (2011) Adaptor protein-3 (AP-3) complex mediates the biogenesis of acidocalcisomes and is essential for growth and virulence of Trypanosoma brucei. J Biol Chem 286:36619-30
de Jesus, Teresa Cristina Leandro; Tonelli, Renata Rosito; Nardelli, Sheila C et al. (2010) Target of rapamycin (TOR)-like 1 kinase is involved in the control of polyphosphate levels and acidocalcisome maintenance in Trypanosoma brucei. J Biol Chem 285:24131-40

Showing the most recent 10 out of 12 publications