Toxoplasma gondii is an obligate intracellular parasite that is responsible for a wide spectrum of disease affecting humans and many animals. In immunoincompetent host, disease could be very severe. T. gondii is now a major cause of opportunistic infection in people with AIDS. There is an urgent need for alternative drugs for the treatment of human toxoplasmosis. Studies of the basic biochemistry of T. gondii could lead to the rational design of new and more effective drugs. We have identified an acidic organelle rich in calcium possibly involved in the regulation of Ca2+ and pH homeostasis in T. gondii that we named the acidocalcisome. We also found that a pyrophosphate is apparently associated with these organelles. Inorganic pyrophosphate occurs in these parasites at concentrations higher than ATP. In addition, we found a """"""""plant-like"""""""" enzymatic activity possibly associated with the same organelle in T. gondii: a H+-translocating pyrophosphatase. These results could have important implications because the novel metabolic pathways identified in Toxoplasma could be targets for chemotherapeutic intervention. We intend to focus on studying the acidocalcisomes with the following specific aims:
specific aim 1 : identification and characterization of the pyrophosphate present in acidocalcisomes;
specific aim 2 : characterization of T. gondii H+-pyrophosphatase;
specific aim 3 : investigation of the role of acidocalcisomes in intracellular Ca2+ and pH homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043614-04
Application #
6511051
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rogers, Martin J
Project Start
1999-05-01
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
4
Fiscal Year
2002
Total Cost
$244,488
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Miranda, Kildare; de Souza, Wanderley; Plattner, Helmut et al. (2008) Acidocalcisomes in Apicomplexan parasites. Exp Parasitol 118:2-9
Fang, Jianmin; Marchesini, Norma; Moreno, Silvia N J (2006) A Toxoplasma gondii phosphoinositide phospholipase C (TgPI-PLC) with high affinity for phosphatidylinositol. Biochem J 394:417-25
Luo, Shuhong; Ruiz, Felix A; Moreno, Silvia N J (2005) The acidocalcisome Ca2+-ATPase (TgA1) of Toxoplasma gondii is required for polyphosphate storage, intracellular calcium homeostasis and virulence. Mol Microbiol 55:1034-45
Karasov, Ariela O; Boothroyd, John C; Arrizabalaga, Gustavo (2005) Identification and disruption of a rhoptry-localized homologue of sodium hydrogen exchangers in Toxoplasma gondii. Int J Parasitol 35:285-91
Arrizabalaga, Gustavo; Ruiz, Felix; Moreno, Silvia et al. (2004) Ionophore-resistant mutant of Toxoplasma gondii reveals involvement of a sodium/hydrogen exchanger in calcium regulation. J Cell Biol 165:653-62
Moreno, Silvia N J; Docampo, Roberto (2003) Calcium regulation in protozoan parasites. Curr Opin Microbiol 6:359-64
Lovett, Jennie L; Marchesini, Norma; Moreno, Silvia N J et al. (2002) Toxoplasma gondii microneme secretion involves intracellular Ca(2+) release from inositol 1,4,5-triphosphate (IP(3))/ryanodine-sensitive stores. J Biol Chem 277:25870-6
Rodrigues, Claudia O; Ruiz, Felix A; Rohloff, Peter et al. (2002) Characterization of isolated acidocalcisomes from Toxoplasma gondii tachyzoites reveals a novel pool of hydrolyzable polyphosphate. J Biol Chem 277:48650-6
Docampo, R; Moreno, S N (2001) The acidocalcisome. Mol Biochem Parasitol 114:151-9
Luo, S; Vieira, M; Graves, J et al. (2001) A plasma membrane-type Ca(2+)-ATPase co-localizes with a vacuolar H(+)-pyrophosphatase to acidocalcisomes of Toxoplasma gondii. EMBO J 20:55-64

Showing the most recent 10 out of 13 publications