UGA Cellular Biology | Faculty

SILVIA MORENO

Professor
Ph.D., 1981
University of Buenos Aires

RESEARCH

Studies on the biochemistry and physiology of Toxoplasma gondii:

Our work centers on the discovery of the acidocalcisome, novel acidic organelle containing large amounts of calcium, magnesium, sodium and zinc. Our interest is to understand the function of this novel organelle and also its molecular characterization. In the last five years we were able to purify these organelles from Toxoplasma gondii tachyzoites for further characterization. In addition, we found that T. gondii contains massive amounts of the high-energy phosphate compound pyrophosphate, and short- and long-chain polyphosphate and that most of these compounds are localized in the acidocalcisome. Another important finding was that common FDA-approved bisphosphonates (pyrophosphate analogs) currently used in the treatment of bone resorption disorders inhibit the proliferation of T. gondii in vitro and in vivo but do not harm the host cells.

Several T. gondii mutant cells deficient in acidocalcisome enzymes have been created with the purpose of studying the function of this novel organelle.

Schematic representation of a typical acidocalcisome.

Transmission electron microscopy of a T. gondii
tachyzoite showing the acidocalcisomes as small black spheres.
Photo by Kildare Miranda

Current research projects include:
1) The metabolism of polyphosphate (polyP) and its role in the physiology and survival of T. gondii.
2) The composition of purified acidocalcisomes from T. gondii by proteomic, lipid, amino acid, and carbohydrate analyses.
3) Pyrophosphate-linked enzymes and their role in the physiology and development of T. gondii.
4) The characterization of the effect of pyrophosphate analogs in vitro and in vivo against T. gondii and structure-activity relationship studies to facilitate drug design

In addition, we have an ongoing project on the T. gondii farnesyl pyrophosphate synthase FPPS (TgFPPS), which we have validated as an appropriate target for chemotherapy and that is inhibited by bisphosphonates, pyrophosphate analogs.

The Phosphatidylinositol phospholipase C from trypanosomes and apicomplexan parasites.

We found a novel phosphatidylinositol phospholipase C (TcPI-PLC) present in Trypanosoma cruzi, the etiologic agent of Chagas� disease. We found that this enzyme is the only known PI-PLC that is lipid modified by N-myristoylation and S-palmitoylation and could represent the first member of a new group of PI-PLCs. In addition, the enzyme is developmentally regulated and its expression and intracellular activity is induced during the differentiation of trypomastigotes to amastigotes. TcPI-PLC associates to the plasma membrane of amastigotes.

T. cruzi spimastigote forms expressing GFP.

Research projects:
1) The characterization of the phosphatidylinositol phospholipase C as the enzyme involved in the hydrolysis of GPI anchors.
2) Investigation of the role of TcPI-PLC in differentiation of T. cruzi and T. brucei and their interaction with the host cell and the role of fatty acid modifications in TcPI-PLC localization.
3) Characterization of the PI-PLC from Toxoplasma gondii to investigate the involvement of this enzyme in host-parasite interaction.

CONTACT INFORMATION

(706) 542-4736, smoreno@cb.uga.edu

Dr.Moreno is a member of the Center for Tropical and Emerging Global Diseases

MORENO-DOCAMPO LAB PAGE

Undergraduate Coordinator
350A Paul Coverdell Center
University of Georgia
Athens, GA 30602
USA

Call the departmental office (724 Biological Sciences, 706-542-3310)
for an appointment.

REPRESENTATIVE PUBLICATIONS

Miranda, K. de Souza, W. Plattner, H. Hentschel, J. Kawazoe, U. and Moreno, S.N.J. Acidocalcisomes in Apicomplexan parasites (2008). Exp. Parasitol. Special issue. 118:2-9.

Moreno, S.N.J., Miranda, K., Fang, J., Rohloff, P. and de Souza. W. (2007) Calcium storage and homeostasis in Toxoplasma gondii. In: “Toxoplasma gondii: The Model Apicomplexan---Perspective and Methods”. Editors: Louis M. Weiss and Kami Kim. Elsevier-Academic Press. Chapter 10.

Ling Y, Li ZH, Miranda K, Oldfield E, Moreno S.N.J. The farnesyl diphosphate/geranylgeranyl diphosphate synthase of Toxoplasma gondii is a bifunctional enzyme and the molecular target of bisphosphonates (2007) J. Biol. Chem. 282:3-804-16.

Nagamune K, Beatty WL, Moreno S.N.J., Sibley, LD. Artemisinin induces calcium-dependent secretion in Toxoplasma gondii (2007) Antimicrob. Agents Chemother. 51:3816-23.

Fang J, Marchesini N, Moreno S.N.J. (2006) A Toxoplasma gondii phosphoinositide phospholipase C (TgPI-PLC) with high affinity for phosphatidylinositol. Biochem. J. 394:417.

Ling, Y., Sahota, G., Odeh, S., Chan, J.M., Araujo, F., Moreno, S.N.J. and Oldfield, E. (2005) Bisphosphonate inhibitors of Toxoplasma gondii growth: in vitro, QSAR and in vivo investigations. J. Med. Chem, 48:3130-3140.

Okura M, Fang J, Salto ML, Singer RS, Docampo R, Moreno S.N.J. (2005) A lipid-modified phosphoinositide-specific phospholipase C (TcPI-PLC) is involved in differentiation of trypomastigotes to amastigotes of Trypanosoma cruzi. J. Biol. Chem., 280:16235-43.

Docampo, R., de Souza, W., Miranda, K., Rohloff, R., and Moreno, S.N.J. (2005) Acidocalcisomes –conserved from bacteria to man. Nat. Rev. Microbiol. 3:251-261.

Luo, S., Ruiz, F.A., and Moreno, S.N.J. (2005) The acidocalcisome Ca2+-ATPase (TgA1) of Toxoplasma gondii is required for polyphosphate storage, intracellular calcium homeostasis and virulence. Mol. Microbiol. 55:1034-1045.

Wetzel, D.M., Chen, L.A., Ruiz, F.A., Moreno, S.N.J., and Sibley, L.D. (2004) Calcium-mediated protein secretion potentiates motility by Toxoplasma gondii. J. Cell Sci. 117: 5739-5748.

Arrizabalaga, G., Ruiz, F., Moreno, S.N.J. and Boothroyd, J.A. (2004) Ionophore-resistant mutant of Toxoplasma gondii reveals involvement of a sodium/hydrogen exchanger in calcium regulation. J. Cell Biol. 165:653-662.

Rodrigues, C.O., Ruiz, F.A., Rohloff, P., Scott, D.A., and Moreno, S.N.J. (2002) Characterization of isolated acidocalcisomes from Toxoplasma gondii tachyzoites reveals a novel pool of hydrolysable polyphosphate. J. Biol. Chem. 277, 48650-48656.

Shuhong L., Vieira, M. A., Zhong, L, Graves, J., and Moreno S.N.J. (2000) Cloning, functional expression and co-localization of the vacuolar Ca2+-ATPase with a vacuolar H+-pyrophosphatase to acidocalcisomes of Toxoplasma gondii EMBO J. 20, 55-64.

Furuya, T., Kashuba, C., Docampo, R., and Moreno, S.N.J. (2000) A novel phosphatidylinositol-phospholipase C of Trypanosoma cruzi that is lipid modified and activated during trypomastigote to amastigote differentiation. J. Biol. Chem. 275, 6428-6438.