Morbidity and mortality associated with Chagas disease in Latin America exceed better-known conditions such as malaria, tuberculosis, or AIDS. Millions of people are affected by this trypanosomiasis. No vaccines are available to prevent this disease and drug treatments have serious side effects and 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 make possible the development of specific inhibitors as possible means of controlling the parasites without damaging the hosts. One of the most interesting characteristics of Trypanosoma cruzi, the etiologic agent of Chagas disease, is its possession of two closely associated organelles, the acidocalcisomes and the contractile vacuole. Acidocalcisomes are acidic calcium stores rich in pyrophosphate (PPi) and polyphosphate (polyP). The contractile vacuole is present in free-living protists and also in Leishmania spp., but has not been described in T. brucei, while acidocalcisomes are present in all trypanosomatids. Our preliminary results suggest that the contractile vacuole is a trafficking hub for the transfer of proteins important for the pathogenesi of T. cruzi infection to the plasma membrane. We have found that trans-sialidases, which are important for the establishment of T. cruzi infection, are trafficked through the contractile vacuole in their way to the plasma membrane. PolyP is a linear polymer of a few to many hundreds of phosphate (Pi) residues linked by high-energy phosphoanhydride bonds and is ubiquitous from bacteria to mammals. In contrast to several functions ascribed to polyP in bacteria, the functions of this polymer in eukaryotic cells are relatively undefined. With the discovery of the potent modulatory activity of this polymer on blood coagulation and inflammation there has been renewed interest in this molecule as of potential importance in virulence of polyP-containing microorganisms. Recent results from our laboratory suggest that polyP and/or PPi could be involved in the pathogenesis of T. cruzi infection. We propose to study the roles of acidocalcisomes and the contractile vacuole in the pathogenesis of T. cruzi infection.

Public Health Relevance

Morbidity and mortality associated with Chagas disease in Latin America exceed better-known conditions such as malaria, tuberculosis, or AIDS. Millions of people are affected by this trypanosomiasis. No vaccines are available to prevent this disease and drug treatments have serious side effects and 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 make possible the development of specific inhibitors as possible means of controlling the parasites without damaging the hosts. We are investigating the role of two organelles, acidocalcisomes and the contractile vacuole in the pathogenesis of Trypanosoma cruzi infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI107663-01
Application #
8710952
Study Section
Special Emphasis Panel (ZRG1-IDM-M (02))
Program Officer
Wali, Tonu M
Project Start
2013-08-15
Project End
2014-07-31
Budget Start
2013-08-15
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$350,150
Indirect Cost
$115,150
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
Lander, Noelia; Chiurillo, Miguel A; Vercesi, Aníbal E et al. (2017) Endogenous C-terminal Tagging by CRISPR/Cas9 in Trypanosoma cruzi. Bio Protoc 7:
Chiurillo, Miguel A; Lander, Noelia; Bertolini, Mayara S et al. (2017) Different Roles of Mitochondrial Calcium Uniporter Complex Subunits in Growth and Infectivity of Trypanosoma cruzi. MBio 8:
Lander, Noelia; Chiurillo, Miguel A; Docampo, Roberto (2016) Genome Editing by CRISPR/Cas9: A Game Change in the Genetic Manipulation of Protists. J Eukaryot Microbiol 63:679-90
Chao, María N; Li, Catherine; Storey, Melissa et al. (2016) Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii. ChemMedChem 11:2690-2702
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; Chiurillo, Miguel A; Storey, Melissa et al. (2016) CRISPR/Cas9-mediated endogenous C-terminal Tagging of Trypanosoma cruzi Genes Reveals the Acidocalcisome Localization of the Inositol 1,4,5-Trisphosphate Receptor. J Biol Chem 291:25505-25515
Niyogi, Sayantanee; Jimenez, Veronica; Girard-Dias, Wendell et al. (2015) Rab32 is essential for maintaining functional acidocalcisomes, and for growth and infectivity of Trypanosoma cruzi. J Cell Sci 128:2363-73
Veiga-Santos, Phercyles; Li, Kai; Lameira, Lilianne et al. (2015) SQ109, a new drug lead for Chagas disease. Antimicrob Agents Chemother 59:1950-61
Jimenez, Veronica; Docampo, Roberto (2015) TcPho91 is a contractile vacuole phosphate sodium symporter that regulates phosphate and polyphosphate metabolism in Trypanosoma cruzi. Mol Microbiol 97:911-25
Lander, Noelia; Li, Zhu-Hong; Niyogi, Sayantanee et al. (2015) CRISPR/Cas9-Induced Disruption of Paraflagellar Rod Protein 1 and 2 Genes in Trypanosoma cruzi Reveals Their Role in Flagellar Attachment. MBio 6:e01012

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