Apicomplexa are responsible for a number of important human diseases including malaria, toxoplasmosis, cryptosporidiosis and cyclosporidiosis. Management of these diseases rests heavily on chemotherapy but anti-parasitic drug treatment faces multiple challenges. These include poor overall potency, restriction to certain life-cycle stages, unwanted side effects, and rapidly emerging multiple drug resistance. A constant stream of new drugs and potential drug targets is required to stay abreast of the threat posed by these pathogens. One of the most promising sources of such parasite specific targets is the apicomplexan plastid or apicoplast. The apicoplast is unique to the parasite and its function is essential to parasite survival. This organelle is a holdover from a free-living photosynthetic past. The structure and biology of the apicoplast is remarkably complex as it is derived from the endosymbiotic marriage of two eukaryotes: a red alga and an auxotrophic protist. The goal of this application is to unravel the complexity of this biology in mechanistic detail and to identify future targets for intervention. Using Toxoplasma as a model organism we will conduct genetic, cell biological and biochemical approaches to characterize the function of two pathways that unfold in the outer compartments of the organelle and that we hypothesize are essential to the organelle and the parasites. We will complement this focused approach with a broader effort to define a comprehensive set of plastid proteins to continue to feed a pipeline of hypothesis-driven mechanistic experiments with strong candidate genes.

Public Health Relevance

Toxoplasma gondii is an important human pathogen that causes disease in the unborn fetus, young children and patients with a weakened immune system. We are a studying a unique cellular structure of the parasite that is related to the chloroplast of plants. A detailed understanding of the biology of this structure will lead us to new parasite specific interventions to treat and prevent disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064671-09
Application #
8584226
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Rogers, Martin J
Project Start
2005-04-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
9
Fiscal Year
2014
Total Cost
$300,713
Indirect Cost
$98,213
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
Daher, Wassim; Morlon-Guyot, Juliette; Sheiner, Lilach et al. (2015) Lipid kinases are essential for apicoplast homeostasis in Toxoplasma gondii. Cell Microbiol 17:559-78
Francia, Maria E; Striepen, Boris (2014) Cell division in apicomplexan parasites. Nat Rev Microbiol 12:125-36
Bowman, Jessica D; Merino, Emilio F; Brooks, Carrie F et al. (2014) Antiapicoplast and gametocytocidal screening to identify the mechanisms of action of compounds within the malaria box. Antimicrob Agents Chemother 58:811-9
Vinayak, Sumiti; Brooks, Carrie F; Naumov, Anatoli et al. (2014) Genetic manipulation of the Toxoplasma gondii genome by fosmid recombineering. MBio 5:e02021
Sheiner, Lilach; Striepen, Boris (2013) Protein sorting in complex plastids. Biochim Biophys Acta 1833:352-9
Li, Zhu-Hong; Ramakrishnan, Srinivasan; Striepen, Boris et al. (2013) Toxoplasma gondii relies on both host and parasite isoprenoids and can be rendered sensitive to atorvastatin. PLoS Pathog 9:e1003665
Cai, Guobin; Deng, Lisheng; Xue, Jian et al. (2013) Expression, characterization and inhibition of Toxoplasma gondii 1-deoxy-D-xylulose-5-phosphate reductoisomerase. Bioorg Med Chem Lett 23:2158-61
Agrawal, Swati; Chung, Duk-Won D; Ponts, Nadia et al. (2013) An apicoplast localized ubiquitylation system is required for the import of nuclear-encoded plastid proteins. PLoS Pathog 9:e1003426
van Dooren, Giel G; Striepen, Boris (2013) The algal past and parasite present of the apicoplast. Annu Rev Microbiol 67:271-89
Ramakrishnan, Srinivasan; Serricchio, Mauro; Striepen, Boris et al. (2013) Lipid synthesis in protozoan parasites: a comparison between kinetoplastids and apicomplexans. Prog Lipid Res 52:488-512

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