The obligate intracellular parasite Toxoplasma gondii is a major opportunistic pathogen of the AIDS epidemic. As it develops within host cells, the parasite implements a coordinated pattern of sequential gene expression. In response to stress and changes in its environment, the parasite completely alters its metabolism, surface antigens, and cell cycle to transition from tachyzoite to bradyzoite. Understanding how T. gondii regulates gene expression is fundamental for understanding the pathogenesis of toxoplasmosis. Epigenetic factors govern developmental transitions and expression of virulence traits, and are also implicated in T. gondii bradyzoite differentiation. How chromatin remodeling complexes interact with transcriptional machinery in T. gondii is not known. Recently, a plant-like transcription factor family, the APETELA 2 (or AP2) family, has been discovered and proposed as the primary transcription factors of T. gondii and other Apicomplexa. We hypothesize that conserved Apicomplexa AP2 family members have conserved functions in T. gondii as sequence-specific transcription factors that interact with general transcription factors and chromatin remodeling complexes to regulate gene expression. We have previously developed a epigenomic map of tachyzoites that defines functional regions of the genome. We will use this prior work to assist us in determining the genes regulated by TgAP2. The DNA binding specificity of AP2 proteins will be identified using a multidisciplinary approach. Proteins that interact with TgAP2 will be identified using proteomics. These studies will form a scaffold upon which we will build systems biology model to understand how gene networks govern biologically significant events such as bradyzoite formation.

Public Health Relevance

Toxoplasma gondii is a parasitic pathogen that causes severe disease in immunocompromised individuals including people with AIDS. This parasite undergoes a carefully orchestrated developmental program within infected cells and also can respond to changes in its environment by changing into persistent, hardier bradyzoite forms. These transitions involve tight coordination of gene expression. Recently we have begun to characterize newly discovered T. gondii genes that appear to regulate gene expression. These genes, the AP2 family, may be new drug targets because they resemble plant genes rather than genes seen in mammals. The genes are also conserved in many other apicomplexan organisms that affect AIDS patients such as Cryptosporidium. Understanding the function of AP2 proteins may lead to new treatments that will prevent of treat T. gondii infection in individuals with AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI087625-01A1
Application #
7950538
Study Section
Special Emphasis Panel (ZRG1-AARR-C (02))
Program Officer
Joy, Deirdre A
Project Start
2010-03-15
Project End
2015-02-28
Budget Start
2010-03-15
Budget End
2011-02-28
Support Year
1
Fiscal Year
2010
Total Cost
$642,780
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Jeffers, Victoria; Tampaki, Zoi; Kim, Kami et al. (2018) A latent ability to persist: differentiation in Toxoplasma gondii. Cell Mol Life Sci 75:2355-2373
Naumov, Anatoli; Kratzer, Stella; Ting, Li-Min et al. (2017) The Toxoplasma Centrocone Houses Cell Cycle Regulatory Factors. MBio 8:
Yakubu, Rama R; Silmon de Monerri, Natalie C; Nieves, Edward et al. (2017) Comparative Monomethylarginine Proteomics Suggests that Protein Arginine Methyltransferase 1 (PRMT1) is a Significant Contributor to Arginine Monomethylation in Toxoplasma gondii. Mol Cell Proteomics 16:567-580
Wijetunga, N Ari; Johnston, Andrew D; Maekawa, Ryo et al. (2017) SMITE: an R/Bioconductor package that identifies network modules by integrating genomic and epigenomic information. BMC Bioinformatics 18:41
Sugi, Tatsuki; Ma, Yan Fen; Tomita, Tadakimi et al. (2016) Toxoplasma gondii Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite Development. MBio 7:
El Bissati, Kamal; Suvorova, Elena S; Xiao, Hui et al. (2016) Toxoplasma gondii Arginine Methyltransferase 1 (PRMT1) Is Necessary for Centrosome Dynamics during Tachyzoite Cell Division. MBio 7:e02094-15
Lorenzi, Hernan; Khan, Asis; Behnke, Michael S et al. (2016) Local admixture of amplified and diversified secreted pathogenesis determinants shapes mosaic Toxoplasma gondii genomes. Nat Commun 7:10147
Nardelli, Sheila C; Ting, Li-Min; Kim, Kami (2015) Techniques to study epigenetic control and the epigenome in parasites. Methods Mol Biol 1201:177-91
Silmon de Monerri, Natalie C; Yakubu, Rama R; Chen, Allan L et al. (2015) The Ubiquitin Proteome of Toxoplasma gondii Reveals Roles for Protein Ubiquitination in Cell-Cycle Transitions. Cell Host Microbe 18:621-33
Kim, Kami (2015) A Bradyzoite is a Bradyzoite is a Bradyzoite? Trends Parasitol 31:610-612

Showing the most recent 10 out of 32 publications