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 #
5R01AI087625-05
Application #
8613429
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
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$722,349
Indirect Cost
$287,199
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
Croken, Matthew McKnight; Ma, Yanfen; Markillie, Lye Meng et al. (2014) Distinct strains of Toxoplasma gondii feature divergent transcriptomes regardless of developmental stage. PLoS One 9:e111297
Silmon de Monerri, Natalie C; Kim, Kami (2014) Pathogens hijack the epigenome: a new twist on host-pathogen interactions. Am J Pathol 184:897-911
Wang, Jiachen; Dixon, Stacy E; Ting, Li-Min et al. (2014) Lysine acetyltransferase GCN5b interacts with AP2 factors and is required for Toxoplasma gondii proliferation. PLoS Pathog 10:e1003830
Croken, Matthew McKnight; Qiu, Weigang; White, Michael W et al. (2014) Gene Set Enrichment Analysis (GSEA) of Toxoplasma gondii expression datasets links cell cycle progression and the bradyzoite developmental program. BMC Genomics 15:515
Walker, Robert; Gissot, Mathieu; Huot, Ludovic et al. (2013) Toxoplasma transcription factor TgAP2XI-5 regulates the expression of genes involved in parasite virulence and host invasion. J Biol Chem 288:31127-38
Walker, Robert; Gissot, Mathieu; Croken, Matthew M et al. (2013) The Toxoplasma nuclear factor TgAP2XI-4 controls bradyzoite gene expression and cyst formation. Mol Microbiol 87:641-55
Joyce, Bradley R; Tampaki, Zoi; Kim, Kami et al. (2013) The unfolded protein response in the protozoan parasite Toxoplasma gondii features translational and transcriptional control. Eukaryot Cell 12:979-89
Suvorova, Elena S; Croken, Matthew; Kratzer, Stella et al. (2013) Discovery of a splicing regulator required for cell cycle progression. PLoS Genet 9:e1003305
Nardelli, Sheila C; Che, Fa-Yun; Silmon de Monerri, Natalie C et al. (2013) The histone code of Toxoplasma gondii comprises conserved and unique posttranslational modifications. MBio 4:e00922-13
Croken, Matthew M; Nardelli, Sheila C; Kim, Kami (2012) Chromatin modifications, epigenetics, and how protozoan parasites regulate their lives. Trends Parasitol 28:202-13

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