DESCRIPTION (provided by applicant): 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.
|Effective start/end date||3/15/10 → 2/29/16|
- Immunology and Microbiology(all)