This application focuses upon the Apicomplexa, etiologic agents of many diseases in the developing world and relevant to global health (thematic area 4). It uses genomics and other high throughput technologies (thematic area 1) with a systems-level integration, analysis and mining of large datasets with the overarching goal of translating our discoveries into new insights into therapy and disease prevention (thematic area 2). To accomplish our goals, we have assembled a multidisciplinary collaborative team with expertise in infectious diseases, diabetes, metabolism, pathology, molecular biology, animal models and pathophysiology to conduct an innovative study in challenging biomedical areas (thematic area 5). As major emerging and reemerging pathogens, Apicomplexan parasites infect more than a third of the world's population. These obligate intracellular parasites include Toxoplasma gondii, Plasmodium species and Cryptosporidium. Toxoplasma gondii is a major opportunistic pathogen of the AIDS epidemic, a cause of birth defects and is also a Category B priority agent due to its association with waterborne outbreaks. Plasmodium species, the agents of malaria, infect over 267 million people per year and cause nearly 1 million deaths per year. Despite the importance of these parasites in human disease, there are no effective vaccines for these pathogens, and new strategies for treatment and prevention of disease are needed. Very little is understood how the Apicomplexa regulate virulence traits and respond to changes in their environment. The development of new high-throughput technologies has enabled collection of large genomic and proteomics datasets. These can be used to develop an integrated understanding of how eukaryotic cells regulate gene expression. We will take advantage of genome manipulation, genome-wide arrays, high throughput sequencing, and proteomics to develop datasets that will facilitate an integrated systems approach to understanding regulation of gene expression and epigenetics in the model apicomplexan T.gondii. We will test the essentiality of chromatin remodellers and candidate transcription factors using a moderate through-put gene disruption strategy. Using epitope tagged chromatin remodelers and transcription factors, we will use high throughput sequencing of chromatin immunoprecipitates and expression microarrays to identify groups of co-regulated genes. Finally, we will perform high-throughput proteomics to characterize the constituents of macromolecular complexes involved in regulation of gene expression. These epigenomic, transcriptome, and proteomic datasets will facilitate computational approaches to model how epigenetic and genetic factors in the Apicomplexa interact within gene networks. This effort will create important community resources to enable a systems biology approach toward understanding expression of virulence traits and identification of novel drug targets for apicomplexan parasites.

Public Health Relevance

Toxoplasma gondii is a parasitic pathogen that causes severe disease in immunocompromised individuals including people with AIDS, causes birth defects, and is a Biodefense Category B pathogen due to its association with waterborne outbreaks. Finally it is a model system for other parasites like Plasmodium, which cause human malaria. These parasites affect over a third of the world's population. We are trying to generate large datasets that will help us understand how these parasitic pathogens change in response to interaction with human hosts and how they regulate genes that cause disease. These data take advantage of genome sequencing projects and will use new powerful high throughput technologies. Gathering these data will be important for developing new treatments that will prevent T. gondii from persisting in infected people, and understanding how Apicomplexan parasites cause disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Impact Research and Research Infrastructure Programs—Multi-Yr Funding (RC4)
Project #
1RC4AI092801-01
Application #
8048844
Study Section
Special Emphasis Panel (ZRG1-IDM-L (55))
Program Officer
Joy, Deirdre A
Project Start
2010-09-30
Project End
2013-09-29
Budget Start
2010-09-30
Budget End
2013-09-29
Support Year
1
Fiscal Year
2010
Total Cost
$5,630,177
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
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
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
Rhee, David B; Croken, Matthew McKnight; Shieh, Kevin R et al. (2015) toxoMine: an integrated omics data warehouse for Toxoplasma gondii systems biology research. Database (Oxford) 2015:bav066
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
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
Bogado, Silvina S; Dalmasso, María C; Ganuza, Agustina et al. (2014) Canonical histone H2Ba and H2A.X dimerize in an opposite genomic localization to H2A.Z/H2B.Z dimers in Toxoplasma gondii. Mol Biochem Parasitol 197:36-42
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
Radke, Joshua B; Lucas, Olivier; De Silva, Erandi K et al. (2013) ApiAP2 transcription factor restricts development of the Toxoplasma tissue cyst. Proc Natl Acad Sci U S A 110:6871-6

Showing the most recent 10 out of 20 publications