Toxoplasma gondii infections continue to be a public health hazard for millions of individuals that contact this pathogen annually. More than 50 million individuals in the US are chronically infected with Toxoplasma gondii and thousands of healthy individuals develop eye disease due to this infection that can lead to permanent vision loss. The Centers for Disease Control and Prevention considers Toxoplasma one of the five most important neglected parasitic infections. Individuals can be reasonably treated (despite significant side effects) if clinical toxoplasmosis is presented, however, there is a lack of drugs to treat or prevent the tissue cyst that is responsible for long-term infections. This therapy failure leaves at-risk individuals who become infected vulnerable to disease relapse throughout their lifetimes. Understanding the developmental mechanisms responsible for tissue cyst formation are needed to develop therapies to combat life-long disease. The Toxoplasma biology that underlies chronic disease is a reversible transformation of the asexual replicating tachyzoite into the latent bradyzoite stage. This critical developmental transition is accompanied by significant changes in gene expression controlled by poorly defined transcriptional mechanisms. Recent experiments of our group have identified key cell cycle regulated and stress-induced Toxoplasma ApiAP2 factors that prevent or activate bradyzoite gene expression. We hypothesize these discoveries reveal a transcriptional network that directs the competing needs of tachyzoite growth against development of the dormant tissue cyst required for parasite transmission. To understand how this transcriptional network operates, we propose two specific aims:
In Aim 1, the experimental focus will be ApiAP2 transcriptional repressors that are expressed in the second half of the tachyzoite cell cycle whose mechanisms we will define at the molecular level and characterize in cell culture and animal models of parasite development.
In Aim 2, we will determine how the stress-induced ApiAP2 repressors and activators compete to control bradyzoite gene expression and determine how these mechanisms influence Toxoplasma development in the intermediate host.

Public Health Relevance

Toxoplasma gondii infections continue to be a public health hazard for millions of individuals that contact this pathogen annually. Chronic infections with this pathogen are prevalent in the US populations and elsewhere in the world (1 in 2 chance if infection by age 50), yet Toxoplasma remains a neglected protozoan pathogen in public health investments. Life-long Toxoplasma infections are due to the development of the tissue cyst, which is effectively invisible to the immune system and currently untreatable. Studies of the mechanisms that control bradyzoite-cyst formation are critically needed if new approaches to combat toxoplasmosis are to be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI124682-04
Application #
9980272
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcgugan, Glen C
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of South Florida
Department
Type
University-Wide
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33617
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Radke, Joshua B; Worth, Danielle; Hong, David et al. (2018) Transcriptional repression by ApiAP2 factors is central to chronic toxoplasmosis. PLoS Pathog 14:e1007035
Hong, Dong-Pyo; Radke, Joshua B; White, Michael W (2017) Opposing Transcriptional Mechanisms Regulate Toxoplasma Development. mSphere 2:
Huang, Sherri; Holmes, Michael J; Radke, Joshua B et al. (2017) Toxoplasma gondii AP2IX-4 Regulates Gene Expression during Bradyzoite Development. mSphere 2: