Developmental switches regulating tissue cyst formation

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Project Summary 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.