RT Journal Article SR Electronic T1 Transcriptional repression by ApiAP2 factors is central to chronic toxoplasmosis JF bioRxiv FD Cold Spring Harbor Laboratory SP 100628 DO 10.1101/100628 A1 Joshua B. Radke A1 Danielle Worth A1 Dong-Pyo Hong A1 Sherri Huang A1 William J. Sullivan, Jr A1 Emma H. Wilson A1 Michael White YR 2017 UL http://biorxiv.org/content/early/2017/01/15/100628.abstract AB Bradyzoite differentiation is marked by major changes in gene expression resulting in a parasite that expresses a new repertoire of surface antigens hidden inside a modified parasitophorous vacuole called the tissue cyst. The factors that control this important life cycle transition are not well understood. Here we describe an important Toxoplasma repressor mechanism controlling bradyzoite differentiation that operates exclusively in the tachyzoite stage. The ApiAP2 factor, AP2IV-4, is a nuclear factor dynamically expressed in late S phase through mitosis/cytokinesis of the tachyzoite cell cycle and absent from the bradyzoite. Remarkably, deletion of the AP2IV-4 locus resulted in the increased expression of bradyzoite mRNAs in replicating tachyzoites and in two different genetic lineages, we confirmed the misexpression of tissue cyst wall components (e.g. BPK1, MCP4, CST1) and the bradyzoite surface antigen SRS9 in the tachyzoite stage. In the murine animal model, the loss of AP2IV-4 had profound biological consequences. Prugniaud strain parasites lacking AP2IV-4 were unable to form tissue cysts in brain tissue and the absence of this factor also recruited a potent immune response characterized by increases inflammatory monocytes, IFN-γ and higher numbers of both CD8+ and CD4+ T-cells. Altogether these results indicate that suppression of bradyzoite antigens by AP2IV-4 during acute infection is required for Toxoplasma to establish a chronic infection in the immune-competent host.Author Summary The Toxoplasma biology that underlies the establishment of a chronic infection is developmental conversion of the acute tachyzoite stage into the latent bradyzoite-tissue cyst stage. Despite the important clinical consequences of this developmental pathway, the molecular basis of the switch mechanisms that control formation of the tissue cyst is still poorly understood. Experimental evidence demonstrates tissue cyst formation is accompanied by significant changes in gene expression. Here we show the transcription factor AP2IV-4 directly silences bradyzoite mRNA and protein expression exclusively in the acute tachyzoite stage demonstrating that developmental control of tissue cyst formation is as much about when not to express bradyzoite genes as it is about when to activate them. The loss of control of bradyzoite gene expression in the acute tachyzoite stage caused by deleting AP2IV-4 blocked the establishment of chronic disease in healthy animals through the pre-arming of the immune system suggesting a possible strategy for preventing chronic Toxoplasma infections.