Role of c-Myc up-regulation in Toxoplasma infection

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 DESCRIPTION (provided by applicant): Toxoplasma is a ubiquitous pathogen that infects and reproduces in virtually any nucleated cell of warm- blooded animals. This single-celled eukaryote is of great medical importance not least because infections in AIDS patients can lead to life-threatening illness. While use of anti-retroviral treatments (ART) has reduced the incidence of Toxoplasmic encephalitis (TE) in western countries with access to the therapy, it remains a significant AIDS-related opportunistic infection among people with late HIV diagnosis or without access to ART. Our results show that a key host regulator, c-Myc, is induced in human cells infected by Toxoplasma. Importantly, the increase of c-Myc is not a result of a nonspecific host immune response, as the closely related intracellular parasite, Neospora caninum, does not elicit this phenotype. Furthermore, a coinfection of cells with both Toxoplasma and Neospora results in an increase in host c-Myc showing that c-Myc is actively upregulated by Toxoplasma (rather than repressed by Neospora). Here, we propose a novel approach that employs genetic tools for Toxoplasma, developed in this and other labs, with cutting-edge technologies developed in the c-Myc field to examine the mechanism and role of c-Myc regulation during Toxoplasma infection. This study will test the hypothesis that the activation of c-Myc in Toxoplasma-infected host cells is mediated by specific Toxoplasma gene(s). Forward genetic screens have already yielded a candidate gene for this effect and mutants in this gene will be used to uncover the mechanism underlying c-Myc induction as well as the role of c-Myc induction in the context of Toxoplasma infection. The results of this study will reveal valuable information about Toxoplasma's interaction with its host and make possible future investigation aimed at interfering with c-Myc induction as a novel treatment for the infection.