Apicomplexan parasites are important pathogens of humans that cause diseases with widespread impacts on global health. The life cycles of these obligate intracellular parasites are complex, involving multiple proliferative and non-growing stages that ensure successful parasite transmission. Pathogenesis, virulence, and disease severity are critically influenced by asexual stage growth rates that can lead to increased parasite biomass and significant tissue destruction and inflammation. Consequently, mechanisms controlling parasite growth rate are important to virulence. Building new daughter parasites requires tight control over the delivery of protein products, and in Plasmodium and Toxoplasma a cascade of >2800 mRNAs serially unfolds during each division cycle. Transcription in apicomplexa pathogens is poorly understood, however, the recent discovery of plant-like transcription factors in the Apicomplexa has uncovered an important set of factors that may control cell cycle transcription in these parasites. Nearly a third of all Toxoplasma AP2 genes are periodically expressed during tachyzoite replication with a timing distributed across the division cycle. We hypothesize that these factors are responsible for the "just-in-time" delivery of gene products required to build new parasites. Through their binding to specific promoter DNA sequence, TgAP2 factors regulate cell cycle transcription, and thereby influence the efficiency and fidelity of Toxoplasma replication. In this proposal, we will characterize the role of TgAP2 factors in the parasite cell cycle by determining the precise order of expression for key cell cycle TgAP2 proteins, by discovering the promoters they regulate through whole-genome protein binding studies, and by validating the in vivo function of these proteins in parasite replication through the generation of loss and mis- expression mutants. These studies will provide fundamental knowledge of a new set of mechanisms required to produce parasite replication that is relevant to acute disease caused by the growth of Toxoplasma in the immunocompromised human host.
Recent genetic analysis of parasite virulence confirms that there is an important link between increased parasite burden and disease caused by Toxoplasma gondii. The factors that control parasite replication are not understood, but it is clear that the factors regulating progression through the parasite cell cycle are critical to parasite burden in the host. In this proposal, we will investigate the genetic program responsible for the delivery of proteins at the right time and in the correct amount to produce viable progeny. The factors orchestrating this complex process are not found in the human host, and thus, new potential drug targets will be identified upon which novel therapies may be developed.
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