Mechanisms of RNA regulation in the persistence of the AIDS pathogen Toxoplasma

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 DESCRIPTION (provided by applicant): Toxoplasma gondii can cause fatal infections in persons who are immunocompromised by AIDS. Patients with AIDS are especially vulnerable because there is no effective therapy against an established chronic infection of T. gondii. The paucity of effective therapeutics against T. gondii chronic infection in AIDS patients stems largely from the fact that few in vivo cyst drug targets have been identified. Our primary goal in studying T. gondii is to understand the molecular basis by which it causes disease to identify proteins that can be targeted to prevent T. gondii cyst development and/or maintenance. Using next generation sequencing methods, we have identified novel mechanisms of post-transcriptional RNA regulation during T. gondii chronic infection. We have seen that two of the 37 T. gondii CCCH zinc finger genes are more than 100- fold upregulated from acute to chronic infection. CCCH zinc finger proteins bind to and regulate mRNA abundance, and have been shown to control stage-specific development in the protozoan parasite Trypanosoma brucei. For this proposal, we will perform a mechanistic analysis of these two chronic infection-specific CCCH zinc finger proteins during chronic infection establishment and/or maintenance. In the first aim, we will determine the intracellular localization of these proteins as well as their RNA, DNA and protein-binding partners. In the second aim, we will use RNA-seq to define the potential mRNAs that these CCCH zinc finger proteins regulate. Successful completion of our synergistic yet independent aims will produce both potential mechanisms and new candidate target mRNAs for these zinc finger proteins. We are optimistic that these studies will provide new drug targets for pharmaceutical intervention against chronic T. gondii infections in AIDS patients.