Identifying novel players in Toxoplasma autophagy during chronic infection”

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The protozoan parasite Toxoplasma gondii renders nearly one third of the global human population at risk of experiencing disease due to reactivation of chronic infection. Current treatments fail to eliminate the slow replicating, persistent Toxoplasma bradyzoite cysts that seed reactivation and ensuing disease in the eyes, brain, heart or lungs. Individuals with ocular toxoplasmosis are particularly at risk of experiencing progressive loss of vision due to sequential periods of reactivation. Our long-term goal is to identify critical liabilities for disrupting Toxoplasma persistence, thereby precluding reactivated disease in at risk individuals. Toward this goal, we have recently demonstrated that the viability of bradyzoite cysts in culture and in infected mice relies on the parasite having a functional autophagy pathway. However, little is known about autophagy in Toxoplasma and exploiting parasite autophagy to impact infection requires identifying new and divergent components in the pathway. To meet this need, leveraging our recent genetic screen we will identify novel components of the autophagy pathway by developing for the first time in T. gondii a “prime editing” approach for pooled identification of phenotype driving single nucleotide variants, define the general roles of novel components in parasite autophagy, and measure their impact on acute and chronic infection. Completing the proposed studies is expected to identify at least 4 new and divergent components of T. gondii autophagy that can be prioritized for deeper analysis and open novel avenues of investigation in the next phase of this work.