Metabolic basis for the persistence of dormant Toxoplasma gondii infection

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Dormant Toxoplasma gondii [Toxoplasma] infection is characterized by dormant bradyzoite stage parasites that reside within thick-walled cysts that develop inside neurons in the central nervous system. Cysts provide a structural and physiological habitat that sustains the viability of dormant bradyzoite stage parasites. While many targets and therapeutics have been identified to effectively treat the active Toxoplasma infection that is defined by rapidly replicating tachyzoite stage parasites, therapeutic strategies or drugs that eliminate dormant bradyzoites and their cysts have not been identified. The identification of potential targets to perturb or eliminate dormancy has proven challenging for many microbes, including Toxoplasma, because microbial dormancy is characterized by a reduced metabolic state that sustains viability but not replication. Several lines of evidence support the hypothesis that dormant bradyzoites have markedly reduced mitochondrial functions and rely more heavily on acquiring host glucose not just for energy production but also to meet an increased demand for glucose to build bradyzoite-stage amylopectin and cyst wall glycan biomass. Consistent with this hypothesis, our data has shown that blocking the utilization of host glucose markedly reduced the development as well as the persistence of dormant stage bradyzoites. Here, we propose to define the metabolic basis that underpins the ability of glucose starvation to prevent the development and persistence of dormant bradyzoites. Targeting mitochondrial functions such as the electron transport chain has been shown to have a partial ability to perturb but not to eliminate dormancy. We hypothesize that targeting glucose or glucose + lactate utilization in combination with inhibition of mitochondrial function will accelerate the demise of dormant bradyzoites and their cysts. The work in this proposal charts a way forward to identify a metabolic basis to eliminate Toxoplasma dormancy.