Metabolic Networks governing Toxoplasma gondii Persistence and Transmission

Toxoplasma gondii is a successful obligate intracellular parasite, with the remarkable ability to infect virtually all warm-blooded animals. It is transmitted to humans through consumption of undercooked meat containing tissue cysts, ingestion of oocysts shed in the feces of infected cats or congenitally in case of a primary infection during pregnancy. This parasite establishes a lifelong chronic infection that reactivates in situations of immunosuppression and can lead to fatal toxoplasmosis. Development of T. gondii stages that can be transmitted to a new host, i.e. Sporozoites and Bradyzoites, entails differentiation and adaptation to very distinctive host niches. These developmental programs are characterized by a distinct physical separation of the parasite from the host environment and a predilection for specific tissues or cell types. The infectious forms of T. gondii: Tachyzoites (Acute infection), Bradyzoites and Sporozoites (Chronic infection) face fundamentally distinct challenges to survive and adapt to various environments, nutrient accessibilities and immune pressures. It is thought that, considerable remodeling and adaptation of the parasite metabolic pathways occurring during the preparatory phase as well as the final execution of the differentiation programs, is required for parasitic persistence and transmission. The objective of this project is therefore, to construct stage-specific metabolic models of Toxoplasma gondii, for a better understanding of the versatility ensuring the parasites’ survival and successful transmission. An interdisciplinary approach, beginning with the collection of biological samples, used to generate stage–specific transcriptomes and metabolomes, to then fuel into a recently built global metabolic model, will be applied. Transcriptomic data will be obtained from genome-wide RNA-Seq analyses, followed by stage-specific metabolomics profiling, and finally generating metabolic readouts for transgenic parasites mutated in selective metabolic pathways, such as gluconeogenesis and beta-oxidation, for integration into the model. Overall, the goal of the constructing refined stage-specific metabolic networks for Toxoplasma will be instrumental in investigating central questions regarding stage conversion and parasite differentiation and to identify bottlenecks as candidates for developing intervention strategies.