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. The complex life cycle of T. gondii takes place in a wide range of vertebral intermediate hosts, including humans, and undergoes a sexual phase of development to generate infectious oocysts only in the intestine of a definitive felid host. Significant stage-differentiation events occur during this protozoans’ life cycle, as it faces fundamentally distinct challenges to survive and adapt to the various host environments, accessibility to nutrients and immune pressures. It has therefore been hypothesized that considerable remodeling and adaptation of the parasitic metabolic pathways occurs during stage-differentiation, and is required for parasitic persistence and transmission. The objective of this project is to construct stage-specific metabolic models of T. gondii for a better understanding of the versatility that ensures the parasites’ survival and successful transmission. An interdisciplinary approach, beginning with the generation of stage-specific transcriptomes and metabolomes, to then fuel into the global metabolic model will be applied. To examine the importance of selective metabolic pathways such as gluconeogenesis and beta-oxidation, in the context of differentiation and adaptation, readouts from transgenic parasites will be obtained and integrated into the model. Overall, the goal of constructing refined, stage-specific metabolic networks for T. gondii will be instrumental in investigating central questions regarding stage conversion and parasite differentiation, and also in identifying potential targets for developing intervention strategies against Toxoplasma and possibly other coccidia.
Keywords: Toxoplasma gondii, stage-specific metabolic networks, constraint-based modeling, central carbon metabolism, gluconeogenesis, beta-oxidation, transgenic parasites, metabolic profilingback