The obligate intracellular parasite Toxoplasma gondii is auxotrophic for several key metabolites and must scavenge these from the host. It is unclear how T. gondii manipulates host metabolism to support its overall growth rate and non-essential metabolites. To investigate this question, we measured changes in the joint host-parasite metabolome over a time course of infection. Host and parasite transcriptomes were simultaneously generated to determine potential changes in expression of metabolic enzymes. T. gondii infection changed metabolite abundance in multiple metabolic pathways, including the tricarboxylic acid cycle, the pentose phosphate pathway, glycolysis, amino acid synthesis, and nucleotide metabolism. Our analysis indicated that changes in some pathways, such as the tricarboxylic acid cycle, were mirrored by changes in parasite transcription, while changes in others, like the pentose phosphate pathway, were paired with changes in both the host and parasite transcriptomes. Further experiments led to the discovery of a T. gondii enzyme, sedoheptulose bisphosphatase, which funnels carbon from glycolysis into the pentose phosphate pathway through an energetically driven dephosphorylation reaction. This additional route for ribose synthesis appears to resolve the conflict between the T. gondii tricarboxylic acid cycle and pentose phosphate pathway, which are both NADP+ dependent. Sedoheptulose bisphosphatase represents a novel step in T. gondii central carbon metabolism that allows T. gondii to energetically-drive ribose synthesis without using NADP+.
The obligate intracellular parasite T. gondii is commonly found among human populations worldwide and poses severe health risks to fetuses and individuals with AIDS. While some treatments are available they are limited in scope. A possible target for new therapies is T. gondii’s incomplete metabolism, which makes it heavily reliant on its host. In this study, we generated a joint host/parasite metabolome to better understand host manipulation by the parasite and to discover unique aspects of T. gondii metabolism that could serve as the next generation of drug targets. Metabolomic analysis of T. gondii infection over time found broad alterations to host metabolism by the parasite in both energetic and biosynthetic pathways. We discovered a new T. gondii enzyme, sedoheptulose bisphosphatase, which redirects carbon from glycolysis into the pentose phosphate pathway. The wholesale remodeling of host metabolism for optimal parasite growth is also of interest, although the mechanisms behind this host manipulation must be further studied before therapeutic targets can be identified.