Dual metabolomic profiling uncovers Toxoplasma manipulation of the host metabolome and the discovery of a novel parasite metabolic capability

Abstract

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+.

Phosphoproteomic Comparison of Four Eimeria tenella Life Cycle Stages

“…In addition, the PPP can channel into glycolysis via its non-oxidative arm to make ATP and NADPH (mode 3) [23]. In T. gondii, both the oxidative and non-oxidative arms of the PPP are functional [24,25], and the key enzymes driving carbon from glycolysis to the non-oxidative arm have been identified [25]. In the P. falciparum life cycle, the PPP also functions through different modes [23].…”

“…In this study, we characterized five phosphoproteins involved in the PPP, all of which were up-regulated in sporozoites. For example, glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme of the oxidative arm of the PPP [25], while phosphoglucomutase and transaldolase are involved in non-oxidative reactions of the PPP [25]. Phosphoglucomutase converts five-carbon sugars or D-ribose-1-phosphate generated during the salvage of purines into R5P, which can be processed and utilized in glycolysis [23].…”

NOD-Like Receptors: Guards of Cellular Homeostasis Perturbation during Infection

“…Similarly, the Apicomplexa parasite Theileria induces aerobic glycolysis in bovine leukocytes [132,133] by stabilizing host pyruvate kinase isoform M2 (PKM2) [134]. To utilize host glucose as a carbon source, T. gondii also promotes glycolysis in murine dendritic cells [135] and in fibroblasts [136,137] by increasing the expression of enzymes involved in glycolysis [135][136][137]. T. cruzi enhances host glucose uptake to fuel its metabolism, yet without affecting glycolysis [138].…”

Comparisons of the Sexual Cycles for the Coccidian Parasites Eimeria and Toxoplasma

“…It is known that T. gondii tachyzoites usurp and modify host metabolism to fulfill their metabolic needs and replicate intracellularly ( Krishnan et al., 2020 ; Olson et al., 2020 ). It has been hypothesized that the massive replication during merogony has a higher energy demand than tachyzoite replication ( Behnke et al., 2014 ; Hehl et al., 2015 ).…”