Toxoplasma gondii Reprogram Metabolism of the Host During Infection
Authors: Gendlina Inessa , Kim Kami 
Published: November 2023

Toxoplasma gondii is an obligate intracellular eukaryotic parasite able to infect mammals including humans. After initial infection, people can remain latently infected for many years, however, parasite reactivation in people who have AIDS or are otherwise immunocompromised, and during pregnancy, has dramatic deleterious consequences. Both host and parasite factors are responsible for disease progression, and in recent years it has become evident that the host‐parasite interplay is complex with significant amount of crosstalk. As an obligate intracellular parasite that is dependent on the host for biomaterials, T. gondii has to acquire nutrients yet protect itself from the host response. In order to successfully survive and replicate within its host, parasites must subvert host machinery to their benefit, simultaneously avoiding host defenses and early host demise.

Recent studies have demonstrated that T. gondii infection induces significant changes to the host transcriptome, and some of these changes occur in genes involved in the nutrient pathways of glucose and lipid metabolism. Furthermore, it has been shown that one of the main pathways altered during parasite infection includes Hypoxia‐inducible Factor (HIF) ‐ a central regulator of host metabolism also targeted during other parasitic infection, suggesting that parasites intentionally subvert host metabolism. Metabolic landscape restructuring has been shown to occur and be essential in a wide range of processes including immune cell activation and in cancer. Oncogenic transformation causes cellular metabolic shift away from oxidative phosphorylation toward glycolysis under aerobic conditions – known as the “Warburg effect”. Recent studies revealed that metabolic shifts also occur during infection by some pathogens including viruses, bacteria and other parasites (Mycobacteria, Theileria and Leishmania). To date, the exact changes that take place in the host metabolism during infection with T. gondii have not been described.

Objective

characterize metabolic shifts in the host cell during infection with T. gondii parasites.

Methods

Seahorse extracellular flux analysis allows sensitive evaluation of cell's metabolism including both glycolytic and oxidative phosphorylation components. We utilize Seahorse flux analyzer to study glycolysis and mitochondrial respiration in fibroblast cells infected with T. gondii parasites.

Results

Modulation of HIF, together with computational analyses, suggest that T. gondii parasites induce metabolic dysregulation in the host cell. Our results demonstrate that similar to other pathogens, infection with T. gondii induces metabolic alteration in infected cells. However, unlike classical Warburg effect of cancer cells, T. gondii do not cause a shift away from mitochondrial metabolism but instead lead to increase in both glycolysis and mitochondrial respiration.

Conclusions

We have developed framework utilizing Seahorse bioanalyzer to study metabolic states of cells during parasite infection, and have demonstrated that metabolic alterations during infection with T. gondii parasites are distinct from changes observed in cancer and immune cell activation. Further studies will focus on elucidating mechanism of this metabolic interplay between the parasite and its host.

Support or Funding Information

2T32AI070117‐06A1 Geographic Medicine and Emerging Infections