Elucidating the metabolic and lipidic adaptation of Toxoplasma gondii towards its human host nutritional environment – ApicoLipidAdapt

Apicomplexa parasites are intracellular pathogens responsible for major human diseases such as malaria and toxoplasmosis. The absence of efficient vaccine, resistance and toxicity to existing treatments, all argue for the identification of new drug targets. Renewal of the therapeutic arsenal against Apicomplexa depends on deciphering the metabolic pathways that sustain parasite survival within the host and its physiological environment. Throughout their life cycle, Apicomplexa require large amount of nutrients, especially lipids for propagation and survival. The researchers have recently uncovered that apicomplexan parasites and more particularly Toxoplasma parasites are capable of sensing and adapting to the fluctuating nutritional conditions provided by the human host. However, how the parasites orchestrate metabolic adaptation upon environmental changes in its host is currently unknown. To answer this institute performed genome-wide CRISPR genetic screens in Toxoplasma gondii under changing host nutritional conditions, and identified the putative key players in these mechanisms: The past work have identified a central transcriptional regulator and key lipid effectors candidates, putatively fulfilling these essential functions. T. gondii is a parasite that alternates between a fast replicating form, responsible for the acute phase of the disease it causes in humans (called toxoplasmosis), and a persistent and slow-growing form responsible for a chronic phase. Not only nutrient availability may be one of the external stimuli that govern stage conversion for the parasite, but because of their potentially very different metabolic needs, these developmental forms may respond differently to nutrient shortage. This project will thus study the function of the abovementioned protein candidates both in the context of acute and chronic toxoplasmosis. This project has the strong potential to unravel key metabolic adaptative mechanisms from the parasite and for its survival within the human hostnthat may later be exploited for potential therapeutic approaches.

Project details

Basic Science

Oct 2021 — Oct 2025

$529,920

France