Abstract
Toxoplasma gondii is a member of the phylum of Apicomplexa that includes many parasites responsible for zoonoses. T. gondii is an obligate intracellular parasite with a complex cycle involving various hosts. It harbors two organelles of endosymbiotic origin: the mitochondrion and the apicoplast (originated from secondary endosymbiosis). Both contain metabolic pathways important to the parasites. Among the pathways present in the apicoplast are the FASII fatty acid pathway and the isoprenoid biosynthesis pathway. The proper functioning of these pathways as well as many other cellular functions, such as the mitochondrial respiratory chain, require the use of proteins containing Iron-Sulfur (Fe-S) centers. The biosynthesis pathways for generating Fe-S proteins is largely understudied in Apicomplexa, although some investigations have shown some are essential in the malaria-causing parasite Plasmodium.Within the other branches of the tree of life, different Fe-S biosynthetic pathways have been described: the ISC mitochondrial pathway, the CIA cytoplasmic pathway, the SUF plastidic pathway. As T. gondii contains two organelles of endosymbiotic origin (the mitochondrion and the apicoplast), it has these three biosynthetic pathways. During my PhD project, I focused on components of the ISC and SUF pathways and sought to evaluate how they contribute to parasite fitness.I have discovered that impacting the expression of the SufS cysteine desulfurase leads to a defect in the lytic cycle of T. gondii, which is likely linked to a defect in apicoplast-related function. We observed defects in the synthesis of apicoplast-derived fatty acids, which could be linked to a loss of function of the LipA Fe-S protein (which is important for the synthesis of acetyl-CoA, a precursor of the FASII pathway). Impairing the SUF pathway leads to abnormal formation of daughter cells during parasite replication, followed by delayed but irreversible death of the parasites. It thus appears that the SUF pathway is necessary for the survival of T. gondii.On the other hand, impacting the mitochondrial ISC pathway by targeting the IscU scaffold protein, induces stress and metabolic changes (to adapt to the demise of Fe-S-dependent electron transport chain) that did not kill the parasites, but instead allowed its differentiation into an encysted resistance form.Therefore, our characterization in T. gondii of the plastidic and mitochondrial Fe-S cluster synthesis pathways has shown that their function has been conserved during evolution, and that they contribute differently, yet importantly, to the fitness of the parasite. These pathways should then be investigated further to look for new potential therapeutic drug targets.