Toxoplasma gondii, a parasite that causes fatal brain infections in people with weakened immune systems and birth defects in over 200,000 newborns each year, relies on stealing sulfur-containing nutrients from its host cells to survive—yet no one has studied how it does this. This matters because existing drugs for toxoplasmosis have severe side effects, fail to clear the parasite’s chronic stages, and are facing growing resistance. The parasite’s transporters—proteins that pull nutrients across its membrane—are often completely different from human transporters, making them promising drug targets. But for sulfur metabolites, which are essential for everything from DNA repair to protein production, the transporters have never been identified. If this research succeeds, it will reveal exactly how Toxoplasma scavenges sulfur compounds and how it uses them during infection. That knowledge could uncover new drug targets that block the parasite’s nutrient supply without harming human cells. Because many related parasites, including those causing malaria and cryptosporidiosis, likely use similar systems, the findings may apply broadly across apicomplexan infections.
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Apicomplexans are a group of obligate intracellular parasites that place an enormous burden on human and animal health, causing diseases of global importance such as malaria, toxoplasmosis and cryptosporidiosis. Malaria is caused by Plasmodium spp and results in >600,000 deaths annually. Toxoplasma gondii, the causative agent of toxoplasmosis, causes fatal encephalitis in those with weakened immune systems and causes congenital toxoplasmosis, resulting in serious birth defects and stillbirth, with >200,000 cases recorded annually. Frontline drugs have many drawbacks including severe side effects, evolution of resistance and incomplete clearance of chronic stages of the parasite, particularly in the case of Toxoplasma. New drugs and therapeutic interventions are urgently required. Many existing drugs target metabolic pathways in the parasite that are absent, or at least highly divergent, in the host. Therefore, understanding parasite metabolism, and the key areas it diverges from the host, is important for developing new and effective therapeutic strategies. Intracellular parasites must fulfil their metabolic needs by stealing nutrients from the host environment. A key nutrient class are sulfur-containing metabolites, which includes many vitamins, cofactors, amino acids and glutathione. Sulfur containing metabolites are essential for cell function, playing central roles in crucial life processes such as redox control, respiration, DNA metabolism, and protein translation. Acquiring sulfur metabolites from this host is essential for the parasite to perform all of the biochemical processes it needs to replicate and cause infection. Nutrients are taken up by the parasite by specialised transporter proteins. Transporters present in the host are often absent in the parasite, as they have evolved novel parasite-specific transporters. Transporters are particularly abundant hits in drug screens, and numerous medications target transporters, making parasite transporters of essential metabolites a potentially rich set of targets. Identifying and understanding how parasitic transporters work is therefore important, although to date few have been characterised in detail. Despite its importance for parasite survival how Toxoplasma acquires sulfur-compounds from the host cell environment has not been explored. Using Toxoplasma gondii as a tractable apicomplexan model, I will address two fundamental questions about parasite sulfur metabolism: how the parasite acquires sulfur nutrients from the host environment and how these resources are integrated and used during infection. To achieve this, I will identify parasitic transporters of sulfur metabolites through proteomic approaches and understand how they work through a series of cutting-edge biochemical and structural investigations. Then, using a diverse array of molecular parasitology and metabolomics approaches, including making mutants of key transporters, I will study how these transporters are used by the parasites and their importance for parasite fitness. I will then study key enzymes required for integrating sulfur into parasite metabolism, through the sulfur assimilation pathway. The biosynthesis of key sulfur metabolites, cysteine and glutathione, will be explored, with particular focus on their importance in the understudied chronic life-stage of the parasite. Together, this work will reveal how Toxoplasma obtains a key unstudied class of nutrients and advance our understanding of a major knowledge gap in parasite metabolism. The findings will uncover novel underlying biology of an important human pathogen, likely applicable to other apicomplexan parasites and infection models. The more we learn about how parasites scavenge and metabolise key nutrients, the better we are able to develop new and effective therapeutic strategies; therefore this work and has the potential to uncover attractive therapeutic drug targets.
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