Fatty acid synthesis in the apicomplexan parasite Toxoplasma gondii
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Apicomplexan parasites are obligate intracellular pathogens infecting humans and many animals. Members of this group are causative agents of severe diseases like malaria, cryptosporidiosis, toxoplasmosis and babesiosis. Similar to other intracellular pathogens, apicomplexan parasites rely on both synthetic and import mechanisms to obtain necessary nutrients for growth. Consequently, these metabolic pathways have been the focus of drug development studies. Components of the metabolism of fatty acids are validated drug targets against intracellular bacterial and viral pathogens. Likewise, this process has been considered as a suitable target against apicomplexan infections. However, fatty acid synthesis in apicomplexan parasites seems to be a very complex phenomenon due to presence of multiple mechanisms for lipid synthesis and acquisition. Understanding the details of these mechanisms is key to identifying the strongest drug target. Toxoplasma gondii is an apicomplexan parasite, which habors three mechanisms of fatty acid synthesis. The parasite harbors both prokaryotic type II (FASII) and eukaryotic type I (FASI) pathways of fatty acid synthesis. Additionally, the parasite appears to contain a fatty acid elongation machinery. In this research, we attempt to determine the role and significance of these pathways in T. gondii tachyzoites, the parasite life cycle stage responsible for acute toxoplasmosis. While the FASII pathway is essential for parasite growth, its precise contribution towards overall fatty acid synthesis has not been determined yet. Little is known about the function and significance of FASI and FAE pathways in T. gondii. Characterizing these pathways has been especially challenging due to expected similarity in their products and substrates. Here, we have developed a novel strategy by coupling genetics with metabolomics to individually dissect the precise role of each synthesis mechanism. We show that fatty acid synthesis is a crucial determinant for T. gondii infection. We also show that the parasite selectively uses these pathways to generate specific products that are necessary for continuous growth and thereby for establishing an acute infection.