Synthesis versus Salvage of Ester- and Ether-linked Phosphatidylethanolamine in the Intracellular Protozoan Pathogen Toxoplasma gondii

Abstract Toxoplasma gondii is a prevalent zoonotic pathogen infecting livestock as well as humans. The exceptional ability of this parasite to reproduce in several types of nucleated host cells necessitates a coordinated usage of endogenous and host-derived nutritional resources for membrane biogenesis. Phosphatidylethanolamine is the second abundant phospholipid in T. gondii, but how its requirement in the acutely-infectious and fast-dividing tachyzoite stage is satisfied remains enigmatic. This work reveals that the parasite deploys de novo synthesis and salvage pathways to pacify its demand for ester- and ether-linked PtdEtn, respectively. Auxin-mediated depletion of the phosphoethanolamine cytidylyltransferase (ECT) caused a lethal phenotype in tachyzoites due to impaired invasion and cell division, disclosing a vital role of the CDP-ethanolamine pathway during the lytic cycle. In accord, the inner membrane complex and mitochondrion were disrupted concurrent with a decline in major phospholipids. Not least, integrated lipidomics and stable isotope analyses of the TgECT mutant unveiled the endogenous synthesis of ester-PtdEtn, and salvage of ether-linked lipids from host cells. In brief, this study demonstrates how T. gondii operates various means to produce distinct forms of PtdEtn while featuring the therapeutic relevance of its de novo synthesis.