Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
Life Sciences Mass Spectrometry, Department of Inorganic and Analytical Chemistry, University of Geneva, 24 Quai Ernest Ansermet, 1211 Geneva 4, Switzerland.
Cell Rep. 2022 Aug 16;40(7):111224. doi: 10.1016/j.celrep.2022.111224.
Toxoplasma gondii possesses sphingolipid synthesis capabilities and is equipped to salvage lipids from its host. The contribution of these two routes of lipid acquisition during parasite development is unclear. As part of a complete ceramide synthesis pathway, T. gondii expresses two serine palmitoyltransferases (TgSPT1 and TgSPT2) and a dihydroceramide desaturase. After deletion of these genes, we determine their role in parasite development in vitro and in vivo during acute and chronic infection. Detailed phenotyping through lipidomic approaches reveal a perturbed sphingolipidome in these mutants, characterized by a drastic reduction in ceramides and ceramide phosphoethanolamines but not sphingomyelins. Critically, parasites lacking TgSPT1 display decreased fitness, marked by reduced growth rates and a selective defect in rhoptry discharge in the form of secretory vesicles, causing an invasion defect. Disruption of de novo ceramide synthesis modestly affects acute infection in vivo but severely reduces cyst burden in the brain of chronically infected mice.
刚地弓形虫具有合成神经酰胺的能力，并能从宿主中获取脂质。在寄生虫发育过程中，这两种脂质获取途径的贡献尚不清楚。作为完整神经酰胺合成途径的一部分，刚地弓形虫表达两种丝氨酸棕榈酰转移酶（TgSPT1 和 TgSPT2）和一种二氢神经酰胺去饱和酶。在这些基因缺失后，我们确定了它们在体外和急性及慢性感染期间寄生虫发育中的作用。通过脂质组学方法进行详细的表型分析，揭示了这些突变体中神经酰胺代谢的紊乱，特征是神经酰胺和神经酰胺磷酸乙醇胺的急剧减少，但鞘磷脂不受影响。关键的是，缺乏 TgSPT1 的寄生虫表现出适应性降低，生长速度降低，以分泌囊泡形式的棒状体排出选择性缺陷，导致入侵缺陷。从头合成神经酰胺的破坏对体内急性感染的影响较小，但严重降低了慢性感染小鼠脑中囊泡的负担。
