Metabolomic Characterisation of Host-Parasite-Interactions of the Apicomplexans Toxoplasma gondii and Plasmodium falciparum

弓形虫和恶性疟原虫是人类重要的病原体。作为专性胞内寄生虫，它们完全依赖于宿主养分的吸收。然而，营养的可获得性如何影响它们的生理仍不清楚。弓形虫几乎感染任何温血动物，能量代谢非常灵活。在没有外源葡萄糖的情况下，它可以利用其他碳源通过糖异生来满足其对己糖的需求。然而，非己糖营养物质对弓形虫胞内的可用性和重要性在很大程度上还不清楚。相比之下，红细胞内疟原虫绝对依赖于葡萄糖摄取，但最近对临床分离株的转录研究表明，有条件地共同利用其他碳源。然而，缺乏提供自然营养环境的培养系统掩盖了疟原虫新陈代谢的功能。为了解决这些基本问题，我们提出了以下研究：1通过感染宿主细胞的代谢产物谱来鉴定弓形虫的碳源2测试糖异生在弓形虫中的意义3建立恶性疟原虫恒化器培养物通过代谢足迹和同位素标记来确定生理状态4鉴定葡萄糖在恶性疟原虫中的个体作用及其与替代营养物质的冗余我们将通过在已定义的营养环境中研究两种互补的apicomexan寄生虫的代谢结构和动力学来表征代谢宿主-寄生虫的相互作用。为此，我们将使用建立的气、液-质联用和核磁共振为基础的分析平台。了解寄生虫在生理情况下代谢的可塑性，是揭示关键的宿主-寄生虫相互作用和评估杀寄生虫药物的体内作用模式和耐药机制的迫切需要。

Toxoplasma gondii and Plasmodium falciparum are important human pathogens. As obligate intracellular parasites they depend entirely on the uptake of host nutrients. However, it remains unclear how the nutrient availability influences their physiology. T. gondii infects virtually any warm-blooded animal and has a very flexible energy metabolism. In the absence of exogenous glucose it can utilise other carbon sources to satisfy its need for hexoses via gluconeogenesis. However, the availability and significance of non-hexose nutrients for intracellular T. gondii is largely uncharacterised. In contrast, intraerythrocytic Plasmodium parasites absolutely depend on glucose uptake but recent transcriptomic studies on clinical isolates suggested a conditional co-utilisation of other carbon sources. However, a lack of culture systems that provide natural nutrient environments conceals the functional capabilities of the Plasmodiums metabolism. To address these fundamental questions we propose the following research:1 Identification of carbon sources for T. gondii by metabolite profiling of infected host cells2 Testing of the significance of gluconeogenesis in T. gondii3 Establishment of chemostat P. falciparum cultures to define physiological states via metabolic footprinting and isotopomer labelling4 Identification of individual roles of glucose and their redundancy with alternative nutrients in P. falciparumWe will characterise metabolic host-parasite interactions by investigating the metabolic structure and dynamics of two complementary apicomplexan parasites in context of defined nutrient environments. To this end we will use an established gas and liquid chromatography-mass spectrometry and NMR-based analytical platform. Understanding the plasticity of parasite metabolism in physiological scenarios is urgently required to reveal critical host-parasite interactions and to evaluate the in vivo mode of action and resistance mechanisms of parasitocidal drugs.