The parasitophorous vacuole nutrient channel is critical for drug access in malaria parasites and modulates the artemisinin resistance fitness cost
The parasitophorous vacuole nutrient channel is critical for drug access in malaria parasites and modulates the artemisinin resistance fitness cost
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DOI：
10.1016/j.chom.2021.11.002
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发表时间：
2021-12-08
影响因子：
30.3
通讯作者：
Spielmann, Tobias
中科院分区：
文献类型：
--
作者：
Mesen-Ramirez, Paolo;Bergmann, Baerbel;Spielmann, Tobias
红细胞内疟原虫以寄生液泡膜（PVM）为界增殖。PVM含有传导小分子的营养可渗透通道（npc），但它们与寄生虫生长中单个代谢物的相关性在很大程度上未经测试。这里我们表明，主要碳和能源的增长相关水平是通过npc实现的。此外，我们发现npc是几种抗疟疾药物的大门，突出了它们的渗透性作为药物设计的关键因素。研究人员发现，氨基酸缺乏是导致抗青蒿素（artemisinin resistant， ARTR）寄生虫适应成本的一个原因，并提供证据表明，在体外和人类感染中，NPC上调以增加氨基酸获取是arr寄生虫补偿这种适应成本的机制。因此，NPCs对于营养和药物的获取是重要的，并揭示了氨基酸剥夺是arr寄生虫的一个关键限制。
Intraerythrocytic malaria parasites proliferate bounded by a parasitophorous vacuolar membrane (PVM). The PVM contains nutrient permeable channels (NPCs) conductive to small molecules, but their relevance for parasite growth for individual metabolites is largely untested. Here we show that growth-relevant levels of major carbon and energy sources pass through the NPCs. Moreover, we find that NPCs are a gate for several antimalarial drugs, highlighting their permeability properties as a critical factor for drug design. Looking into NPC-dependent amino acid transport, we find that amino acid shortage is a reason for the fitness cost in artemisinin-resistant (ARTR) parasites and provide evidence that NPC upregulation to increase amino acids acquisition is a mechanism of ARTR parasites in vitro and in human infections to compensate this fitness cost. Hence, the NPCs are important for nutrient and drug access and reveal amino acid deprivation as a critical constraint in ARTR parasites.