Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht Str. 74, 20359 Hamburg, Germany.
UMR7042 Université de Strasbourg‒CNRS‒UHA, Laboratoire d'Innovation Moléculaire et Applications (LIMA), Team Bio(IN)organic and Medicinal Chemistry, European School of Chemistry, Polymers and Materials (ECPM), 25 Rue Becquerel, F-67087 Strasbourg, France.
Cell Host Microbe. 2021 Dec 8;29(12):1774-1787.e9. doi: 10.1016/j.chom.2021.11.002. Epub 2021 Dec 3.
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 (ART) parasites and provide evidence that NPC upregulation to increase amino acids acquisition is a mechanism of ART 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 ART parasites.
疟原虫在滋养液泡膜（PVM）的包裹下进行裂体增殖。PVM 含有营养可通透的通道（NPCs），有利于小分子物质通过，但 NPCs 对单个代谢物是否与寄生虫生长相关在很大程度上尚未得到验证。本研究表明，重要的碳源和能源物质以与生长相关的水平通过 NPCs。此外，我们发现 NPCs 是几种抗疟药物的作用靶点，这突出了它们的通透性是药物设计的关键因素。在研究 NPC 依赖性氨基酸转运时，我们发现氨基酸缺乏是青蒿素耐药（ART）寄生虫出现适应性代价的原因，并提供证据表明 NPC 的上调以增加氨基酸的摄取是 ART 寄生虫在体外和人体感染中补偿这种适应性代价的一种机制。因此，NPCs 对于营养物质和药物的进入很重要，并揭示了氨基酸缺乏是 ART 寄生虫的一个关键限制因素。
