抑制疟原虫裂殖子 V 活性可阻断疟原虫配子体形成和向蚊子传播。
Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes.
机构信息
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia.
Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan 4111, QLD, Australia.
出版信息
Cell Rep. 2019 Dec 17;29(12):3796-3806.e4. doi: 10.1016/j.celrep.2019.11.073.
Plasmodium falciparum gametocytes infect mosquitoes and are responsible for malaria transmission. New interventions that block transmission could accelerate malaria elimination. Gametocytes develop within erythrocytes and activate protein export pathways that remodel the host cell. Plasmepsin V (PMV) is an aspartyl protease that is required for protein export in asexual parasites, but its function and essentiality in gametocytes has not been definitively proven, nor has PMV been assessed as a transmission-blocking drug target. Here, we show that PMV is expressed and can be inhibited specifically in P. falciparum stage I-II gametocytes. PMV inhibitors block processing and export of gametocyte effector proteins and inhibit development of stage II-V gametocytes. Gametocytogenesis in the presence of sublethal inhibitor concentrations results in stage V gametocytes that fail to infect mosquitoes. Therefore, PMV primes gametocyte effectors for export, which is essential for the development and fitness of gametocytes for transmission to mosquitoes.
疟原虫配子体感染蚊子，是疟疾传播的罪魁祸首。新的阻断传播的干预措施可以加速疟疾的消除。配子体在红细胞内发育，并激活蛋白输出途径，重塑宿主细胞。裂殖体蛋白酶 V（PMV）是一种天冬氨酸蛋白酶，在无性寄生虫的蛋白输出中是必需的，但它在配子体中的功能和必要性尚未得到明确证实，也没有将 PMV 评估为一种阻断传播的药物靶点。在这里，我们表明 PMV 在疟原虫 I-II 期配子体中表达并可以被特异性抑制。PMV 抑制剂阻断配子体效应蛋白的加工和输出，并抑制 II-V 期配子体的发育。在亚致死浓度的抑制剂存在下的配子体发生导致无法感染蚊子的 V 期配子体。因此，PMV 为配子体效应蛋白的输出做好准备，这对于配子体的发育和对蚊子传播的适应性是必不可少的。
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