Increased Ca(++) uptake by erythrocytes infected with malaria parasites: Evidence for exported proteins and novel inhibitors.
Increased Ca(++) uptake by erythrocytes infected with malaria parasites: Evidence for exported proteins and novel inhibitors.
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DOI：
10.1111/cmi.12853
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发表时间：
2018-09
影响因子：
3.4
通讯作者：
Desai SA
中科院分区：
文献类型：
--
作者：
Kushwaha AK;Apolis L;Ito D;Desai SA
疟疾寄生虫将许多蛋白质输出到其宿主红细胞中，并增加膜对各种溶质的渗透性。虽然大多数溶质使用广泛的选择性通道，称为疟原虫表面阴离子通道（PSAC），增加Ca++的摄取是由一个独特的，表征不佳的机制，似乎是必不可少的细胞内寄生虫介导。在这里，我们研究了感染细胞的Ca++摄取与动力学荧光测定和致命的人类病原体，恶性疟原虫。用N-羟基磺基琥珀酰亚胺酯的细胞表面标记揭示了对运输到感染和未感染细胞的不同影响，表明在感染细胞表面的Ca++摄取是由宿主膜上新的或改变的蛋白质介导的。PTEX是一种将寄生虫蛋白质输出到宿主细胞中的易位子，条件性敲低PTEX显著降低了感染细胞的Ca++渗透性，表明寄生虫编码的蛋白质被贩运到宿主细胞膜。高通量化学筛选确定了第一个对疟原虫感染细胞有活性的Ca++转运抑制剂。这些新的化学支架抑制摄取和寄生虫生长;在降低的游离[Ca++]下提高的体外效力与通过对一种或多种Ca++转运蛋白的作用特异性杀死寄生虫一致。这些抑制剂应提供机制的见解疟疾寄生虫Ca++运输，并可能成为新的抗疟药物的起点。
Malaria parasites export many proteins into their host erythrocytes and increase membrane permeability to diverse solutes. While most solutes use a broad-selectivity channel known as the plasmodial surface anion channel (PSAC), increased Ca++ uptake is mediated by a distinct, poorly characterized mechanism that appears to be essential for the intracellular parasite. Here, we examined infected cell Ca++ uptake with a kinetic fluorescence assay and the virulent human pathogen, P. falciparum. Cell surface labeling with N-hydroxysulfosuccinimide esters revealed differing effects on transport into infected and uninfected cells, indicating that Ca++ uptake at the infected cell surface is mediated by new or altered proteins at the host membrane. Conditional knockdown of PTEX, a translocon for export of parasite proteins into the host cell, significantly reduced infected cell Ca++ permeability, suggesting involvement of parasite-encoded proteins trafficked to the host membrane. A high-throughput chemical screen identified the first Ca++ transport inhibitors active against Plasmodium-infected cells. These novel chemical scaffolds inhibit both uptake and parasite growth; improved in vitro potency at reduced free [Ca++] is consistent with parasite-killing specifically via action on one or more Ca++ transporters. These inhibitors should provide mechanistic insights into malaria parasite Ca++ transport and may be starting points for new antimalarial drugs.
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