Conditional permeabilization of the P. falciparum plasma membrane in infected cells links cation influx to reduced membrane integrity.
Conditional permeabilization of the P. falciparum plasma membrane in infected cells links cation influx to reduced membrane integrity.
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受感染细胞中恶性疟原虫质膜的条件透化将阳离子流入与膜完整性降低联系起来。
DOI：
10.1371/journal.pone.0283776
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
细胞内的人疟疾寄生虫恶性疟原虫使用PfATP 4阳离子泵来维持寄生虫胞质溶胶中的Na+和H+稳态。PfATP 4是晚期抗疟药的靶点，其在受感染的红细胞内产生许多知之甚少的代谢紊乱。在这里，我们表达了哺乳动物配体门控TRPV 1离子通道在寄生虫质膜研究离子调节和检查阳离子泄漏的影响。TRPV 1表达耐受性良好，与通过非活化通道的离子通量可忽略不计一致。TRPV 1配体在其激活浓度下在转染株系中产生快速寄生虫死亡，但对野生型亲本无害。激活触发胆固醇再分布在寄生虫质膜，复制PfATP 4抑制剂的影响，并直接牵连在这个过程中的阳离子失调。与预测相反，TRPV 1在低Na+介质中的激活加重了寄生虫杀灭，但PfATP 4抑制剂的疗效不变。对配体抗性突变体的选择揭示了TRPV 1中先前未表征的G683 V突变，该突变阻断了下通道门，暗示通透性降低是寄生虫对抗疟药靶向离子稳态的抗性机制。我们的研究结果为疟疾寄生虫离子调节提供了关键的见解，并将指导作用于宿主-病原体界面的高级抗疟药物的作用机制研究。
The intracellular human malaria parasite, Plasmodium falciparum, uses the PfATP4 cation pump to maintain Na+ and H+ homeostasis in parasite cytosol. PfATP4 is the target of advanced antimalarial leads, which produce many poorly understood metabolic disturbances within infected erythrocytes. Here, we expressed the mammalian ligand-gated TRPV1 ion channel at the parasite plasma membrane to study ion regulation and examine the effects of cation leak. TRPV1 expression was well-tolerated, consistent with negligible ion flux through the nonactivated channel. TRPV1 ligands produced rapid parasite death in the transfectant line at their activating concentrations, but were harmless to the wild-type parent. Activation triggered cholesterol redistribution at the parasite plasma membrane, reproducing effects of PfATP4 inhibitors and directly implicating cation dysregulation in this process. In contrast to predictions, TRPV1 activation in low Na+ media accentuated parasite killing but a PfATP4 inhibitor had unchanged efficacy. Selection of a ligand-resistant mutant revealed a previously uncharacterized G683V mutation in TRPV1 that occludes the lower channel gate, implicating reduced permeability as a mechanism for parasite resistance to antimalarials targeting ion homeostasis. Our findings provide key insights into malaria parasite ion regulation and will guide mechanism-of-action studies for advanced antimalarial leads that act at the host-pathogen interface.
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影响因子：
16.2
作者：
Cao E;Cordero-Morales JF;Liu B;Qin F;Julius D
通讯作者：
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影响因子：
3.4
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DOI：
10.1073/pnas.1414221111
发表时间：
2014-12-16
影响因子：
11.1
作者：
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通讯作者：
Guy, R. Kiplin
DOI：
10.1073/pnas.0504679102
发表时间：
2005-11-08
影响因子：
11.1
作者：
Balu, B;Shoue, DA;Adams, JH
通讯作者：
Adams, JH