Dramatic Consequences of Reducing Erythrocyte Membrane Cholesterol on Plasmodium falciparum.
Dramatic Consequences of Reducing Erythrocyte Membrane Cholesterol on Plasmodium falciparum.
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DOI：
10.1128/spectrum.00158-22
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发表时间：
2022-02-23
影响因子：
3.7
通讯作者：
Vaidya AB
中科院分区：
文献类型：
--
作者：
Ahiya AI;Bhatnagar S;Morrisey JM;Beck JR;Vaidya AB
胆固醇是红细胞中含量最多的脂质。在其血液阶段的发展，疟疾寄生虫建立了一个积极的胆固醇梯度，在感染的红细胞内的各种膜系统。有趣的是，一些抗疟化合物最近已被证明破坏胆固醇稳态在红细胞内阶段的恶性疟原虫。这些研究指出了胆固醇对寄生虫生长的重要性。以前，通过甲基-β-环糊精（MβCD）处理减少红细胞膜上的胆固醇被证明可以抑制寄生虫的侵袭和生长。此外，MβCD处理滋养体阶段恶性疟原虫显示可导致寄生虫从宿主细胞中排出。我们通过使用实时视频显微镜，超微结构分析和抗疟化合物的反应重新审视了这些现象。通过使用荧光标记寄生虫的延时视频显微镜，我们发现MβCD处理仅30分钟就导致滋养体阶段寄生虫的显著排出。这种强有力的驱逐发生在10秒内。值得注意的是，寄生虫被排出的宿主细胞的质膜似乎没有受到损害。寄生空泡膜（PVM）继续包围挤出的寄生虫，但PVM出现损坏。靶向PfATP 4或PfNCR 1的抗疟化合物治疗可阻止Mβ CD介导的寄生虫排出，表明胆固醇动力学在排出现象中的潜在作用。我们还证实了红细胞膜胆固醇在恶性疟原虫侵袭和生长中的重要作用。这种缺陷可以部分地由胆固醇和链固醇补充，但不能与表胆固醇补充，揭示了胆固醇功能的立体特异性。总的来说，我们的研究推进了以前的观察，并揭示了受感染的红细胞质膜胆固醇耗竭的不寻常的细胞生物学特征。重要性疟疾仍然是世界许多地区面临的重大挑战。疟疾的症状是由属于疟原虫属的寄生虫的生长引起的。在红细胞（RBC）内，导致其破坏。寄生虫依赖其宿主来满足其大部分营养需求。胆固醇是红细胞质膜中的主要脂质，这是疟疾寄生虫这种脂质的唯一来源。我们以前已经表明，某些新的抗疟化合物破坏恶性疟原虫胆固醇稳态。在这里，我们使用实时延时视频显微镜显示，当RBC的胆固醇含量降低时，寄生虫从宿主RBC中大量排出。值得注意的是，这种排出被破坏脂质稳态的抗疟药抑制。我们还显示了胆固醇在支持红细胞内寄生虫生长方面的立体特异性。总的来说，这些结果表明胆固醇在疟疾寄生虫的生理学中起着关键作用。
Cholesterol is the most abundant lipid in the erythrocyte. During its blood-stage development, the malaria parasite establishes an active cholesterol gradient across the various membrane systems within the infected erythrocyte. Interestingly, some antimalarial compounds have recently been shown to disrupt cholesterol homeostasis in the intraerythrocytic stages of Plasmodium falciparum. These studies point to the importance of cholesterol for parasite growth. Previously, reduction of cholesterol from the erythrocyte membrane by treatment with methyl-β-cyclodextrin (MβCD) was shown to inhibit parasite invasion and growth. In addition, MβCD treatment of trophozoite-stage P. falciparum was shown to result in parasite expulsion from the host cell. We have revisited these phenomena by using live video microscopy, ultrastructural analysis, and response to antimalarial compounds. By using time-lapse video microscopy of fluorescently tagged parasites, we show that MβCD treatment for just 30 min causes dramatic expulsion of the trophozoite-stage parasites. This forceful expulsion occurs within 10 s. Remarkably, the plasma membrane of the host cell from which the parasite has been expelled does not appear to be compromised. The parasitophorous vacuolar membrane (PVM) continued to surround the extruded parasite, but the PVM appeared damaged. Treatment with antimalarial compounds targeting PfATP4 or PfNCR1 prevented MβCD-mediated extrusion of the parasites, pointing to a potential role of cholesterol dynamics underlying the expulsion phenomena. We also confirmed the essential role of erythrocyte plasma membrane cholesterol for invasion and growth of P. falciparum. This defect can be partially complemented by cholesterol and desmosterol but not with epicholesterol, revealing stereospecificity underlying cholesterol function. Overall, our studies advance previous observations and reveal unusual cell biological features underlying cholesterol depletion of the infected erythrocyte plasma membrane. IMPORTANCE Malaria remains a major challenge in much of the world. Symptoms of malaria are caused by the growth of parasites belonging to Plasmodium spp. inside the red blood cells (RBCs), leading to their destruction. The parasite depends upon its host for much of its nutritional needs. Cholesterol is a major lipid in the RBC plasma membrane, which is the only source of this lipid for malaria parasites. We have previously shown that certain new antimalarial compounds disrupt cholesterol homeostasis in P. falciparum. Here, we use live time-lapse video microscopy to show dramatic expulsion of the parasite from the host RBC when the cholesterol content of the RBC is reduced. Remarkably, this expulsion is inhibited by the antimalarials that disrupt lipid homeostasis. We also show stereospecificity of cholesterol in supporting parasite growth inside RBC. Overall, these results point to a critical role of cholesterol in the physiology of malaria parasites.
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