Membrane and host cytoskeleton reorganization during malaria parasite egress from erythrocytes

疟疾寄生虫从红细胞中排出期间的膜和宿主细胞骨架重组

基本信息

批准号：
MR/P010288/1
负责人：
Helen Saibil
金额：
$ 56.28万
依托单位：
Birkbeck, University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FP010288%2F1
关键词：
Membrane host cytoskeleton reorganization during

项目摘要

Malaria is a major global killer, most deadly for children in the developing world. Of the five species that infect humans, Plasmodium falciparum is the most lethal. Although there are currently effective anti malarial drugs, the appearance and spread of resistant strains of P falciparum pose an increasing threat. The parasite has a complex life cycle with several different stages in its mosquito and human hosts, but the clinical symptoms in humans arise from waves of parasite release during the asexual blood stages, in which parasites invade red blood cells and multiply within an internal membrane compartment called a vacuole. The growing parasites hijack their host blood cells, consume their haemoglobin, and redirect the cell activity for the benefit of the parasite. Of particular importance, the parasite exports some of its own proteins to build new structures on the surface of the blood cell. A uniquely lethal aspect of P. falciparum is that it creates surface protrusions (called knobs) on the blood cell that make it adhere to the lining of blood vasculature. This prevents the infected cells from being captured and destroyed by the spleen, but can also block brain blood capillaries, the main cause of death in malaria infection. Once they have matured, 16-24 daughter parasites break through their surrounding vacuole membrane as well as the red blood cell membrane (a process collectively called egress) to enter the bloodstream, where they immediately invade a fresh round of blood cells. The processes of invasion, adhesion and egress are regulated through a cascade of enzyme reactions, as well as expression and transport of structural components. Some of these components are unique to malaria, making them potential targets for future drug development. Currently, most of them are poorly characterised.In this project, we focus on the steps by which the mature parasites break through the two bounding membranes to undergo egress. A highly regulated series of steps leads to the explosive release of parasites from the blood cell. To examine these membrane breakage events in detail, we use electron microscopy to image at nanoscale resolution the three-dimensional structures of the infected cells during the late stages of parasite development. This imaging is combined with use of parasite mutants and drug-like molecules and enzyme inhibitors to trap the parasites at different steps of egress. This approach has already led us to discover a new, initial step in egress that had not been previously detected. We now know that the process begins with the parasites causing the membrane surrounding their vacuole to become leaky. Subsequently, this membrane is completely disrupted, allowing the parasites to move freely inside the blood cell. Shortly after that, the blood cell membrane itself becomes leaky and then finally the cell membrane and its underlying cytoskeleton rupture to allow the parasites to escape and invade new host blood cells. With recent advances in gene editing technology, it has now become possible to conditionally modify gene expression in P. falciparum, and we will use this powerful technology to probe the molecular nature, functions and subcellular localisations of key malaria components involved in the sequence of steps during egress. The results of these studies could form the basis for future development of novel therapeutics.

疟疾是全球主要的杀手，对发展中国家的儿童最致命。在感染人类的五种物种中，恶性疟原虫是最致命的。尽管目前有有效的抗疟疾药物，但P恶性菌的抗性菌株的出现和传播构成了越来越多的威胁。该寄生虫具有复杂的生命周期，其蚊子和人类宿主中有几个不同的阶段，但是人类的临床症状来自无性血液阶段的寄生虫释放波，寄生虫在其中寄生虫入侵红血细胞，并在内部膜内部多数。称为液泡。生长的寄生虫劫持了他们的宿主血细胞，消耗其血红蛋白，并将细胞活性重定向，以使寄生虫受益。特别重要的是，寄生虫导出了一些自己的蛋白质，以在血细胞表面建立新的结构。恶性疟原虫的一个独特的致命方面是，它在血细胞上产生表面突起（称为旋钮），使其粘附在血管的衬里。这样可以防止被感染的细胞被脾脏捕获和破坏，但也可以阻止脑血液毛细血管，这是疟疾感染的主要死亡原因。一旦它们成熟，16-24个女儿寄生虫突破了周围的液泡膜以及红细胞膜（集体称为Egress的过程）进入血液，在那里它们立即入侵了新的血细胞。浸润，粘附和出口的过程通过一系列酶反应以及结构成分的表达和运输来调节。其中一些成分是疟疾所独有的，使它们成为未来药物开发的潜在目标。目前，他们中的大多数人的性格都很差。在这个项目中，我们专注于成熟的寄生虫穿过两个边界膜以进行出口的步骤。一系列高度调节的步骤导致寄生虫从血细胞中爆炸。为了详细检查这些膜破裂事件，我们使用电子显微镜在纳米级分辨率下图像在寄生虫发育的后期阶段，感染细胞的三维结构。该成像与使用寄生虫突变体和药物样分子和酶抑制剂相结合，以在出口的不同步骤中捕获寄生虫。这种方法已经使我们发现了以前未检测到的新的出口第一步。现在，我们知道该过程始于寄生虫，导致其液泡周围的膜变得漏水。随后，该膜完全破坏，使寄生虫可以自由移动在血细胞内。此后不久，血细胞膜本身就会泄漏，然后最后该细胞膜及其潜在的细胞骨架破裂，使寄生虫能够逃脱并侵入新的宿主血细胞。随着基因编辑技术的最新进展，现在已经有可能改变恶性疟原虫中的基因表达，我们将使用这项强大的技术来探测关键疟疾成分的分子本质，功能和亚细胞位置在出口期间。这些研究的结果可能是新型治疗剂未来发展的基础。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sequential roles for red blood cell binding proteins enable phased commitment to invasion for malaria parasites.

DOI：
10.1038/s41467-023-40357-z
发表时间：
2023-08-01
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Hart, Melissa N.;Mohring, Franziska;DonVito, Sophia M.;Thomas, James A.;Mueller-Sienerth, Nicole;Wright, Gavin J.;Knuepfer, Ellen;Saibil, Helen R.;Moon, Robert W.
通讯作者：
Moon, Robert W.

Sequential roles for red blood cell binding proteins enable phased commitment to invasion for malaria parasites

红细胞结合蛋白的连续作用使得疟疾寄生虫能够分阶段入侵

DOI：
10.1101/2022.08.09.503398
发表时间：
2022
期刊：
影响因子：
0
作者：
Hart M
通讯作者：
Hart M

A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells.

DOI：
10.1038/s41564-018-0111-0
发表时间：
2018-04
期刊：
Nature microbiology
影响因子：
28.3
作者：
Thomas JA;Tan MSY;Bisson C;Borg A;Umrekar TR;Hackett F;Hale VL;Vizcay-Barrena G;Fleck RA;Snijders AP;Saibil HR;Blackman MJ
通讯作者：
Blackman MJ

Malaria Parasite Schizont Egress Antigen-1 Plays an Essential Role in Nuclear Segregation during Schizogony.

DOI：
10.1128/mbio.03377-20
发表时间：
2021-03-09
期刊：
mBio
影响因子：
6.4
作者：
Perrin AJ;Bisson C;Faull PA;Renshaw MJ;Lees RA;Fleck RA;Saibil HR;Snijders AP;Baker DA;Blackman MJ
通讯作者：
Blackman MJ

Peptidic boronic acids are potent cell-permeable inhibitors of the malaria parasite egress serine protease SUB1.

DOI：
10.1073/pnas.2022696118
发表时间：
2021-05-18
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Lidumniece E;Withers-Martinez C;Hackett F;Collins CR;Perrin AJ;Koussis K;Bisson C;Blackman MJ;Jirgensons A
通讯作者：
Jirgensons A