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Formation and function of the parasitophorous vacuole membrane in Plasmodium falciparum-infected erythrocytes

恶性疟原虫感染红细胞寄生液泡膜的形成和功能

基本信息

批准号：
MR/R008485/1
负责人：
Christiaan Van Ooij
金额：
$ 140.3万
依托单位：
London School of Hygiene & Tropical Medicine
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FR008485%2F1
关键词：
Formation function parasitophorous vacuole membrane

项目摘要

Malaria parasites cause disease by infecting red blood cells. During the process of invading these cells, the parasites become surrounded by a membrane, referred to as the parasitophorous vacuole membrane (PVM). Throughout the entire replication cycle inside the red blood cell, this membrane separates the parasite from the cytosol of the red blood cell, which consists primarily of haemoglobin. However, the membrane also makes the uptake of nutrients and the transport of proteins from the parasite to the red blood cell much more difficult. It is not understood why the parasite would maintain such a barrier, whereas related organisms that can also replicate in red blood cells can remove it and live free in the cytosol of the red blood cell. It is likely that the PVM performs an essential function, or multiple functions, for the parasites, but that function is entirely unclear. Also, it is not known how the PVM is made, maintained and expanded as the parasite grows inside the red blood cell. The aim of this research programme is to determine how the PVM is made and determine the role of the proteins that normally reside in the PVM in its development and maintenance, and ultimately answer the question how this membrane helps the parasite survive inside the red blood cell. Previous research has identified a protein, named PFA0210c, which may be involved in the formation of the PVM soon after the parasite has entered the red blood cell and again at later stages of the growth inside red blood cell. PFA0210c is a phospholipid transfer protein that can transfer phospholipids, the building blocks of cellular membranes, from one membrane to another. The PVM of parasites that do not produce this protein are much smaller than normal, indicating that potentially the role of PFA0210c is to transport phospholipids from the parasite to the PVM. Part of this research is aimed at discovering exactly how this protein functions and what its role in the formation of the PVM is. Another aspect of this study is the investigation of proteins that are known to reside in the PVM. Only about fifteen of such proteins are known, and twelve of them will be investigated: eleven members of a family of proteins called ETRAMPS and a protein called EXP1. By investigating these proteins, initially through the creation of parasites in which the genes that encode these proteins can be rapidly deleted through the addition of a small molecule, it may be possible to determine the function of these proteins. This will provide insight into the function of the PVM and hence the ability of the parasite to survive inside the red blood cell. Lastly, part of the research is aimed at the PVM itself. Parasites will be produced in which the synthesis of proteins that can break down phospholipids or produce large holes in membranes can be turned on. If this results in the loss of the PVM, then the role of the PVM can be observed directly by determining what happens to the parasite when it no longer has the protective coat that the PVM offers.Ultimately the study of these proteins and the PVM could be used to search for more anti-malarial compounds. PFA0210c has been shown to be essential for the survival of the parasite and several PVM proteins, including EXP1, could be essential proteins and do not resemble proteins in the human host - important characteristics for proteins that are the targets of anti-malaria drugs. Hence, not only could this research lead to much deeper insight into the interaction of the parasite with its host, it could stimulate the search for anti-malaria drugs that target these proteins.

疟疾寄生虫通过感染红细胞引起疾病。在侵入这些细胞的过程中，寄生虫被一层膜包围，称为寄生液泡膜（PVM）。在红细胞内的整个复制周期中，该膜将寄生虫与红细胞的细胞质（主要由血红蛋白组成）分开。然而，膜也使得营养物质的吸收和蛋白质从寄生虫到红细胞的运输变得更加困难。目前尚不清楚为什么寄生虫会维持这样的屏障，而同样可以在红细胞中复制的相关生物体可以去除它并在红细胞的细胞质中自由生活。 PVM 很可能对寄生虫执行一种基本功能或多种功能，但该功能完全不清楚。此外，尚不清楚当寄生虫在红细胞内生长时，PVM 是如何产生、维持和扩展的。该研究计划的目的是确定 PVM 是如何制造的，并确定通常驻留在 PVM 中的蛋白质在其发育和维持中的作用，并最终回答该膜如何帮助寄生虫在红细胞内生存的问题。先前的研究已经鉴定出一种名为 PFA0210c 的蛋白质，它可能在寄生虫进入红细胞后不久以及在红细胞内生长的后期参与 PVM 的形成。 PFA0210c 是一种磷脂转移蛋白，可以将磷脂（细胞膜的组成部分）从一个膜转移到另一个膜。不产生这种蛋白的寄生虫的 PVM 比正常的小得多，表明 PFA0210c 的潜在作用是将磷脂从寄生虫转运到 PVM。这项研究的一部分目的是确切地发现这种蛋白质的功能及其在 PVM 形成中的作用。这项研究的另一个方面是研究已知存在于 PVM 中的蛋白质。此类蛋白质中只有大约 15 种是已知的，其中 12 种将被研究：ETRAMPS 蛋白质家族的 11 名成员和 EXP1 蛋白质。通过研究这些蛋白质，首先通过创建寄生虫，在寄生虫中编码这些蛋白质的基因可以通过添加小分子而被快速删除，从而有可能确定这些蛋白质的功能。这将有助于深入了解 PVM 的功能以及寄生虫在红细胞内生存的能力。最后，部分研究是针对 PVM 本身的。将产生寄生虫，其中可以打开可以分解磷脂或在膜上产生大孔的蛋白质的合成。如果这导致 PVM 丧失，那么可以通过确定寄生虫不再具有 PVM 提供的保护层时发生的情况来直接观察 PVM 的作用。最终，对这些蛋白质和 PVM 的研究可用于寻找更多的抗疟疾化合物。 PFA0210c 已被证明对于寄生虫的生存至关重要，并且包括 EXP1 在内的几种 PVM 蛋白可能是必需蛋白，并且与人类宿主中的蛋白不同——这是抗疟疾药物靶标蛋白的重要特征。因此，这项研究不仅可以更深入地了解寄生虫与其宿主的相互作用，还可以刺激人们寻找针对这些蛋白质的抗疟疾药物。