Unravelling the molecular mechanisms regulating cell division in the malaria parasite

揭示调节疟原虫细胞分裂的分子机制

• 批准号: MR/K011782/1
• 负责人: Rita Tewari
• 金额: $ 67.2万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK011782%2F1
• 关键词: Unravelling; molecular; mechanisms; regulating; cell

Malaria is the third largest global health problem caused by a single infectious agent after HIV and TB, affecting millions of people, and resulting in one million deaths annually (http://www.who.int/topics/malaria/). The emergence of resistance to antimalarial drugs and the lack of any effective vaccine highlight the great need to develop new tools to control the disease. The symptoms of the disease are caused when the malaria parasite invades human red blood cells and multiplies many times every two days eventually leading to destruction of red blood cells and followed by further invasion and cell division. Some of these parasite cells may cease to divide and they become sex cells (male and female gametocytes). When a female mosquito bites an infected person they ingest parasites along with the blood and this acts as a trigger to activate the parasite sex cells within the mosquito gut. The male gametocytes undergo rapid cell division to produce eight male gametes, which then fertilise the female gametes and the parasite life cycle continues in the mosquito gut. After further development and multiplication the parasite moves to the mosquito's salivary glands and is passed again to a new human host.The divisions made by parasites in blood cells and during sexual development are very different, but both are essential for the parasite If the parasite was unable to multiply and divide in the blood stream then it would not cause disease and if the male gametocytes were unable to divide then parasite transmissionwould be blocked. Therefore it is critically important to understand how the parasite multiplies and divides at these two stages so that we can develop ways to interfere with them by developing appropriate drugs. The molecules that control these two types of cell division in the parasite are very poorly understood. The project proposed here is to identify what they are and how they work. We can start by using the knowledge gathered in model systems and applying this in the parasite. For example in yeast and other well-studied systems, a complex of proteins called the anaphase promoting complex/cyclosome (APC/C), plays a key role in cell multiplication and division. It is activated by the action of other proteins for example one called the cell division cycle protein-20 (CDC20). These proteins are also further regulated by the addition or removal of small 'tags', for example phosphate groups that can turn on or turn off particular functions.We have recently identified one of these proteins (CDC20) in the malaria parasite and shown that it has a key role in regulating male gamete formation, and also that it is itself regulated by addition of phosphate tags. In preliminary work showing that our approach is feasible, we have obtained evidence for the presence of components of the APC/C protein complex in both the parasite multiplying within the red blood cell and in the male sex cell. Recent advances in analysing genes in malaria allow us to study the function of these molecules. For example, we can see what happens if the proteins are no longer made, and if they are tagged experimentally with a fluorescent marker we can see where they are located in the parasite under the microscope. Therefore, we are now in a position where we can explore further to understand how cell division in malaria is controlled by these different molecules. We will also study how these molecules interact together.This research will enable us to identify mechanisms essential for parasite growth and multiplication that might be targeted in the development of new anti-malarial treatments. Our study may identify molecular targets important in parasite cell division in red blood cells and in the formation of male gametes, and therefore effective against either the stage responsible for the disease in humans or the transmission from one individual to another through the mosquito.

疟疾是继艾滋病毒和结核病之后由单一传染源引起的第三大全球健康问题，影响数百万人，每年导致一百万人死亡 (http://www.who.int/topics/malaria/)。抗疟药物耐药性的出现以及有效疫苗的缺乏凸显了开发新工具来控制该疾病的巨大需求。这种疾病的症状是由于疟原虫侵入人体红细胞，每两天繁殖多次，最终导致红细胞被破坏，进而进一步侵入和细胞分裂。其中一些寄生虫细胞可能会停止分裂，并变成性细胞（雄性和雌性配子细胞）。当雌性蚊子叮咬感染者时，它们会随着血液一起摄入寄生虫，这会触发蚊子肠道内的寄生虫性细胞。雄配子细胞经历快速细胞分裂，产生八个雄配子，然后使雌配子受精，寄生虫的生命周期在蚊子肠道中继续。经过进一步的发育和繁殖，寄生虫移动到蚊子的唾液腺，并再次传递给新的人类宿主。寄生虫在血细胞中和性发育过程中进行的分裂有很大不同，但两者对于寄生虫来说都是必需的。无法在血流中繁殖和分裂，则不会引起疾病，如果雄配子体无法分裂，则寄生虫传播将被阻止。因此，了解寄生虫在这两个阶段如何繁殖和分裂至关重要，以便我们能够通过开发适当的药物来干扰它们。人们对寄生虫中控制这两种细胞分裂的分子知之甚少。这里提出的项目是为了确定它们是什么以及它们如何工作。我们可以首先使用模型系统中收集的知识并将其应用到寄生虫中。例如，在酵母和其他经过充分研究的系统中，一种称为后期促进复合物/环体 (APC/C) 的蛋白质复合物在细胞增殖和分裂中发挥着关键作用。它由其他蛋白质的作用激活，例如一种称为细胞分裂周期蛋白 20 (CDC20) 的蛋白质。这些蛋白质还可以通过添加或去除小“标签”来进一步调节，例如可以打开或关闭特定功能的磷酸基团。我们最近在疟原虫中鉴定了其中一种蛋白质 (CDC20)，并表明它在调节雄配子形成中具有关键作用，并且它本身是通过添加磷酸盐标签来调节的。在初步工作中，我们的方法是可行的，我们已经获得了红细胞内和雄性细胞内繁殖的寄生虫中存在 APC/C 蛋白复合物成分的证据。分析疟疾基因的最新进展使我们能够研究这些分子的功能。例如，我们可以看到如果不再制造蛋白质会发生什么，如果用荧光标记对它们进行实验标记，我们可以在显微镜下看到它们在寄生虫中的位置。因此，我们现在可以进一步探索以了解这些不同分子如何控制疟疾中的细胞分裂。我们还将研究这些分子如何相互作用。这项研究将使我们能够确定寄生虫生长和繁殖所必需的机制，这些机制可能是开发新的抗疟疾治疗方法的目标。我们的研究可能会确定在红细胞中寄生虫细胞分裂和雄配子形成中重要的分子靶标，因此可以有效对抗导致人类疾病的阶段或通过蚊子从一个个体传播到另一个个体的疾病。

项目成果

MRE11 is crucial for malaria transmission and its absence affects expression of interconnected networks of key genes essential for life

MRE11 对于疟疾传播至关重要，它的缺失会影响生命必需的关键基因互连网络的表达

• DOI: 10.1101/2020.08.24.258657
• 发表时间: 2020
• 作者: Guttery D

The repeat region of the circumsporozoite protein is critical for sporozoite formation and maturation in Plasmodium.

• DOI: 10.1371/journal.pone.0113923
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ferguson DJ;Balaban AE;Patzewitz EM;Wall RJ;Hopp CS;Poulin B;Mohmmed A;Malhotra P;Coppi A;Sinnis P;Tewari R
• 通讯作者: Tewari R

Changes in genome organization of parasite-specific gene families during the Plasmodium transmission stages.

• DOI: 10.1038/s41467-018-04295-5
• 发表时间: 2018-05-15
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bunnik EM;Cook KB;Varoquaux N;Batugedara G;Prudhomme J;Cort A;Shi L;Andolina C;Ross LS;Brady D;Fidock DA;Nosten F;Tewari R;Sinnis P;Ay F;Vert JP;Noble WS;Le Roch KG
• 通讯作者: Le Roch KG

Compositional and expression analyses of the glideosome during the Plasmodium life cycle reveal an additional myosin light chain required for maximum motility.

• DOI: 10.1074/jbc.m117.802769
• 发表时间: 2017-10-27
• 期刊: The Journal of biological chemistry
• 作者: Green JL;Wall RJ;Vahokoski J;Yusuf NA;Ridzuan MAM;Stanway RR;Stock J;Knuepfer E;Brady D;Martin SR;Howell SA;Pires IP;Moon RW;Molloy JE;Kursula I;Tewari R;Holder AA
• 通讯作者: Holder AA