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.

疟疾是仅次于艾滋病毒和结核病的单一感染源造成的第三大全球健康问题，影响着数以百万计的人，每年导致100万人死亡(http://www.who.int/topics/malaria/).对抗疟疾药物的抗药性的出现和缺乏任何有效的疫苗突出表明，迫切需要开发新的工具来控制这种疾病。这种疾病的症状是当疟疾寄生虫入侵人类红细胞并每两天繁殖多次，最终导致红细胞破坏，然后进一步入侵和细胞分裂时引起的。其中一些寄生虫细胞可能停止分裂，成为性细胞(雄配子体和雌配子体)。当雌性蚊子叮咬感染者时，它们会与血液一起摄入寄生虫，这就触发了蚊子肠道内寄生虫性细胞的激活。雄配子体经历快速的细胞分裂，产生8个雄配子，然后使雌配子受精，寄生虫的生命周期在蚊子的肠道中继续。在进一步发育和繁殖后，寄生虫移动到蚊子的唾液腺，并再次传递给新的人类宿主。寄生虫在血细胞和性发育过程中进行的分裂非常不同，但两者对寄生虫都是必不可少的。如果寄生虫不能在血液中繁殖和分裂，它就不会致病，如果雄配子细胞不能分裂，寄生虫的传播就会被阻断。因此，了解寄生虫在这两个阶段是如何繁殖和分裂的至关重要，这样我们就可以通过开发适当的药物来开发干扰它们的方法。寄生虫中控制这两种细胞分裂的分子知之甚少。这里提出的项目是确定它们是什么以及它们是如何工作的。我们可以首先使用在模型系统中收集的知识，并将其应用于寄生虫。例如，在酵母和其他研究得很好的系统中，一种被称为后期促进复合体/环体(APC/C)的蛋白质复合体在细胞增殖和分裂中发挥关键作用。它被其他蛋白质激活，例如一种叫做细胞分裂周期蛋白-20(CDC20)的蛋白质。这些蛋白质还受到小标签的添加或移除的进一步调节，例如可以开启或关闭特定功能的磷酸基团。我们最近在疟疾寄生虫中发现了其中一种蛋白质(CDC20)，并表明它在调节雄配子形成方面具有关键作用，而且它本身也受到磷酸标签的调节。在初步工作中，我们证明了我们的方法是可行的，我们已经获得了证据，证明在红细胞内繁殖的寄生虫和在男性性细胞中都存在APC/C蛋白复合体的成分。最近在分析疟疾基因方面的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，如果用荧光标记器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疟疾的细胞分裂是如何由这些不同的分子控制的。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的关键机制，这些机制可能是开发新的抗疟疾药物的目标。我们的研究可能确定在红细胞寄生虫细胞分裂和雄配子形成中重要的分子靶点，因此对人类疾病的阶段或通过蚊子从一个人传播到另一个人有效。

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

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

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