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因素引起的第三大全球健康问题，每年影响数百万人，并导致一百万人死亡（http://www.who.int/topics/malaria/）。对抗疟药抗药性的出现以及缺乏任何有效的疫苗突出了开发新工具来控制疾病的巨大需求。当疟疾寄生虫入侵人类红细胞并每两天多次乘以每两天乘以疾病，最终导致红细胞销毁，然后再进一步侵袭和细胞分裂时，该疾病的症状是引起的。这些寄生虫细胞中的一些可能停止分裂，它们成为性细胞（男性和女性配子细胞）。当雌性蚊子咬伤感染者时，他们将寄生虫与血液一起摄取，这是激活蚊子内寄生虫性细胞的触发因素。雄性配子细胞经历了快速的细胞分裂，以产生八个男配子，然后在蚊子肠道中施肥雌配子，寄生虫生命周期仍在继续。经过进一步的开发和繁殖，寄生虫转移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期间的划分非常不同，但是如果寄生虫无法在血液中繁殖，那么如果寄生虫无法造成疾病，那么这对寄生虫而言至关重要。因此，了解寄生虫如何在这两个阶段繁殖和分裂至关重要，以便我们可以通过开发适当的药物来开发干扰它们的方法。控制寄生虫中这两种细胞分裂的分子对寄生虫的了解很少。这里提出的项目是确定它们是什么以及它们的工作方式。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中。例如，在酵母和其他良好的系统中，一种称为促进复合物/循环体（APC/C）的蛋白质复合物在细胞繁殖和分裂中起关键作用。它是由其他蛋白质的作用激活的，例如一种称为细胞分裂蛋白-20（CDC20）的作用。这些蛋白质也通过添加或去除小的“标签”进一步调节，例如可以打开或关闭特定功能的磷酸基团。我们最近在疟原虫寄生虫中确定了这些蛋白质之一（CDC20），并表明它在调节男性游戏形成以及通过磷酸盐量来调节磷酸盐中具有关键作用。在初步的工作表明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和男性性细胞中繁殖的寄生虫中APC/C蛋白复合物的成分。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，如果它们用荧光标记在实验上进行标记，我们可以看到它们位于显微镜下的寄生虫中。因此，我们现在处于一个可以进一步探索的位置，以了解疟疾中的细胞分裂如何由这些不同的分子控制。我们还将研究这些分子如何一起相互作用。这项研究将使我们能够确定可能针对新的抗疟疾治疗的寄生虫生长和乘法所必需的机制。我们的研究可以鉴定在红细胞中寄生细胞分裂和雄性配子的形成中重要的分子靶标，因此有效地防止了导致人类疾病的阶段或通过蚊子从一个人到另一个人传播的阶段。

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