Functional dissection of Condensin and Cohesin in atypical mitosis and meiosis in Plasmodium

疟原虫非典型有丝分裂和减数分裂中Condensin和Cohesin的功能剖析

• 批准号: MR/N023048/1
• 负责人: Rita Tewari
• 金额: $ 51.68万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN023048%2F1
• 关键词: Functional; dissection; Condensin; Cohesin; atypical

Plasmodium is the causative agent of malaria and is responsible for about 584,000 human deaths annually, mostly children under the age of 5. The increasing resistance of the parasite to existing drugs and the lack of an efficient vaccine represent the main obstacles to combat this burden. Therefore, there is an urgent need for the development of innovative therapeutics. Plasmodium has a complex life cycle with diverse host environments, changes in cell shape, size and motility and an atypical mode of cell proliferation. The symptoms of the disease are manifest when malaria parasites invade host red blood cells, wherein the parasite divides and multiplies many times (endomitosis), eventually leading to destruction of the host cell. Some of the parasite cells may cease to divide and they become precursor 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 precursor sex cells within the mosquito gut. The male gametocytes undergo rapid cell division (endoreduplication) 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 when the mosquito feeds.The process of Plasmodium cell division in host red blood cells, and during sexual development in the mosquito vector is very different, but both are essential for parasite growth and transmission. If any of these stages are blocked then both proliferation and transmission are curtailed. Therefore, it is critically important to understand how the parasite multiplies and divides at these stages so that we can devise ways to interfere with them by developing appropriate drugs. The molecules that control these types of atypical cell division in the parasite are very poorly understood. The project proposed here is to study the role of two important protein complexes: condensin and cohesin. Although these complexes are known to be involved in cell division in many model systems, there is no knowledge of how they function during malaria parasite cell division and proliferation. We can start by using the knowledge gathered in model systems and applying this to the malaria parasite. For example, we have recently identified one such protein (CDC20) in the malaria parasite and showed that it has a key role in regulating male gamete formation. In preliminary work showing that our approach is feasible, we have obtained evidence for the presence of condensin and cohesin in the parasite multiplying within the red blood cell, in the male sex cell and in the meiotic cell (an ookinete). Recent advances in analysing genes in malaria allow us to study the function of these molecules. For example, by taking away the gene, we can see what happens when the proteins are no longer made, and if they are tagged experimentally with a fluorescent marker we can see under the microscope where they are located in the parasite. We will also study how these molecules interact with other proteins during various processes such as chromosome segregation and cytokinesis, to name two. We can also purify these protein complexes and study their interactions using mass spectroscopy-based approaches. Therefore, we are now in a position where we can explore how cell division in malaria is controlled by these complexes and we can study how these molecules regulate different stages of cell division.Our study may identify molecular targets important in parasite cell division in host red blood cells and in the cells dividing within the mosquito vector. As a result, we may identify potential targets for drugs or vaccines that could in the future be used to block parasite replication in the blood and transmission from one individual to another through the mosquito.

疟原虫是疟疾的病原体，每年造成约584，000人死亡，其中大多数是5岁以下的儿童。寄生虫对现有药物的抗药性不断增加，缺乏有效的疫苗，是克服这一负担的主要障碍。因此，迫切需要开发创新疗法。疟原虫具有复杂的生命周期，具有不同的宿主环境，细胞形状，大小和运动性的变化以及非典型的细胞增殖模式。当疟疾寄生虫侵入宿主红细胞时，该疾病的症状是明显的，其中寄生虫分裂和繁殖多次（内有丝分裂），最终导致宿主细胞的破坏。一些寄生虫细胞可能停止分裂，成为前体性细胞（雄性和雌性配子母细胞）。当雌蚊叮咬受感染的人时，它们会沿着血液摄入寄生虫，这就像一个触发器，激活了蚊子肠道内的前体性细胞。雄配子母细胞进行快速细胞分裂（核内复制），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。疟原虫在蚊子的唾液腺中繁殖，并在蚊子进食时再次传播给新的人类宿主。疟原虫在宿主红细胞中的细胞分裂过程与蚊子的性发育过程非常不同，但两者都是疟原虫生长和传播的必要条件。如果这些阶段中的任何一个被阻断，那么增殖和传播都会受到限制。因此，了解寄生虫如何在这些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设计干扰它们的方法。控制寄生虫中这些类型的非典型细胞分裂的分子非常不清楚。本研究的目的是研究两种重要的蛋白质复合物：凝聚素（condensin）和粘附素（cohesin）。虽然已知这些复合物在许多模型系统中参与细胞分裂，但不知道它们在疟原虫细胞分裂和增殖期间如何发挥作用。我们可以从使用模型系统中收集的知识开始，并将其应用于疟疾寄生虫。例如，我们最近在疟疾寄生虫中发现了一种这样的蛋白质（CDC 20），并表明它在调节雄性配子形成中起着关键作用。在初步工作中，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、雄性性细胞和减数分裂细胞（动合子）内繁殖的寄生虫中存在凝聚素和粘着素。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，通过去除基因，我们可以看到当蛋白质不再产生时会发生什么，如果用荧光标记物实验性地标记它们，我们可以在显微镜下看到它们在寄生虫中的位置。我们还将研究这些分子如何在各种过程中与其他蛋白质相互作用，如染色体分离和胞质分裂，仅举两例。我们还可以纯化这些蛋白质复合物，并使用基于质谱的方法研究它们的相互作用。因此，我们现在可以探索这些复合物是如何控制疟疾细胞分裂的，我们可以研究这些分子如何调节细胞分裂的不同阶段，我们的研究可能会确定在宿主红细胞中寄生虫细胞分裂和蚊子载体内细胞分裂中重要的分子靶点。因此，我们可以确定药物或疫苗的潜在靶点，这些药物或疫苗将来可以用于阻止寄生虫在血液中复制，并通过蚊子从一个个体传播到另一个个体。

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

Molecular characterization of the conoid complex in Toxoplasma reveals its conservation in all apicomplexans, including Plasmodium species.

• DOI: 10.1371/journal.pbio.3001081
• 发表时间: 2021-03
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Koreny L;Zeeshan M;Barylyuk K;Tromer EC;van Hooff JJE;Brady D;Ke H;Chelaghma S;Ferguson DJP;Eme L;Tewari R;Waller RF
• 通讯作者: Waller RF

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

Nutrient sensing modulates malaria parasite virulence.

• DOI: 10.1038/nature23009
• 发表时间: 2017-07-13
• 期刊: Nature
• 影响因子: 64.8
• 作者: Mancio-Silva L;Slavic K;Grilo Ruivo MT;Grosso AR;Modrzynska KK;Vera IM;Sales-Dias J;Gomes AR;MacPherson CR;Crozet P;Adamo M;Baena-Gonzalez E;Tewari R;Llinás M;Billker O;Mota MM
• 通讯作者: Mota MM

Plasmodium DEH is ER-localized and crucial for oocyst mitotic division during malaria transmission.

• DOI: 10.26508/lsa.202000879
• 发表时间: 2020-12
• 期刊: Life science alliance
• 影响因子: 4.4
• 作者: Guttery DS;Pandey R;Ferguson DJ;Wall RJ;Brady D;Gupta D;Holder AA;Tewari R
• 通讯作者: Tewari R