Can malaria transmission be prevented through catastrophic failure of gametocyte quiescence?

配子体静止的灾难性失败能否预防疟疾传播？

基本信息

批准号：
MR/V010034/1
负责人：
Michael Delves
金额：
$ 150.44万
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：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FV010034%2F1
关键词：
malaria transmission prevented through catastrophic

项目摘要

Despite recent gains in 2000-20016, progress has stalled and malaria is still a devastating disease, killing ~405,000 people each year and infecting 228 million. Plasmodium falciparum, the parasite causing the most deadly form of malaria spreads when a female mosquito ingests specialised parasite cells called male and female gametocytes whilst biting an infected person. These gametocytes have no control over when a mosquito might bite, therefore, to maximise their chances of transmission they become "quiescent" (i.e. dormant) for up to 22 days in human blood. Most antimalarial drugs are not effective against quiescent gametocytes thus allowing the disease (and drug resistance genes) to escape and spread throughout the population. Cellular quiescence is a process that is fundamental to all of life. In response to an unfavourable environment or a specific signal, cells can stop growing and become quiescent for a period of time. When conditions become more favourable, quiescent cells then exit this dormancy and resume their normal programmed growth. Cells carry out quiescence by a number of different methods, however common processes occur within the cell to keep them alive: 1. Reduced or efficient energy generation; 2. A shift in resource production from those needed for growth, to those necessary for survival; 3. Efficient damage and repair mechanisms.I hypothesise that interfering with gametocyte quiescence mechanisms will have catastrophic effects on their infectiousness, leaving them unable to transmit to mosquitoes. Studying these processes will help the design and discovery of new transmission-blocking antimalarial therapies targeting gametocyte quiescence.My fellowship focuses on how quiescent gametocytes regulate their energy production. Parasite stages in the mosquito generate energy by consuming glucose in a process called mitochondrial respiration, which is carried out in a specialised part of the cell called the mitochondrion. Mitochondrial respiration is essential for the parasite to survive in the mosquito but less important whilst it is in the human. Gametocytes must be ready to "switch on" mitochondrial respiration at a moment's notice. However, too much unwanted mitochondrial respiration is damaging for cells as it produces toxic "free radicals" that can kill the cell and thus would limit the lifespan of the gametocyte and lower its chances of transmission. Therefore, gametocytes appear to have several mechanisms to control their energy generation. It is hypothesised that one mechanism is to divert glucose away from the mitochondrion and out of the cell before it has been consumed. Alternatively, energy production could be reduced by replacing key enzymes (proteins that manufacture materials needed by the cell) involved in the process with less efficient alternatives. I have identified four enzymes made by gametocytes that may be responsible for this control. To study the role these play, I will genetically modify the parasite to lack these proteins and observe how this affects gametocytes and mosquito transmission. This will involve feeding parasites to live mosquitoes. I will also trace how glucose use by the parasite is affected in the mutant parasites using a technique called metabolomics which separates and identifies individual chemicals made by the cell. To identify additional proteins important for maintaining gametocytes in their quiescent state, I will label newly made proteins within the gametocyte with a chemical "tag" which will allow me to "capture" them and identify them using a technique called mass spectroscopy. By using this approach on male and female gametocytes individually, I will determine whether there is a sex difference in how gametocytes maintain quiescence. Finally, I will study how disrupting gametocyte energy metabolism impacts their ability to repair themselves.Ultimately, my research will identify which steps in the quiescence pathway could by targeted by new therapeutics.

尽管最近在2000 - 20016年获得了进展，但进展仍停滞不前，疟疾仍然是一种毁灭性的疾病，每年造成约405,000人，并感染了2.28亿。恶性疟原虫是寄生虫，导致最致命的疟疾形式传播时，当雌性蚊子摄入专门的寄生虫细胞时，称为男性和雌性配子细胞，同时咬住感染者。这些配子细胞无法控制蚊子何时会咬人，因此，为了最大程度地发出传播的机会，它们会在人类血液中最多22天“静止”（即休眠）。大多数抗疟药对静态配子细胞无效，因此使该疾病（和耐药性基因）逃脱并分布在整个人群中。细胞静止是一个对整个生命至关重要的过程。为了响应不利的环境或特定的信号，细胞可以停止生长并在一段时间内变得静止。当条件变得更加有利时，静态细胞会退出此休眠状态，并恢复其正常编程的生长。细胞通过多种不同的方法进行静止，但是在细胞内发生了常见的过程以保持它们的生存：1。降低或有效的能量产生； 2。资源生产从增长所需的生产转变为生存所必需的； 3。有效的损害和修复机制。我假设干扰配子细胞静止机制将对其传染性产生灾难性影响，从而使它们无法传播到蚊子。研究这些过程将有助于设计和发现针对配子细胞静止的新传输阻滞抗疟药疗法。我的研究金集中于静态的配子细胞如何调节其能量产生。蚊子中的寄生虫阶段通过在称为线粒体呼吸的过程中消耗葡萄糖来产生能量，该过程在称为线粒体的专门部分中进行。线粒体呼吸对于寄生虫在蚊子中生存至关重要，但在人类中却不重要。 Gametocytes必须准备好一刻的通知来“打开”线粒体呼吸。但是，太多不需要的线粒体呼吸对细胞造成了损害，因为它会产生有毒的“自由基”，从而可以杀死细胞，从而限制配子细胞的寿命并降低其传播的机会。因此，配子细胞似乎具有控制能量产生的几种机制。假设一种机制是将葡萄糖从线粒体转移到细胞之前，然后将其移出。另外，可以通过更效率较低的替代方法来替换参与该过程的关键酶（生产细胞所需的材料）来减少能源生产。我已经确定了可能导致该控制的四种酶制造的酶。为了研究这些发挥的作用，我将基因修改寄生虫缺乏这些蛋白质，并观察这如何影响配子细胞和蚊子传播。这将涉及将寄生虫喂食蚊子。我还将使用称为代谢组学的技术在突变寄生虫中影响寄生虫的葡萄糖使用如何分离和鉴定细胞制造的单个化学物质。为了鉴定对将配子细胞保持在静态状态的重要蛋白质，我将用化学“标签”在配子细胞中标记新制成的蛋白质，这将使我可以“捕获”它们，并使用称为质谱的技术来识别它们。通过单独使用这种方法，我将确定配子细胞保持静止的方式是否存在性别差异。最后，我将研究加油站能量代谢的破坏如何影响他们修复自身的能力。在文化中，我的研究将确定静止途径中的哪些步骤可以通过新的治疗剂靶向。