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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年取得了进展，但进展已经停滞，疟疾仍然是一种毁灭性的疾病，每年造成约405，000人死亡，2.28亿人感染。恶性疟原虫是一种引起最致命疟疾的寄生虫，当雌蚊叮咬感染者时，会摄入称为雄性和雌性配子体的特殊寄生虫细胞。这些配子母细胞无法控制蚊子何时叮咬，因此，为了最大限度地提高它们的传播机会，它们在人类血液中变得“静止”（即休眠）长达22天。大多数抗疟药物对静止的配子体无效，从而使疾病（和耐药基因）逃逸并在整个人群中传播。细胞静止是一个对所有生命都至关重要的过程。为了应对不利的环境或特定的信号，细胞可以停止生长并静止一段时间。当条件变得更有利时，静止细胞然后退出这种休眠并恢复其正常的程序化生长。细胞通过许多不同的方法进行静止，然而细胞内发生的共同过程使它们存活：1.减少或有效的能源生产; 2。资源生产从增长所需转向生存所需; 3.有效的损伤和修复机制。我假设，干扰配子体静止机制将对它们的传染性产生灾难性的影响，使它们无法传播给蚊子。研究这些过程将有助于设计和发现针对配子体静止的新的传播阻断抗疟疗法。我的研究重点是静止的配子体如何调节它们的能量产生。蚊子的寄生阶段通过消耗葡萄糖来产生能量，这一过程称为线粒体呼吸，这是在细胞的一个专门部分中进行的，称为线粒体。线粒体呼吸对于寄生虫在蚊子中的生存是必不可少的，但在人类中则不那么重要。配子细胞必须随时准备好“打开”线粒体呼吸。然而，太多不必要的线粒体呼吸对细胞有害，因为它产生有毒的“自由基”，可以杀死细胞，从而限制配子体的寿命并降低其传播的机会。因此，配子体似乎有几种机制来控制其能量产生。据推测，一种机制是在葡萄糖被消耗之前将葡萄糖从葡萄糖转运到细胞外。或者，可以通过用效率较低的替代品取代参与该过程的关键酶（制造细胞所需材料的蛋白质）来减少能量产生。我已经确定了四种由配子母细胞产生的酶，它们可能负责这种控制。为了研究这些蛋白质所起的作用，我将对寄生虫进行基因改造，使其缺乏这些蛋白质，并观察这如何影响配子体和蚊子传播。这将涉及喂养寄生虫活蚊子。我还将追踪寄生虫对葡萄糖的利用是如何影响突变寄生虫的，使用一种称为代谢组学的技术，该技术分离并识别细胞产生的单个化学物质。为了确定其他对维持配子体处于静止状态很重要的蛋白质，我将用一种化学“标签”标记配子体中新产生的蛋白质，这将使我能够“捕获”它们，并使用一种称为质谱的技术来识别它们。通过使用这种方法对男性和女性的配子体单独，我将确定是否有一个性别差异，配子体如何保持静止。最后，我将研究破坏配子体能量代谢如何影响它们的自我修复能力。最终，我的研究将确定新疗法可以针对静止途径中的哪些步骤。