Mechanisms Governing Translational Regulation During Plasmodium Transmission

摘要 疟疾感染仍然是当今严重的全球卫生问题之一，已有近60万人死亡，数百万人死亡 每年发生的新感染的数量。疟原虫(疟疾的病原体)传播 在蚊子媒介和它们的哺乳动物宿主之间，他们已经开发出复杂的系统来 为传播做好充分准备，然后牢固地确定感染。因为相对较少的 寄生虫是在宿主和蚊媒之间传播的，这两种传播事件都有很长的时间 被列为药物和疫苗干预的最佳着眼点。 最近的研究表明，疟原虫已经进化到使用选择性翻译 在传输事件之前进行抑制，以存储它在以下步骤中将需要的mRNA 发展。为了这些目的而调整翻译抑制是一个合乎逻辑的选择，因为 被传播的配子体和子孢子无法预测它们何时被传播，而这个系统 使寄生虫始终保持准备状态，以便发生那一刻的传播。 虽然已经确定了参与这些事件的一些关键蛋白质和mRNAs，但许多重要的 问题仍然存在。哪些蛋白质负责选择翻译抑制的mRNAs？什么 蛋白质起到抑制它们的作用？信使核糖核酸的哪些属性会将其标记为选择进行翻译 压抑？在这项拟议的工作中，我们将利用新的技术和实验方法来回答 这些问题，通过这样做，我们将更好地了解寄生虫具有的基本机制 进化成在配子体和子孢子阶段都能有效传播。此外，我们将观察到 在两种啮齿动物中，寄生虫在这两个阶段如何使用翻译抑制的异同- 具有传染性和人类传染性的寄生虫。 综上所述，这些发现将提供第一个蛋白质/RNA复合体的机制研究。 子孢子，将允许跨阶段和物种的功能比较，并将突出分子 寄生虫传播所需的组件和功能，未来可能会被利用为目标 寻找新的治疗剂。

Abstract Malarial infections are still one of today's great global health problems, with nearly 600,000 deaths and millions of new infections occurring annually. Plasmodium parasites (the causative agents of malaria) are transmitted between a mosquito vector and their mammalian host, and they have developed intricate systems to adequately prepare for transmission, and to then to firmly establish an infection. Because relatively few parasites are passed between the host and the mosquito vector, these two transmission events have long been prioritized as optimal points for interventions with drugs and vaccines. Recent work has demonstrated that Plasmodium parasites have evolved to use selective translational repression just prior to transmission events to store the mRNAs that it will need for the next steps of development. The adaptation of translational repression for these purposes is a logical choice, as the transmitted gametocytes and sporozoites cannot anticipate when they will be transmitted, and this system allows the parasite to always remain ready for that moment of transmission to occur. While some of the key proteins and mRNAs involved in these events have been identified, many important questions still remain. What proteins are responsible for selecting mRNAs for translational repression? What proteins act to repress them? What attributes of an mRNA will flag it to be selected for translational repression? In this proposed work, we will leverage new technological and experimental approaches to answer these questions, and by doing so, we will better understand the fundamental mechanisms that the parasite has evolved to be efficiently transmitted in both the gametocyte and sporozoite stages. Moreover, we will observe similarities and differences in how the parasite uses translational repression at these two stages in both rodent- infectious, and human-infectious parasites. Taken together, these findings will provide the first mechanistic studies of protein/RNA complexes in sporozoites, will allow a functional comparison across stages and species, and will highlight molecular components and functions that the parasite requires for transmission that may exploited in the future as targets for new therapeutic agents.