Mechanisms Governing Translational Regulation During Plasmodium Transmission

摘要 疟疾感染仍然是当今最大的全球健康问题之一，有近60万人死亡， 每年发生的新感染病例。疟原虫寄生虫（疟疾的病原体）通过 蚊子媒介和哺乳动物宿主之间的联系，他们已经开发出复杂的系统， 为传播做好充分准备，然后牢固地建立感染。因为相对来说 寄生虫在宿主和蚊子媒介之间传递，这两种传播事件长期存在。 作为药物和疫苗干预措施的最佳重点。 最近的研究表明，疟原虫已经进化到使用选择性翻译， 在传播事件之前进行抑制，以储存其下一步所需的mRNA， 发展为了这些目的而采用翻译抑制是一个合乎逻辑的选择， 被传播的配子母细胞和子孢子不能预测它们何时被传播， 让寄生虫时刻准备着等待传播的发生。 虽然参与这些事件的一些关键蛋白质和mRNA已经被确定，但许多重要的蛋白质和mRNA已经被发现。 问题仍然存在。哪些蛋白质负责选择mRNA进行翻译抑制？什么 蛋白质会抑制它们吗mRNA的哪些属性将标记它被选择用于翻译 镇压？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，并通过这样做，我们将更好地了解寄生虫的基本机制， 在配子体和子孢子阶段都能有效地传播。此外，我们将观察 寄生虫在啮齿动物和哺乳动物这两个阶段如何使用翻译抑制的相似性和差异， 传染性和人类传染性寄生虫。 总之，这些发现将提供蛋白质/RNA复合物的第一个机制研究， 孢子，将允许跨阶段和物种的功能比较，并将突出分子 寄生虫传播所需的成分和功能，将来可能被用作目标 新的治疗药物。

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.