Defining and Exploiting the Circadian Clocks in Malaria Parasites

项目摘要|摘要 然而，疟疾巨大的公共卫生负担是毋庸置疑的，自2020年以来，死亡人数不断增加 其特有的节律性发热的机制仍然知之甚少。地球自转一直是一个 生物体进化生物钟以预测日常节律的驱动力。在人类中，昼夜节律时钟 调节生物学的多个生理方面，包括睡眠-觉醒周期、新陈代谢和免疫 防守。人类的昼夜节律导致感染我们的病原体所经历的身体节律。疟疾， 一种每年导致50多万人死亡的寄生虫病，以周期性发烧而闻名。疟疾 周期性发烧是含有寄生虫的宿主红细胞同步爆裂的结果 和新陈代谢废物。长期以来，人们一直认为疟疾周期性发热和寄生虫的复制节律 造成它们的原因是由宿主自身的昼夜节律驱动的。疟疾的存在和作用 寄生虫的内在时钟一直未知。最近的发现表明，疟疾寄生虫的节律是 内在的。即使在感染昼夜节律突变的心律失常宿主时，寄生虫的同步爆发也会持续下去。 然而，疟疾时钟的分子调控和功能仍然难以捉摸。这导致了一种假设 寄生虫钟是寄生虫生物学的重要组成部分，也是导致 寄生虫病。这项提议的总体目标是破译调节昼夜节律的分子过程。 寄生虫的节律，并发现扰乱它们的调控网络如何影响疟疾的发病机制 和变速箱。通过使用正向遗传学筛查、行为、分子和生物信息学方法， 将确定疟疾寄生虫的分子机制。这是一个新兴的研究领域。 传染病的昼夜节律。多种寄生虫感染表现出更多的日常节律 支持这样的假设：寄生虫的昼夜节律对它们的生物学、适合性和潜在的 这种生物节律的放松可能会扰乱它们在 导致感染。这一建议将为发现其他寄生虫的寄生钟提供基础 弓形虫病和利什曼病等疾病。除了这项工作对基础寄生虫学的意义之外 它还可以通过揭示疟疾的发病机制来揭开疾病发病机制的面纱 主要发烧症状。寄生虫病对全球公共卫生构成越来越大的威胁，这一创新 研究将提供新的靶点，直接扰乱导致疾病的节律。

Project Summary | Abstract Malaria’s immense public health burden is undisputable with numbers of deaths increasing since 2020, however the mechanism for its characteristic rhythmic fevers remains poorly understood. Earth rotation has been a driving force for organisms to evolve circadian clocks to anticipate daily rhythms. In humans, circadian clocks regulate multiple physiological aspects of biology, including sleep-wake cycles, metabolism, and immune defense. Human’s circadian biology leads to body rhythms experienced by the pathogens that infect us. Malaria, a parasitic disease that kills over half a million people each year, is famous for its periodic fevers. Malarial periodic fevers are a consequence of the synchronous bursting of the host’s red blood cells, containing parasites and metabolic waste. It has long been assumed that malarial periodic fevers and the parasite replication rhythms that cause them were driven by the host’s own circadian rhythms. The existence and role of the malarial parasites’ intrinsic clocks has been unknown. Recent discoveries showed that malaria parasite rhythms are intrinsic. Parasite’s synchronous bursting persists even when infecting a circadian clock mutant arrhythmic host. However, the molecular regulation and functions of malaria clock remains elusive. This led to the hypothesis that the parasite clock is an essential component of parasite biology and a contributor to pathogenesis of parasitic diseases. The overall aim of this proposal is to decode the molecular processes that regulate circadian rhythms in parasites and discover how disrupting their regulatory networks impacts the pathogenesis of malaria and transmission. By using forward-genetics screens, behavioral, molecular and bioinformatic approaches, the molecular machinery of malaria parasites will be identified. This is an emerging new field of research of circadian rhythms in infectious diseases. The fact that multiple parasitic infections show daily rhythms further supports the hypothesis that circadian rhythm in parasites is essential for their biology, fitness and potentially transmission - and that deregulation of this biological rhythm may disrupt their well-orchestrated success in causing infections. This proposal will provide a foundation for discovering parasite clocks in other parasitic diseases such as toxoplasmosis and leishmaniasis. Beyond the significance of this work to basic parasitology discovery, it could also unravel insights on the disease pathogenesis by uncovering the mechanism for malaria’s main fever symptom. Parasitic diseases pose increasing threats to global public health and this innovative research will provide new targets to directly disrupt the rhythms that contribute to the disease.