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无可争议的，自2020年以来， 其特征性节律性发热的机制仍然知之甚少。地球的自转 生物体进化生物钟以预测日常节奏的驱动力。人类的生物钟 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 防御人类的昼夜节律生物学导致感染我们的病原体经历的身体节律。疟疾， 一种寄生虫病，每年造成50多万人死亡，以周期性发烧而闻名。疟疾 周期性发热是宿主红细胞同步爆发的结果，其中含有寄生虫 和代谢废物。长期以来，人们一直认为疟疾的周期性发热和寄生虫的复制节律 是由宿主自身的昼夜节律驱动的。疟疾的存在和作用 寄生虫的内在生物钟是未知的。最近的发现表明，疟疾寄生虫的节律是 内在的寄生虫的同步爆发即使在感染生物钟突变的寄生虫宿主时也会持续。 然而，疟疾时钟的分子调控和功能仍然是难以捉摸的。这导致了一个假设 寄生虫时钟是寄生虫生物学的重要组成部分，也是寄生虫病发病机制的贡献者。 寄生虫病这项提案的总体目标是解码调节昼夜节律的分子过程 寄生虫的节律，并发现破坏它们的调节网络如何影响疟疾的发病机制 和传输。通过使用正向遗传学筛选，行为，分子和生物信息学方法， 疟疾寄生虫的分子机制将得到确认。这是一个新兴的研究领域， 传染病的昼夜节律。事实上，多种寄生虫感染显示出每日的节奏进一步 支持这一假设，昼夜节律在寄生虫是必不可少的，他们的生物学，健身和潜在的 这种生物节律的失调可能会破坏他们精心策划的成功， 引起感染。这一建议将为在其他寄生生物中发现寄生时钟提供基础 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 这一发现，它也可以通过揭示疟疾的发病机制， 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， 研究将提供新的靶点，直接破坏导致这种疾病的节律。

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.