Elucidating the mechanism for malaria rhythmicity: an underlying circadian clock of the parasite

联系PD/PI：Rijo-Ferreira，Filipa 项目摘要 疟疾是一种致命的寄生虫病。疟疾的主要症状是发烧， 红细胞（RBC）在寄生虫的细胞周期完成后。寄生虫种群 协调地破坏红细胞，重新侵入新的红细胞并复制，直到它们的循环完成，然后 新的红细胞爆发。其结果是阵发性发热，其复发的周期与 寄生虫细胞周期：人类特异性疟原虫种属为48小时或72小时，啮齿动物特异性疟原虫为24小时 物种寄生虫同步性的机制，这是核心的这一现象，仍然未知。 尽管细胞周期的持续时间在疟原虫物种之间不同，但它具有24小时的持续时间倍数， 使我们假设发热周期性的机制是寄生虫的内源性生物钟。 我们的初步数据表明，宿主的营养状况是同步的时间最强的信号， 红细胞破裂但是，是什么机制导致其24小时持续时间？虽然有节奏的爆红 血细胞是由于寄生虫细胞周期，似乎存在一种昼夜节律的计时机制， 独立的细胞周期，因为我的初步数据表明，即使是静止的寄生阶段有24小时 基因表达的节奏。生物钟调节多种生理功能，从基因表达 到行为。生物钟能够预测环境的节律变化，这是一种进化的过程。 有利于生物体。从细菌到人类，生物钟组件的突变或 生物钟和环境（慢性时差）导致健康下降，代谢紊乱， 寿命也已经表明，宿主和寄生虫节律之间的不匹配对于寄生虫的发育是不利的。 疟疾寄生虫感染成功，使宿主受益。 本提案的目标是确定疟原虫同步性的机制。为了解决这个 作为一个基本问题，我将系统地剖析寄生虫细胞周期和系统宿主的贡献 这一现象的信号。通过下一代测序技术，我的目标是确定 当寄生虫1）潜入哺乳动物血液; 2）在静止阶段;和3）在没有 体外系统性宿主信号。后者将允许我测试这些疟疾节律是否是温度 补偿：内源性昼夜节律的一个关键特征。通过降低培养温度 在哺乳动物细胞中，它们的细胞周期持续时间减慢，但它们的生物钟保持为24小时。 这些研究将产生一个全面的框架，以解决疟疾领域一个长期存在的问题。 领域更广泛地说，通过解剖发烧的周期性是由宿主信号还是内部信号驱动， 寄生虫的昼夜节律钟，这些研究将指导破坏寄生虫同步性的策略 以及开发替代方法来应对这种致命疾病。 项目摘要

Contact PD/PI: Rijo-Ferreira, Filipa Project Summary Malaria is a deadly parasitic disease. The major symptom for malaria is fever, which is associated with bursting of red blood cells (RBCs) upon completion of the cell cycle of the parasite. The parasite population coordinately ruptures the RBCs, reinvades new ones and replicates until their cycle is completed, and then a new burst of RBCs occurs. The result is a paroxysmal fever that recurs with the same periodicity as the parasite cell cycle: 48h or 72h for human-specific Plasmodium species and 24h for rodent-specific Plasmodium species. The mechanism for parasite synchronicity, which is central to this phenomenon, remains unknown. Despite the duration of cell cycle varying among Plasmodium species, it has a duration multiple of 24h, which led us to hypothesize that the mechanism for fever periodicity is an endogenous circadian clock of the parasite. Our preliminary data suggest that host nutritional status is the strongest signal for synchronizing the timing of bursting of red blood cells. But what mechanism leads to its 24h duration? Although rhythmic bursting of red blood cells is due to the parasite cell cycle, there seems to exist a circadian timekeeping mechanism that is independent of cell cycle, since my preliminary data suggest that even quiescent parasite-stages have 24h rhythms of gene expression. Circadian clocks regulate multiple physiological functions, from gene expression to behavior. Having circadian clocks that anticipate rhythmic changes in the environment is an evolutionary advantage for organisms. From bacteria to humans, mutations in clock components or desynchrony between the clock and the environment (chronic jet-lag) leads to reduced fitness, metabolic disruption and shorter lifespan. It has also been shown that a mismatch between the host and the parasite rhythms is detrimental for malaria parasite infection success, benefiting the host. The goal of this proposal is to determine the mechanism for Plasmodium synchronicity. To address this fundamental question, I will systematically dissect the contribution of the parasite cell cycle and systemic host signals to this phenomenon. With next-generation sequencing I aim to determine the rhythmic gene expression of the parasite when 1) diving into mammalian blood; 2) in a quiescent-stage; and 3) in the absence of systemic host signals in vitro. The latter will allow me to test whether these malaria rhythms are temperature compensated: a key feature of endogenous circadian rhythms. By decreasing temperature of cultured mammalian cells, their cell cycle duration slows down but their circadian clock remains with 24h. These studies will generate a comprehensive framework to resolve a long-standing question in the malaria field. More broadly, by dissecting whether the periodicity of fevers is driven by host signals or an internal circadian clock of the parasite, these studies will guide strategies to disrupt the synchronicity of the parasite and to the development of alternative approaches to tackle this deadly disease. Project Summary