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

联系PD/PI：Rijo-Ferreira，菲律宾 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，这与爆发有关。 当寄生虫的细胞周期完成时，红血球(RBC)的数量增加。寄生虫种群 协调地破坏RBC，重新入侵新的RBC并进行复制，直到它们的循环完成，然后 出现了新的红细胞暴发。其结果是阵发性发烧，其复发周期与 寄生虫细胞周期：人特异性疟原虫48小时或72小时，啮齿动物特异性疟原虫24小时 物种。寄生虫同步性的机制是这一现象的核心，但仍不清楚。 尽管不同种疟原虫的细胞周期不同，但它的持续时间是24小时的倍数，这 这让我们假设，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 红血球爆裂。但是什么机制导致了它的24小时持续？尽管红色有节奏地迸发 血细胞是由于寄生虫的细胞周期所致，似乎存在一种昼夜计时机制，即 与细胞周期无关，因为我的初步数据表明，即使是静止的寄生虫阶段也有24小时 基因表达的节律。生物钟通过基因表达调节多种生理功能 到行为上。拥有能够预测环境节律变化的生物钟是一种进化 对生物体有利。从细菌到人类，时钟成分的突变或之间的不同步 时钟和环境(慢性时差)会导致体能下降、新陈代谢紊乱和变短 寿命。研究还表明，寄主和寄生虫节律之间的不匹配对 疟疾寄生虫感染成功，惠及宿主。 这项建议的目标是确定疟原虫同步性的机制。要解决这个问题 基本问题，我将系统地剖析寄生虫细胞周期和系统寄主的贡献 这是这一现象的信号。通过下一代测序，我的目标是确定有节奏的基因表达 当1)潜入哺乳动物的血液中时；2)在静止阶段；以及3)在没有 体外系统寄主信号。后者将使我能够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 哺乳动物细胞，它们的细胞周期持续时间减慢，但它们的生物钟保持在24小时。 这些研究将产生一个全面的框架，以解决疟疾中的一个长期问题。 菲尔德。更广泛地说，通过剖析发烧的周期性是由宿主信号还是由内部信号驱动的 这些研究将指导扰乱寄生虫同步性的策略。 以及开发替代方法来应对这种致命的疾病。 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