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

阐明疟疾节律性机制：寄生虫的潜在生物钟

基本信息

批准号：
10449462
负责人：
Filipa Rijo-Ferreira
金额：
$ 2.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-18 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449462
关键词：
Address Bacteria Behavior Bite Blood Blood Cell Count Cell Cycle Cell Cycle Completion Cell division Cells Chronic Circadian Rhythms Culicidae Data Development Disease Dissection Diving Drops Environment Erythrocytes Fever Financial compensation Foundations Gene Expression Genes Genetic Genetic Transcription Goals Hormonal Hormones Human In Vitro Infection Invaded Jet Lag Syndrome Knowledge Lead Life Longevity Malaria Mammalian Cell Measures Metabolic Mus Mutant Strains Mice Mutation Nutrient Nutritional status Organism Output Parasite Control Parasites Parasitic Diseases Parasitic infection Pathway interactions Periodicity Phase Physiological Plasmodium Population Principal Investigator Process Property Research Rodent Rupture Salivary Glands Signal Transduction Sporozoites Symptoms System Technical Expertise Temperature Testing Work burden of illness circadian circadian pacemaker fitness global health malaria infection mouse model next generation sequencing novel success transcriptome

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

联系PD/PI：Rijo-Ferreira，Filipa 项目摘要疟疾是一种致命的寄生疾病。疟疾的主要症状是发烧，与破裂有关寄生虫细胞周期完成后，红细胞（RBC）寄生虫种群协调破裂的RBC，重新启动新的并重复直到其周期完成，然后新的RBC爆发发生。结果是阵发性发烧，其周期性与寄生虫细胞周期：48h或72h，用于人类特异性疟原虫，啮齿动物特异性疟原虫为24h 物种。寄生虫同步性的机制是这种现象的核心，仍然未知。尽管细胞周期的持续时间在疟原虫中有所不同，但它的持续时间为24h，这是导致我们假设发烧周期性的机制是寄生虫的内源性昼夜节律。我们的初步数据表明，宿主营养状况是同步的最强信号红细胞爆发。但是，什么机制导致其持续时间24小时？虽然有节奏的红色爆发血细胞是由于寄生虫细胞周期引起的，似乎存在一种昼夜节律机制独立于细胞周期，因为我的初步数据表明，即使是静态寄生虫阶段也有24小时基因表达的节奏。昼夜节律时钟从基因表达调节多个生理功能行为。拥有预期环境有节奏变化的昼夜节律是进化有机体的优势。从细菌到人类，时钟组件的突变或之间的突变时钟和环境（慢性喷射滞后）导致健身降低，代谢中断和较短寿命。还显示出宿主和寄生虫节奏之间的不匹配是有害的疟疾寄生虫感染成功，使宿主受益。该提案的目的是确定疟原虫同步性的机制。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全身宿主的贡献这一现象的信号。通过下一代测序，我旨在确定节奏基因表达 1）潜入哺乳动物的血液时； 2）在静止阶段； 3）在没有全身性主机信号在体外。后者将使我能够测试这些疟疾节奏是否为温度补偿：内源性昼夜节律的关键特征。通过降低培养的温度哺乳动物细胞，其细胞周期持续时间减慢，但昼夜节律的时钟保持在24小时。这些研究将产生一个全面的框架，以解决疟疾中的长期问题场地。更广泛地，通过剖析发烧的周期性是由主机信号还是内部驱动的寄生虫的昼夜节律时钟，这些研究将指导策略破坏寄生虫的同步性并开发解决这种致命疾病的替代方法。项目摘要

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sleeping Sickness: A Tale of Two Clocks.

DOI：
10.3389/fcimb.2020.525097
发表时间：
2020
期刊：
Frontiers in cellular and infection microbiology
影响因子：
5.7
作者：
Rijo-Ferreira F;Takahashi JS
通讯作者：
Takahashi JS

Circadian rhythms in infectious diseases and symbiosis.

DOI：
10.1016/j.semcdb.2021.09.004
发表时间：
2022-06
期刊：
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
影响因子：
7.3
作者：
Rijo-Ferreira, Filipa;Takahashi, Joseph S.
通讯作者：
Takahashi, Joseph S.

Trypanosoma brucei triggers a broad immune response in the adipose tissue.

DOI：
10.1371/journal.ppat.1009933
发表时间：
2021-09
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Machado H;Bizarra-Rebelo T;Costa-Sequeira M;Trindade S;Carvalho T;Rijo-Ferreira F;Rentroia-Pacheco B;Serre K;Figueiredo LM
通讯作者：
Figueiredo LM