It's about time: the evolution and ecology of circadian rhythms in infectious disease

生物节律似乎是一个优雅的解决方案，以协调活动与地球的日常和季节性旋转的后果的挑战。基因和分子机制支撑着驱动日常节奏的时钟，这一点已经很清楚了。相比之下，对日常节律的成本和收益--包括生物体之间的相互作用--的了解仍然非常少。生物体之间最基本的相互作用之一是宿主和寄生虫之间的相互作用。为什么寄生虫-只生活在其他生物体内-表现出生物节律以及它们的节律是如何调节的，这是一个长期存在的问题，没有令人满意的答案。研究生物节律在疾病中的作用是研究宿主-寄生虫-媒介协同进化的一个新的竞技场。该项目将侧重于疟疾寄生虫，这是一个很好的模式系统的致病生物体，也具有重大的医疗和经济意义。几个世纪以来，感染病人的疟原虫的种类是通过发烧的规律性（每1、2或3天）来诊断的。发热是由于宿主血液中疟原虫的同步爆发，当它们释放出后代感染新的红细胞并引起疟疾症状时。尽管这些古老的知识，为什么这些寄生虫有一个日常的节奏是未知的。然而，我的实验室已经证明，疟原虫的生存和传播取决于它们在宿主血液中复制的时间与宿主进食周期的时间之间的同步性。该项目将研究为什么与宿主进食有关的时间对于寄生虫适应性的关键组成部分-在宿主中的生存和向蚊子媒介的传播至关重要。这个跨学科项目将通过阐明寄生虫节律的适应意义（进化成本和收益）来开辟新的领域。它将整合新的学科组合（进化生态学，时间生物学和寄生虫学），并为疾病控制开辟新的途径。这包括开发药物来破坏寄生虫的节律，利用昼夜节律系统来增强免疫反应，或者精确地定时给药以使治疗更有效。越来越多的证据表明，疟疾寄生虫的每日节律可以赋予抗疟药物耐受性，而蚊帐的使用正在改变传播疟疾的蚊子的叮咬时间，这使得了解寄生虫如何以及为什么表现出每日节律变得越来越紧迫。该项目将使用啮齿动物（夏氏疟原虫）和蚊子的疟疾寄生虫。

Biological rhythms appear to be an elegant solution to the challenge of coordinating activities with the consequences of the Earth's daily and seasonal rotation. The genes and molecular mechanisms underpinning the clocks that drive daily rhythms are well understood. In contrast, the costs and benefits provided by daily rhythms - including how rhythms shape interactions between organisms - remain remarkably poorly understood. One of the most fundamental interactions between organisms is that between hosts and parasites. Why parasites - that exclusively live within the bodies of other organisms - exhibit biological rhythms and how their rhythms are regulated are longstanding questions with no satisfactory answers. Examining the roles of biological rhythms in disease is a new arena for studying host-parasite-vector coevolution. The project will focus on malaria parasites, which are an excellent model system for disease-causing organisms and also of great medical and economic importance. For several centuries, the species of malaria parasite infecting a patient was diagnosed by the regularity of fever (every 1, 2, or 3 days). Fever results from the synchronous bursting of malaria parasites in the host's blood when they release their progeny to infect new red blood cells and cause the symptoms of malaria. Despite such ancient knowledge, why these parasites have a daily rhythm is unknown. However, my lab has shown that the survival and transmission of malaria parasites depends synchrony between the timing of their replication in the host's blood with the timing of the host's feeding cycles. The project will investigate why timing in related to host feeding matters for key components of parasite fitness - survival in the host and transmission to mosquito vectors.This interdisciplinary project will break new ground by elucidating the adaptive significance (evolutionary costs and benefits) of rhythms for parasites. It will integrate a novel mix of disciplines (evolutionary ecology, chronobiology, and parasitology) and open up novel avenues for disease control. This includes the development of drugs to disrupt parasite rhythms, harnessing circadian systems to enhance immune responses, or precisely timing drug administration to make treatment more effective. Growing evidence that the daily rhythms of malaria parasites can confer tolerance to antimalarial drugs, and that the use of bed nets is changing the biting time of the mosquitoes that transmit malaria makes understanding how and why parasites exhibit daily rhythms increasingly urgent. The project will use malaria parasites of rodents (Plasmodium chabaudi) and mosquitoes.