Melatonin: pacemaker for nocturnal periodicity of microfilarial parasites

描述（由申请人提供）：淋巴丝虫病是一种蚊子传播的疾病，它使人虚弱，可怕地毁容，影响整个热带地区估计有1.2亿人。它是由居住在淋巴系统中的丝状线虫（bancrofti Wuchereria和Brugia malayi）引起的。为了延续它们的生命周期，受精的成年雌虫产生数百万微丝虫（mf），这些微丝虫进入血液，希望其中一些微丝虫能被合适的蚊子载体摄入。事实上，患者血液中出现鞘状丝虫病是淋巴丝虫病的明确诊断。在它们的大部分地理分布范围内，bancrofti和B. malayi表现出夜间周期性——也就是说，mf只在午夜时在外周血中变得丰富。在白天，mf被隔离在肺部的肺泡毛细血管中，几乎不存在于外周血中，这不仅使诊断临床医生无法接触到它们，而且也使潜在的蚊子载体无法接触到它们。近几十年来，夜间周期的机制一直是一个被忽视的研究领域，因此，负责使mf与人类宿主的昼夜节律同步的起搏器从未被阐明。假设：调节mf周期性的主要宿主线索是生物活性胺，褪黑激素，它从松果体以规律的昼夜周期分泌到血液中。为了验证这一假设，我们将使用一种具有明显夜间周期性的自然发生的鸟类丝虫病系统（例如，普通白头鸦中的Chandlerella quiscali丝虫）。测试的具体目的是1)确定内源性褪黑激素分泌是否调节微丝虫寄生虫的夜间周期，2)确定褪黑激素受体拮抗剂是否可以施用于微丝虫宿主，以解除宿主和寄生虫的昼夜节律同步，从而防止蚊子摄入mf。意义：如果能防止蚊子摄入mf，那么受感染宿主内的寄生虫就不会传播，疾病的进一步传播就会停止。这项R03应用是一项概念验证研究，可能会导致一种全新的治疗方法来阻断淋巴丝虫病的传播。

DESCRIPTION (provided by applicant): Lymphatic filariasis is a mosquito-borne disease that is debilitating, horribly disfiguring, and affects an estimated 120 million people throughout the tropics. It is caused by filarial nematodes (Wuchereria bancrofti and Brugia malayi) that inhabit the lymphatic system. To perpetuate their life cycle, inseminated adult female worms produce millions of microfilariae (mf) that enter the blood stream, in the hopes that some will be ingested by an appropriate mosquito vector. Indeed, the presence of sheathed mf in patient blood is a definitive diagnosis for lymphatic filariasis. Throughout most of their geographic range, W. bancrofti and B. malayi exhibit nocturnal periodicity - that is, the mf only become abundant in peripheral blood during the middle of the night. During the day, the mf become sequestered in the alveolar capillaries of the lungs and are virtually absent from peripheral blood, making them inaccessible not only to diagnostic clinicians but also to potential mosquito vectors. The mechanism of nocturnal periodicity has been a neglected area of research in recent decades and as a result, the pacemaker responsible for synchronizing the circadian rhythms of the mf with that of their human hosts has never been elucidated. Hypothesis: The primary host cue that regulates mf periodicity is the bioactive amine, melatonin, which is secreted into the blood stream from the pineal gland at a regular, circadian periodicity. To test this hypothesis, we will use a naturally-occurring avian system of filariasis with pronounced nocturnal periodicity (e.g., Chandlerella quiscali filarids in the Common Grackle). The specific aims to be tested are 1) to determine if endogenous melatonin secretion regulates the nocturnal periodicity of microfilarial parasites,and 2) to determine if melatonin receptor antagonists can be administered to microfilaremic hosts in order to de-synchronize the circadian rhythms of host and parasite and thereby prevent the ingestion of mf by mosquitoes. Significance: If mf are prevented from being ingested by mosquitoes, then the parasites within infected hosts will not be spread and further transmission of the disease will be halted. This R03 application is a proof-of-concept study that may lead to an entirely new therapeutic approach to block the transmission of lymphatic filariasis. PUBLIC HEALTH RELEVANCE: The work examines the phenomenon of nocturnal periodicity of filarial parasites from the perspective of hormonal control of host circadian rhythms. It may lead to a new therapeutic approach to block the transmission of lymphatic filariasis.