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，使人衰弱，可怕地毁容，估计在整个热带地区有1.2亿人受到影响。它是由寄生在淋巴系统中的丝虫（班氏丝虫和马来丝虫）引起的。为了延续它们的生命周期，受精的成年雌性蠕虫产生数百万条进入血液的微丝蚴（mf），希望其中一些会被适当的蚊子媒介摄取。事实上，患者血液中存在鞘状mf是淋巴丝虫病的明确诊断。在大部分的地理范围内，W。bancrofti和B.马来人表现出夜间周期性--也就是说，mf只有在半夜才在外周血中变得丰富。在白天，mf被隔离在肺的肺泡毛细血管中，几乎不存在于外周血中，这使得它们不仅不能被临床诊断医生所接近，也不能被潜在的蚊子媒介所接近。近几十年来，夜间周期性的机制一直是一个被忽视的研究领域，因此，负责使mf的昼夜节律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，它以有规律的昼夜节律周期性从松果体分泌到血液中。为了检验这一假设，我们将使用具有明显夜间周期性的自然发生的鸟类丝虫病系统（例如，常见的八哥中的Quiscali丝状菌）。待测试的具体目的是1）确定内源性褪黑激素分泌是否调节微丝蚴寄生虫的夜间周期性，和2）确定褪黑激素受体拮抗剂是否可以施用给微丝蚴病宿主以使宿主和寄生虫的昼夜节律不同步，从而防止蚊子摄入mf。重要性：如果能阻止蚊子摄入MF，那么受感染宿主体内的寄生虫就不会传播，疾病的进一步传播也将被阻止。R 03的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。 公共卫生相关性：这项工作从宿主昼夜节律的激素控制的角度研究了丝虫的夜间周期性现象。这可能为阻断淋巴丝虫病的传播提供一种新的治疗方法。

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.