Innate immune responses in lymphatic filariasis

描述(申请人提供)：这项申请的研究目标是启动研究，以确定特定的先天性免疫受体，包括由丝虫和沃尔巴克氏菌产品激活的Toll样受体(TLR)。此外，还将识别参与炎症反应的早期免疫效应分子，如细胞因子和趋化因子。最初的实验室研究将利用转基因的细胞系和动物模型来识别重要的受体途径。稍后的工作将使用巴布亚新几内亚班克罗夫氏舞蹈菌感染者的外周血单核细胞来证实人类疾病中对丝虫和沃尔巴克氏菌产品的识别和反应机制。实验室技术、研究方法和伦理、实地研究和临床热带医学方面的培训将是该项目的重要组成部分。沃尔巴克氏菌是感染所有具有医学意义的丝虫物种的必备细胞内细菌。最近的观察表明，沃尔巴克氏菌内共生菌的脂多糖(LPS)样产物在哺乳动物宿主中诱导急性炎症反应。用来自幼虫人类的CD14+单核细胞进行的初步研究表明，马来丝虫提取物能刺激肿瘤坏死因子-α、白介素6和白介素10的产生。相比之下，未感染沃尔巴克氏菌的丝状寄生虫维氏棘毛虫或经强力霉素治疗的马来丝虫对单核细胞产生的细胞因子刺激很少或根本没有。用表达人Toll样受体的转基因细胞株和单核细胞暴露于马来丝虫提取物和竞争性的内毒素-TLR4相互作用抑制剂的实验表明，丝虫的刺激作用是通过TLR4和TLR4不依赖的途径发挥的。然而，参与识别线虫和沃尔巴克氏菌配体的受体的区别和相似之处尚未确定。该项目的目的是确定特定的天然免疫受体，包括Toll样受体家族和由丝虫和Wolbachia产物激活的信号通路，并表征人类宿主识别和应答丝虫感染的早期固有免疫机制，包括由内共生Wolbachia介导的感染。

DESCRIPTION (provided by applicant): The research goal of this application is to initiate studies to identify specific innate immune receptors, including toll-like receptors (tlr) that are activated by filarial and Wolbachia products. Additionally, early immune effector molecules involved in the inflammatory response, such as cytokines and chemokines, will be identified. Initial laboratory studies will utilize transfected cell lines and animal models to identify important receptor pathways. Later work will confirm the mechanism of recognition and response to filarial and Wolbachia products in human disease using peripheral blood monocytes from humans infected with Wuchereria bancrofti in Papua New Guinea. Training in laboratory techniques, research methodology and ethics, field based research and clinical tropical medicine will be important components of the project. Wolbachia are obligatory intracellular bacteria that infect all filarial species of medical significance. Recent observations indicate that lipopolysaccharide (LPS)-Iike products of Wolbachia endosymbionts induce acute inflammatory responses in the mammalian host. Preliminary studies using CD14+ monocytes from filadae-naive humans indicate that B. malayi extracts stimulate TNF-alpha, IL-6, and IL-10 production. In contrast, Acanthocheilonema viteae, a filarial parasite not infected with Wolbachia, or B. malayi treated with doxycycline stimulate little to no cytokine production by monocytes. Experiments using transfected cell lines expressing human toll-like receptors and monocytes exposed to B. malayi extracts with competitive inhibitors of the LPS - TLR4 interaction suggest that the stimulatory effects of Brugia are exerted through both TLR4 and TLR4-independent pathways. However, differences and similarities of receptors involved in recognition of nematode versus Wolbachia ligands have not yet been identified. The aims of this project are to identify specific innate immune receptors including the toll-like receptor family and signaling pathways that are activated by filarial and Wolbachia products and to characterize the early innate immune mechanisms by which the human host recognizes and responds to filarial infections including those mediated by endosymbiotic Wolbachia.