Innate immune responses in lymphatic filariasis

描述（由申请人提供）：本申请的研究目标是启动鉴定特异性先天免疫受体的研究，包括被丝虫和沃尔巴克氏体产物激活的toll样受体（tlr）。此外，早期免疫效应分子参与炎症反应，如细胞因子和趋化因子，将被确定。初步的实验室研究将利用转染细胞系和动物模型来确定重要的受体途径。后续工作将利用巴布亚新几内亚感染班氏乌chereria bancroti的人的外周血单核细胞，确认在人类疾病中对丝虫和沃尔巴克氏体产物的识别和反应机制。实验室技术、研究方法和伦理、实地研究和热带临床医学方面的培训将是该项目的重要组成部分。沃尔巴克氏体是一种必需的细胞内细菌，可感染所有具有医学意义的丝虫病种。最近的观察表明，沃尔巴克氏体内共生菌的脂多糖（LPS）样产物可诱导哺乳动物宿主的急性炎症反应。初步研究表明，马来亚麻花提取物可刺激tnf - α、IL-6和IL-10的产生。相比之下，未感染沃尔巴克氏体的棘条线虫（Acanthocheilonema viteae）或用强力霉素处理过的马来芽胞杆菌（B. malayi）对单核细胞产生的细胞因子几乎没有刺激。通过转染表达人toll样受体的细胞系和暴露于具有LPS - TLR4相互作用竞争性抑制剂的马来蓝杆菌提取物的单核细胞进行的实验表明，布鲁吉亚的刺激作用通过TLR4和TLR4非依赖性途径发挥作用。然而，参与识别线虫和沃尔巴克氏体配体的受体的差异和相似性尚未确定。本项目的目的是鉴定特定的先天免疫受体，包括toll样受体家族和由丝虫和沃尔巴克氏体产物激活的信号通路，并表征人类宿主识别和响应丝虫感染的早期先天免疫机制，包括由内共生沃尔巴克氏体介导的感染。

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.