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研究以鉴定特异性先天免疫受体，包括由丝虫和沃尔巴克氏体产物激活的toll样受体（tlr）。此外，还将鉴定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染的细胞系和动物模型来鉴定重要的受体途径。随后的工作将使用来自巴布亚新几内亚班氏吴策线虫感染者的外周血单核细胞，确认人类疾病中对丝虫和沃尔巴克氏体产物的识别和应答机制。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。沃尔巴克氏体是专性细胞内细菌，感染所有具有医学意义的丝虫物种。最近的观察表明，类脂多糖（LPS）产品的沃尔巴克氏体内共生体诱导急性炎症反应的哺乳动物宿主。初步研究表明，使用CD 14+单核细胞从丝虫幼稚的人表明，B。马来提取物刺激TNF-α、IL-6和IL-10的产生。与此相反，棘唇线虫viteae，一种不感染沃尔巴克氏体的丝虫寄生虫，或B。用强力霉素处理的马来人几乎不刺激单核细胞产生细胞因子。使用表达人toll样受体的转染细胞系和暴露于B的单核细胞的实验。具有LPS-TLR 4相互作用的竞争性抑制剂的马来提取物表明，丝虫的刺激作用是通过TLR 4和TLR 4非依赖性途径发挥的。然而，参与识别线虫与沃尔巴克氏体配体的受体的差异和相似性尚未确定。该项目的目的是确定特定的先天免疫受体，包括toll样受体家族和信号通路，激活丝虫和沃尔巴克氏体的产品，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，包括内共生沃尔巴克氏体介导的机制。

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.