The role of fatty acid- and retinol-binding proteins in parasitic nematode infections.

 描述(申请人提供)：寄生线虫能够如此成功地避开和抑制其宿主的免疫系统，以至于全球超过25%的种群被线虫寄生虫感染。目前控制线虫感染的战略是不够的，耐药性的增加是一个全球关切的问题。减少线虫感染流行的一个策略是防止这些寄生虫抑制宿主免疫，从而允许宿主的免疫反应来对抗或消除感染。然而，关于线虫寄生虫如何躲避检测或如何抑制免疫力，人们知之甚少。越来越多的研究表明，线虫脂肪酸和视黄醇结合蛋白(FAR)与寄生虫的寄生有关，并帮助寄生虫抑制免疫。治疗线虫感染最成功和最广泛使用的药物伊维菌素被证明直接结合或干扰线虫Far蛋白的结合。在这里，我建议：1)鉴定寄生线虫分泌到宿主体内的FAR蛋白，2)确定这些FAR蛋白与脂肪酸免疫信号分子的结合亲和力和特异性，3)确定FAR蛋白在体内感染模型中的作用。我将使用昆虫寄生线虫Steinnema carpocapsae和模式昆虫宿主果蝇黑腹果蝇来研究FAR蛋白I线虫感染的作用。这些模型克服了与研究人类寄生虫相关的技术障碍，并已成功地用于增加我们对脊椎动物寄生虫和先天免疫的了解。这项K22奖将提供实验资源、时间和培训，以确定用于寄生虫的FAR蛋白，并确定它们在感染中的功能作用。具体地说，这个奖项将使我能够培养1)纯化和鉴定分泌蛋白质的技能，2)克隆和表达转基因蛋白质的工具和专业知识，3)产生新的重要数据，为新的研究计划奠定基础。这些研究涉及免疫学中一个研究不足的领域：寄生线虫如何抑制宿主免疫。此外，通过利用强大的果蝇和昆虫-寄生线虫模型系统，我将建立一套独特的 定义免疫抑制的分子基础的工具，然后可以在适当的脊椎动物系统中进行测试，并用于开发和测试针对这些寄生虫免疫效应器的治疗方法。

 DESCRIPTION (provided by applicant): Parasitic nematodes are able to avoid and suppress the immune system of their hosts so successfully that more than 25% of the global population is infected by nematode parasites. Current strategies to control nematode infections are inadequate and increased drug resistance is a global concern. One strategy to reduce the prevalence of nematode infections is to prevent these parasites from suppressing host immunity, thus allowing the host's immune response to counter or eliminate infections. However, little is known about how nematode parasites avoid detection or how they suppress immunity. A growing body of research suggests that nematode fatty acid- and retinol-binding (FAR) proteins are involved in parasitism and help the parasites suppress immunity. The most successful and widely used drug to treat nematode infections, Ivermectin, has been show to bind directly to or interfere with the binding of nematode FAR proteins. Here I propose to: 1) identify the arsenal of FAR proteins that parasitic nematodes secrete into hosts, 2) determine the binding affinity and specificity of these FAR proteins to fatty acid immune signaling molecules, and 3) determine the effect of FAR proteins in an in vivo infection model. I will investigate the role of FAR proteins i nematode infections using the insect-parasitic nematode Steinernema carpocapsae and the model insect host Drosophila melanogaster. These models overcome technical obstacles associated with studying human parasites and have been successfully used to increase our understanding of vertebrate parasites and innate immunity. This K22 award will provide the experimental resources, time, and training to identify the FAR proteins used in parasitism and to determine their functional role in infection. Specifically, this award will allow me to develop 1) skills in the purification and identification of secreted proteins, 2) tools and expertise in the cloning and expression of transgenic proteins and, 3) generate novel and important data that will establish the foundation of a new research program. These studies address an understudied area in immunology: how parasitic nematodes suppress host immunity. Moreover, by exploiting the powerful fruit fly and insect-parasitic nematode model systems I will establish a unique set of tools to define the molecular underpinnings of immune suppression that can then be taken and tested in an appropriate vertebrate system and used to develop and test treatments that target these parasitic immune effectors.