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

 描述（由申请人提供）：寄生线虫能够成功地避开和抑制其宿主的免疫系统，以至于全球超过25%的人口被线虫寄生虫感染。目前控制线虫感染的策略是不够的，耐药性增加是一个全球性的问题。减少线虫感染流行的一种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应答对抗或消除感染。然而，关于线虫寄生虫如何避免检测或它们如何抑制免疫力，我们知之甚少。越来越多的研究表明，线虫脂肪酸和视黄醇结合（FAR）蛋白参与寄生，并帮助寄生虫抑制免疫。伊维菌素是治疗线虫感染最成功和最广泛使用的药物，已显示其直接结合或干扰线虫FAR蛋白的结合。我在此提议：1）鉴定寄生线虫分泌到宿主中的FAR蛋白的武库，2）确定这些FAR蛋白对脂肪酸免疫信号分子的结合亲和力和特异性，和3）确定FAR蛋白在体内感染模型中的作用。我将研究FAR蛋白在线虫感染中的作用，使用昆虫寄生线虫Steinernema carpocapsae和模式昆虫宿主果蝇。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理解。该K22奖将提供实验资源，时间和培训，以确定寄生虫中使用的FAR蛋白，并确定其在感染中的功能作用。具体来说，该奖项将使我能够发展1）分泌蛋白的纯化和鉴定技能，2）转基因蛋白克隆和表达的工具和专业知识，3）产生新的重要数据，为新的研究计划奠定基础。这些研究解决了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力。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 工具来定义免疫抑制的分子基础，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免疫效应物的治疗。

 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.