Lectin-Carbohydrate Interactions in the Host-Parasite System

描述（由申请人提供）：寄生虫是一些虫媒传染病的病原体，如疟疾和丝虫病。昆虫对寄生虫感染的反应是细胞免疫和体液免疫。然而，寄生虫已经发展出逃避或抑制其载体的免疫应答的策略。昆虫必须首先识别病原体才能产生免疫反应，而对非自身感染因子的识别是由模式识别受体（PRRs）介导的。我们对昆虫中作为PRR的蛋白质有一些了解，以刺激对细菌或真菌感染的免疫反应。然而，关于昆虫免疫系统如何识别真核寄生虫以及这些寄生虫如何逃避宿主免疫系统的知之甚少。我们建议，寄生虫有其表面的分子特征的变化，这决定了选择性结合的宿主蛋白质的寄生虫和寄生虫的命运。C型凝集素是在先天免疫中具有PRR功能的蛋白质家族。我们已经确定了一组C型凝集素（免疫凝集素）从烟草天蛾，其功能作为PRRs刺激免疫反应。Immulectin-2（IML-2）可直接与秀丽隐杆线虫和马来丝虫结合，IML-2与C.线虫刺激蠕虫的黑化。然而，C型凝集素从蚊子没有得到很好的表征，特别是关于生化功能。因此，我们将使用两个系统，M。研究IML-2和Armigeres C型凝集素与微丝蚴的相互作用，以及IML-2和Armigeres C型凝集素在微丝蚴黑色素包裹中的作用。本研究的两个具体目的是：1）研究昆虫原型C型凝集素--天蛾免疫凝集素2（Manduca immulectin-2）与线虫（B）的分子相互作用。马来B pahangi，黑腹叶蝉D. immitis和C. elegans）作为理解影响模式识别和先天免疫应答结果的潜在凝集素-寄生虫相互作用的指南。2)研究了9种阿蚊C型凝集素对微丝蚴（B.马来B pahangi和D. immitis），并研究了这些凝集素在微丝蚴黑色素包裹中的作用。近白纹的鉴定C. elegans和B. malayi，可以被Manduca immulectin-2或Armigeres C型凝集素识别。寄生虫是一些虫媒传染病如疟疾和丝虫病的病原体。昆虫对寄生虫感染的反应是细胞免疫和体液免疫。然而，昆虫必须首先识别病原体，然后才能产生免疫反应，而对非自身感染因子的识别是由模式识别受体（PRRs）介导的。我们对昆虫中作为PRR的蛋白质有一些了解，以刺激对细菌或真菌感染的免疫反应。然而，人们对昆虫免疫系统如何识别非真菌真核寄生虫知之甚少：这些生物体上与病原体相关的分子模式是什么，PRRs与它们结合在一起？C型（钙依赖性）凝集素是在脊椎动物和无脊椎动物的先天免疫系统中具有PRR功能的蛋白质家族。该项目是研究如何选择性结合宿主蛋白质的寄生虫决定的命运，使用两个系统，烟草天蛾Manduca sexta -线虫和蚊子Armigeres subalbatus -丝虫线虫。

DESCRIPTION (provided by applicant): Parasites are causative agents of some insect-borne infectious diseases such as malaria and filariasis. Insects respond to infection by parasites with both cellular and humoral immune responses. However, parasites have developed strategies to evade or suppress immune responses of their vectors. Insects must first recognize pathogens before they can mount an immune response, and recognition of nonself infective agents is mediated by pattern recognition receptors (PRRs). We have some understanding of the proteins that serve as PRRs in insects to stimulate immune responses to bacterial or fungal infection. However, very little is known about how insect immune systems recognize eukaryotic parasites and how these parasites evade the host immune system. We propose that parasites have variations in the molecular character of their surface, which determine selective binding of host proteins to parasites and the fate of parasites. The C-type lectins are a family of proteins with functions as PRRs in innate immunity. We have identified a group of C-type lectins (immulectins) from the tobacco hornworm Manduca sexta, which function as PRRs to stimulate immune responses. Immulectin-2 (IML-2) directly binds to nematodes Caenorhabditis elegans and Brugia malayi, and binding of IML-2 to C. elegans stimulates melanization of the worms. However, C-type lectins from mosquitoes have not been well characterized, particularly with regard to biochemical functions. Thus, we will use two systems, M. sexta - nematodes and the mosquito Armigeres subalbatus - filarial nematodes, to study interactions of IML-2 and Armigeres C-type lectins with microfilariae, and to study the roles of IML-2 and Armigeres lectins in melanotic encapsulation of microfilariae. The two specific aims are: 1) Investigate molecular interaction of an insect prototype C-type lectin, Manduca immulectin-2, with nematodes (B. malayi, B. pahangi, D. immitis, and C. elegans) as a guide to understanding potential lectin-parasite interactions that influence the outcome of pattern recognition and innate immune responses. 2) Investigate the ligand-binding specificity and affinity of nine selected Armigeres C-type lectins for microfilariae (B. malayi, B. pahangi, and D. immitis), and study functions of these lectins in melanotic encapsulation of microfilariae in Ar. subalbatus. Identify surface proteins or surface polysaccharides of C. elegans and B. malayi that can be recognized by Manduca immulectin-2 or Armigeres C-type lectins. PUBLIC HEALTH RELEVANCE Parasites are causative agents of some insect-borne infectious diseases such as malaria and filariasis. Insects respond to infection by parasites with both cellular and humoral immune responses. However, insects must first recognize pathogens before they can mount an immune response, and recognition of nonself infective agents is mediated by pattern recognition receptors (PRRs). We have some understanding of the proteins that serve as PRRs in insects to stimulate immune responses to bacterial or fungal infection. However, very little is known about how insect immune systems recognize non-fungal eukaryotic parasites: what are the pathogen-associated molecular patterns on such organisms and what PRRs bind to them? The C-type (calcium-dependent) lectins are a family of proteins with functions as PRRs in innate immune systems of vertebrates and invertebrates. This project is to investigate how selective binding of host proteins to parasites determines the fate of parasites using two systems, the tobacco hornworm Manduca sexta - nematodes and the mosquito Armigeres subalbatus - filarial nematodes.