Evolutionary and functional relationships of cytokines expressed by the helminth Echinococcus multilocularis and its mammalian host

寄生蠕虫通过分泌IL-10和转化生长因子-β等细胞因子，诱导调节性T细胞和激活巨噬细胞的免疫抑制效应，诱导与Th2型偏向的免疫反应和免疫抑制相关的长期、慢性感染。作为后生动物，蠕虫与它们的哺乳动物宿主关系密切，利用进化上保守的细胞因子进行细胞-细胞通讯，这些细胞因子也参与调节哺乳动物的先天和获得性免疫反应。本课题研究寄生蠕虫是否利用进化上保守的细胞因子干扰抗寄生虫的免疫反应，改变感染部位的宿主细胞生理。作为一个模型，我们以多房棘球绦虫幼虫阶段为模型，我们为其开发了复杂的体外培养系统，启动了基因组测序计划，并鉴定了几种进化上保守的细胞因子，特别是转化生长因子-β/骨形态发生蛋白家族。本项目首先旨在在哺乳动物表达系统中功能性地表达寄生虫的转化生长因子-β/骨形态发生蛋白同源基因，并研究它们与宿主转化生长因子-β/骨形态发生蛋白受体家族相应的表面受体的相互作用。根据已确定的激活模式，将建立体外实验，研究感染早期和晚期寄生虫来源的细胞因子对免疫效应细胞和主要感染部位肝脏细胞的激活的影响。

Parasitic helminths induce long-lasting, chronic infections associated with Th2-biased immune responses and strong immunosuppressive effects, elicited by regulatory T cells and alternatively activated macrophages through the secretion of cytokines like IL-10 and TGF-β. As metazoans, helminths are closely related to their mammalian hosts and utilize evolutionary conserved cytokines for cell-cell-communication that are also involved in regulating innate and adaptive immune responses in mammals. The present project investigates whether parasitic helminths utilize evolutionary conserved cytokines to interfere with the anti-parasitic immune response and to alter host cell physiology at the site of infection. As a model, we use the larval stage of the tapeworm Echinococcus multilocularis for which we have developed sophisticated in vitro cultivation systems, initiated a genome sequencing project, and characterized several evolutionary conserved cytokines, in particular of the TGF-β/BMP-family. This project first aims to functionally express the parasite’s TGF-β/BMP-orthologs in mammalian expression systems and to study their interaction with corresponding surface receptors of the TGF-β/BMP-receptor families of the host. Based on the identified activation patterns, in vitro assays to study the effects of parasite-derived cytokines from early and late stages of the infection on the activation of immune-effector cells and cells of the liver, the primary site of infection, will be established.