Defining the mechanisms of mucosal defence against gastrointestinal nematodes: the role of the mucus barrier

胃肠道寄生虫(GI)感染是家畜最常见的寄生虫感染类型之一，给农业造成了相当大的动物健康和经济损失。目前的控制机制依赖于使用化疗方法，但由于寄生虫产生抗药性，这种方法的有效性受到严重影响。需要新的方法来控制胃肠道蠕虫。了解宿主固有的和适应性的防御机制是确定新的控制途径的关键。尽管我们对管理胃肠道寄生虫获得性免疫反应的免疫调节机制的了解有了相当大的提高，但在确定保护机制方面进展缓慢。从胃肠道清除如此大的多细胞病原体主要围绕宿主分子和细胞的能力，以直接影响寄生虫的正常代谢活动，降低它们的适合度，或间接改变寄生虫所在的生态位，使其不利于寄生虫的生存。最终结果是寄生虫受到破坏，通常不会被宿主的反应杀死，但无法以最佳方式繁殖，最终在正常的肠道转运过程中被驱逐出宿主。由肠道上皮和覆盖的粘液凝胶组成的粘膜屏障是寄生虫磨损的关键部位。2型细胞因子反应控制着肠道上皮细胞的各种细胞变化，这些变化与宿主对胃肠道线虫的保护有关。一个重要的特征是杯状细胞增生。尽管杯状细胞的主要分泌因子是凝胶形成的粘蛋白，但这些分子在粘膜保护作用方面对胃肠道线虫的保护作用直到最近才被确定。我们已经确定了粘蛋白在对胃肠道线虫的保护性免疫中的关键作用，毛滴虫是一种非常成熟的体内模型，广泛用于确定宿主保护机制。根据我们早期研究的有力证据，我们假设形成凝胶的粘蛋白是参与保护肠道线虫本身的主要效应机制。该项目的目标是利用包括毛滴虫在内的活体小鼠模型，确定凝胶形成的粘蛋白如何介导对胃肠道线虫的保护作用。

Infection by gastrointestinal parasites (GI) is one of the most common types of parasitic infection in domestic livestock responsible for considerable animal ill health and economic losses for the agricultural industry. Current mechanisms of control rely on the use of chemotherapeutic approaches, which, are severely compromised in efficacy by the development of resistance by the parasite. Novel approaches to control GI helminths are needed. An understanding of host innate and adaptive defence mechanisms is key to identifying new avenues for control. Despite a considerable increase in our understanding of the immunoregulatory mechanisms that govern the adaptive immune responses to GI parasites, progress in defining the mechanisms of protection has been slow. Removal of such large multicellular pathogens from the GI tract largely revolves around the capacity of host molecules and cells to directly affect the normal metabolic activity of the parasites reducing their fitness, or indirectly alter the niche in which the parasites live making it unfavourable for parasite survival. The net result is that parasites become damaged, are not often killed by the host response but are unable to reproduce optimally and are ultimately expelled out of the host during normal intestinal transit. The mucosal barrier, comprising the intestinal epithelium and overlying mucus gel, is key site of parasite attrition.Type 2 cytokine responses control a variety of cellular changes in the intestinal epithelia associated with host protection against GI nematodes. One important feature is goblet cell hyperplasia. Despite the fact that the major secreted factors from goblet cells are the gel-forming mucins, a clear role for these molecules in mucosal protection against GI nematodes has only recently been identified. We have identified a critical role for mucins in protective immunity to the GI nematode, Trichuris muris, a very well established in vivo model used extensively to define mechanisms of host protection. Based upon strong evidence from our earlier studies we hypothesise that gel-forming mucins are a major effector mechanism involved in protection against intestinal nematodes per se. The goals of this project are to define how gel-forming mucins mediate protection against GI nematodes using in vivo mouse models including T. muris.