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

胃肠道寄生虫感染是家畜中最常见的寄生虫感染类型之一，造成相当大的动物健康不良和农业经济损失。目前的控制机制依赖于使用化疗方法，但由于寄生虫产生耐药性，化疗的效果受到严重损害。需要新的方法来控制胃肠道蠕虫。了解宿主的先天和适应性防御机制是确定新的控制途径的关键。尽管我们对控制胃肠道寄生虫适应性免疫反应的免疫调节机制的理解有了相当大的提高，但在确定保护机制方面进展缓慢。从胃肠道中清除这些大型多细胞病原体主要是围绕宿主分子和细胞的能力，直接影响寄生虫的正常代谢活动，降低它们的适应性，或间接改变寄生虫生存的生态位，使其不利于寄生虫的生存。最终的结果是，寄生虫受到损害，通常不会被宿主的反应杀死，但无法进行最佳繁殖，并最终在正常的肠道运输过程中被驱逐出宿主。粘膜屏障，包括肠上皮和上覆的粘液凝胶，是寄生虫磨损的关键部位。2型细胞因子反应控制肠道上皮细胞的多种变化，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中对胃肠道线虫的明确作用直到最近才被确定。我们已经确定了粘蛋白在胃肠道线虫保护性免疫中的关键作用，Trichuris muris是一个非常完善的体内模型，广泛用于定义宿主保护机制。基于我们早期研究的有力证据，我们假设凝胶形成的粘蛋白本身是一种主要的效应机制，参与了对肠道线虫的保护。这个项目的目标是定义凝胶形成的粘蛋白是如何通过体内小鼠模型（包括T. muris）介导对胃肠道线虫的保护。

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.