Host-parasite interactions as a model to define immunological regulatory pathways

寄生蠕虫(蠕虫)的影响在加拿大感受到，那里的家畜、同伴动物和人类可能会感染蠕虫。随着抗虫药耐药性的产生和蔓延，对寄生蠕虫的新方法的需求尚未得到满足：它们在加拿大和全球都产生了重大的社会经济影响，例如降低了动物的福祉和生产力。寄生蠕虫和宿主是共同进化的，拆解两者之间的双向通信将产生增强抗蠕虫反应和/或将共病降至最低的方法。我使用绦虫微小膜虫-小鼠模型来定义：(A)旨在根除寄生虫的基本免疫反应；(2)蠕虫试图阻止宿主试图消灭它的机制。 免疫由两个主要手臂组成，它们一致发挥作用，对抗微生物和蠕虫感染：先天和获得性。众所周知，获得性免疫对于驱除肠道中的蠕虫至关重要；然而，先天免疫启动并指导获得性免疫。缺乏有关蠕虫寄生虫的先天免疫反应的数据。为了解决这一知识差距，我将重点放在肠道细菌、上皮细胞和中性粒细胞作为先天免疫的关键元素，这些元素在寄生虫感染方面在很大程度上被忽视：现有数据是描述性的，几乎没有阐明肠道中的这种变化是否/如何影响感染的结果。使用我的实验室或我的合作者建立的尖端方法和模型，将在指导性假设下进行一系列研究，即分析微小毛虫-小鼠模型将揭示免疫调节的新方面，以促进宿主-寄生虫相互作用的知识，这些知识可以转化为寄生虫和免疫调节的新方法。 目标： [1]为了确定感染微小螺旋藻是否以及如何扰乱肠道细菌，以及这些变化在微小螺旋藻引起的肠道炎症抑制中是否重要。 [2]确定微小螺旋体是否直接影响上皮细胞以促进T辅助细胞2的免疫。 [3]为了确定暴露于微小螺旋藻衍生分子是否促进调节性中性粒细胞(一种急性炎性吞噬细胞，通常与杀死细菌和对宿主组织的附带损害有关)的发展。 结果和意义。初步数据显示，这些先天免疫成分中的每一个都会被微小隐翅虫或蠕虫的粗提物感染改变，或直接对感染做出反应。确定这些变化如何塑造适应性免疫以促进蠕虫驱逐可能会彻底改变人们对蠕虫-宿主相互作用的看法，最终影响到操纵哺乳动物免疫反应以对抗蠕虫寄生虫感染、减少组织损伤(或促进组织修复)和管理任何并存疾病的新策略的发展。

The effects of parasitic helminths (worms) are felt in Canada, where domestic livestock, companion animals and humans can suffer from infection with helminths. As anti-worm drug resistance arises and spreads there is an unmet need for new approaches to parasitic helminths: they are of major socio-economic impact in Canada and globally in, for example, reduced animal well-being and productivity. Parasitic helminth and host have co-evolved and unraveling the bi-directional communication between the two will yield ways to enhance anti-worm responses and/or minimize co-morbidities. I use the tapeworm Hymenolepis diminuta-mouse model to define: (a) fundamental immune reactions aimed at eradicating the parasite; and, (2) mechanisms by which the helminth seeks to block the hosts' attempts to eliminate it. Immunity consists of two main arms that function in unison to combat microbial and helminth infections: innate and adaptive. It is well-known that adaptive immunity is critical for the expulsion of worms from the gut; however, innate immunity initiates and directs adaptive immunity. Data on the innate immune response to helminth parasites is lacking. Addressing this gap in knowledge I focus on gut bacteria, the epithelium, and neutrophils as key elements of innate immunity that have been largely ignored with respect to infection with parasitic helminths: available data are descriptive and shed little light on if/how such changes in the gut affect the outcome of infection. Using cutting-edge methods and models established in my lab, or that of my collaborators, a series of studies will be conducted under the Guiding Hypothesis that analysis of the H. diminuta-mouse model will reveal novel aspects of immune regulation to advance knowledge of host-parasite interactions than can be translated into new approaches to parasitism and immune modulation. Aims: [1] To determine if, then how, infection with H. diminuta perturbs the gut bacteria and if these changes are important in the H. diminuta-elicited suppression of inflammation in the gut. [2] To determine if H. diminuta directly affects epithelial cells to promote T-helper 2 immunity. [3] To determine if exposure to H. diminuta-derived molecules promote development of a regulatory neutrophil (an acute inflammatory phagocyte typically associated with killing of bacteria and collateral damage to host tissue). Outcome & Significance. Preliminary data reveal that each of these innate immune elements are changed by, or directly respond to infection with H. diminuta or a crude extract of the worm. Defining how such changes mold adaptive immunity to promote worm expulsion can revolutionize how helminth-host interactions are viewed, ultimately impacting the development of novel strategies to manipulate the mammalian immune response to combat infection with helminth parasites, reduce tissue damage (or promote tissue repair) and manage any co-morbidity.