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

加拿大可以感受到寄生蠕虫（蠕虫）的影响，家畜、伴侣动物和人类都可能感染蠕虫。 随着抗蠕虫药物耐药性的出现和蔓延，对治疗寄生蠕虫的新方法的需求尚未得到满足：它们对加拿大和全球产生重大社会经济影响，例如降低动物福祉和生产力。 寄生蠕虫和宿主共同进化，解开两者之间的双向通讯将产生增强抗蠕虫反应和/或最小化共病的方法。 我使用绦虫 Hymenolepis diminuta 小鼠模型来定义：（a）旨在根除寄生虫的基本免疫反应； (2) 蠕虫试图阻止宿主消灭它的机制。 免疫由两个主要部分组成，它们协同作用来对抗微生物和蠕虫感染：先天性免疫和适应性免疫。 众所周知，适应性免疫对于将蠕虫从肠道中排出至关重要。然而，先天免疫启动并指导适应性免疫。 缺乏对蠕虫寄生虫的先天免疫反应的数据。 为了解决这一知识空白，我重点关注肠道细菌、上皮细胞和中性粒细胞，它们是先天免疫的关键要素，而在寄生虫感染方面，这些要素在很大程度上被忽视了：现有数据是描述性的，并没有说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，将在指导假设下进行一系列研究，即对 H. diminuta 小鼠模型的分析将揭示免疫调节的新方面，以增进对宿主 - 寄生虫相互作用的了解，从而转化为寄生和免疫调节的新方法。 目标： [1] 确定 H. diminuta 感染是否会扰乱肠道细菌，以及如何扰乱肠道细菌，以及这些变化对于 H. diminuta 引起的肠道炎症抑制是否重要。 [2] 确定 H. diminuta 是否直接影响上皮细胞以促进 T 辅助细胞 2 免疫。 [3] 确定接触 H. diminuta 衍生分子是否会促进调节性中性粒细胞（一种急性炎症吞噬细胞，通常与杀死细菌和对宿主组织造成附带损害相关）的发育。 结果与意义。初步数据显示，这些先天免疫元件中的每一个都会因 H. diminuta 或蠕虫粗提物的感染而改变，或直接对其做出反应。 定义这些变化如何塑造适应性免疫以促进蠕虫排出，可以彻底改变人们对蠕虫与宿主相互作用的看法，最终影响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）和管理任何共病的新策略的开发。

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.