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

宿主-寄生虫相互作用作为定义免疫调节途径的模型

• 批准号: RGPIN-2017-03826
• 负责人: McKay, Derek
• 金额: $ 3.5万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=659316
• 关键词: Host; parasite; interactions; model; define

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.*****

寄生蠕虫（蠕虫）的影响在加拿大感受到，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传播，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范围内具有重大的社会经济影响，例如，降低动物福利和生产力。 寄生蠕虫和宿主已经共同进化，解开两者之间的双向通信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-mouse模型来定义：（a）旨在消灭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。 免疫包括两个主要的武器，协调一致地发挥作用，以打击微生物和蠕虫感染：先天性和适应性。 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。 缺乏关于对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，我专注于肠道细菌，上皮细胞和中性粒细胞作为先天免疫的关键要素，这些要素在寄生虫感染方面基本上被忽视了：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。 本研究将利用本实验室或合作者建立的前沿方法和模型，在H。缺陷鼠模型将揭示免疫调节的新方面，以推进宿主与寄生虫相互作用的知识，而这些知识可以转化为寄生和免疫调节的新方法。**目的：*[1]确定是否，然后如何感染H。diminuta干扰肠道细菌，如果这些变化在H.减少引起的肠道炎症抑制。[2]确定H.缺陷直接影响上皮细胞以促进辅助性T细胞2免疫。** [3]以确定是否暴露于H。缺陷衍生的分子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的附带损害有关）的发育。**结果和意义。初步数据显示，这些先天免疫元件中的每一个都被H.虫体或虫体的粗提取物。 定义这些变化如何塑造适应性免疫以促进蠕虫驱逐可以彻底改变如何看待蠕虫-宿主相互作用，最终影响新策略的发展，以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）并管理任何共病。