Giardiasis as a model to study microbial-microbial interactions in the gut

贾第鞭毛虫病作为研究肠道微生物间相互作用的模型

• 批准号: RGPIN-2016-03640
• 负责人: Buret, Andre
• 金额: $ 5.25万
• 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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=708195
• 关键词: Giardiasis; model; study; microbial; interactions

The overarching goal of my now 19-year-old NSERC program is to use the model of giardiasis to understand fundamental mechanisms of host-microbial as well as microbial-microbial interactions that regulate healthy state function in the gut. Infection with Giardia duodenalis, is a cosmopolitan cause of waterborne diarrhea in a broad range of animals, including livestock, making this parasite a significant cause of economic loss to the food-producing industry. In addition to its direct effects on gut function, recent evidence illustrates that giardiasis leads to post-infectious disruptions, in the gut as well as extra-intestinally, via mechanisms that remain unclear (dog/horses urticaria, lameness, impaired weight gain). Our recent findings also demonstrate that Giardia sp. may protect against gut bacterial infection via direct anti-inflammatory properties. Gut commensal microbial communities live as highly structured consortia within spatial organizations called biofilms. The interplay between gut microbiota and host is increasingly recognized as a key to host immunity, development, and physiology; yet little is known of the homeostatic significance of their biofilm phenotype, and how this contributes to homeostasis. Hypothesis : Microbiota biofilm structure and function are key to intestinal homeostasis, and Giardia-induced disruptions of this state may demonstrate its physiological significance. This research therefore will enable us to uncover new aspects of fundamental intestinal physiology. Long-term goal: To improve our understanding of how microbial-microbial interactions and host factors modulate gastrointestinal biology. Using complimentary models of microbiota from porcine or human gut samples, in conjunction with porcine and human intestinal cells, the nematode C. elegans, or in mice, the overall objective of the present application is to identify new mechanisms of how disruptions to commensal gut microbiota biofilms and mucus caused by an enteropathogen (Giardia) may be responsible for post-infectious intestinal disruption, and to evaluate the stabilizing effects of a prototype H2S-releasing compound on these abnormalities in animal models systems. Specific aims will characterize: 1) the effects of G. duodenalis on porcine and human mucosal microbiota biofilms, and mucus. 2) the effects of G. duodenalis on commensal and enteropathogenic bacteria, and gut inflammation. 3) the role of G. duodenalis cysteine protease cathepsin B in these effects. 4) the benefits of a new H2S-releasing compound (which we developed) on these abnormalities. This program will help expand upon our well-recognized international collaborative expertise on the Protozoan Giardia sp. By improving our understanding of the effects of Giardia sp. on the structure and function of microbiota biofilms, this project will shed new light on fundamental aspects of intestinal physiology.

我现在19岁的NSERC计划的首要目标是使用贾第虫病模型来了解宿主-微生物以及微生物-微生物相互作用的基本机制，这些机制调节肠道中的健康状态功能。 贾第鞭毛虫感染是包括牲畜在内的广泛动物中的水传播性腹泻的世界性原因，使这种寄生虫成为食品生产行业经济损失的重要原因。除了对肠道功能的直接影响外，最近的证据表明，贾第虫病通过尚不清楚的机制（犬/马荨麻疹、跛行、体重增加受损）导致肠道和肠道外感染后破坏。我们最近的研究结果还表明，贾第虫属物种可以通过直接抗炎特性防止肠道细菌感染。 肠道微生物群落在称为生物膜的空间组织中以高度结构化的财团形式生活。肠道微生物群和宿主之间的相互作用越来越被认为是宿主免疫、发育和生理学的关键;但对其生物膜表型的稳态意义以及这如何有助于稳态知之甚少。 假设：微生物群生物膜结构和功能是肠道稳态的关键，贾第鞭毛虫诱导的这种状态的破坏可能表明其生理意义。因此，这项研究将使我们能够揭示基本肠道生理学的新方面。 长期目标：提高我们对微生物-微生物相互作用和宿主因素如何调节胃肠道生物学的理解。使用猪或人肠道样品的互补微生物群模型，结合猪和人的肠道细胞，线虫C。在线虫或小鼠中，本申请的总体目的是鉴定由肠病原体（贾第虫属）引起的肠道微生物群生物膜和粘液的破坏如何可能是感染后肠道破坏的原因的新机制，并评估原型H2S释放化合物对动物模型系统中这些异常的稳定作用。 具体目标将包括： 1)G.猪和人类粘膜微生物群生物膜和粘液上的嗜热链球菌。 2)G.对肠道和肠道致病菌，肠道炎症。 3)G.大肠杆菌半胱氨酸蛋白酶组织蛋白酶B在这些影响。 4)一种新的硫化氢释放化合物（我们开发的）对这些异常的好处。 该计划将有助于扩大我们在原生动物贾第鞭毛虫上的国际合作专业知识，通过提高我们对贾第鞭毛虫对微生物群生物膜结构和功能的影响的理解，该项目将为肠道生理学的基本方面提供新的见解。