Gut host-microbiome-pathogen interaction: understanding the pathophysiology of bacterial infections

肠道宿主-微生物组-病原体相互作用：了解细菌感染的病理生理学

• 批准号: RGPIN-2020-06353
• 负责人: Costa, Matheus
• 金额: $ 1.75万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=741158
• 关键词: Gut; host; microbiome; pathogen; interaction

The intestinal tract is a unique organ system. Beyond its key functions of digestion and absorption of nutrients, it harbours a rich and diverse microbiota. In pork production, intestinal infections are a major barrier to optimal animal performance and to the industry economic competitiveness. The host-microbiome-pathogen interactions that takes place in the intestines play a role in both healthy and diseased states. Swine dysentery (SD), characterized by mucoid and bloody diarrhea, is a current challenge in the swine industry. There are no vaccines available, leaving antibiotics as the only way to treat and control the disease. It is caused by the spirochete Brachyspira hyodysenteriae, and during outbreaks up to 100% of a herd can be affected. Despite almost 100 years since SD was first described, we do still not understand how lesions develop. Here we propose to define the mechanisms that lead to SD, and to provide the basis for infection control and prevention strategies. We have previously shown that Brachyspira infection leads to high levels of nitric oxide (NO) by-products in the colon. NO stimulates vasodilation, mucus and chloride secretion in the intestine, all of which contribute to the hallmark clinical sign of SD: bloody diarrhea. Objective 1 will characterize the role and source of NO during the development of colitis and bloody diarrhea. We will employ our in vitro colon culture model, in combination with spatial gene expression and histology techniques, to understand how NO contributes to SD. Next, we will explore how an NO-inhibitor can be applied to prevent clinical signs. Objective 2 will investigate the ability of a novel Brachyspira bacteriocin to select the microbiota in the colon. Others have shown that pigs without a microbiota do not develop the clinical signs of SD. We will use a combination of in vitro and animal trials, molecular imaging and high-throughput sequencing, to clarify how the pathogen actively modulates the colon microbiome in its advantage, culminating in severe disease. Objective 3 will profile the immunosuppressive strategies employed by Brachyspira to avoid the host defences. Using immune cells isolated from the colon, we will explore how the pathogen supresses the initial immune response by profiling the transcriptome of these cells. This objective will shed a light on why previous vaccine development efforts have failed, and help future improvements. In the current post-antibiotic era, in face of multi-drug resistant bacteria, novel alternatives to control intestinal bacterial infections are needed. The work proposed here will clarify the mechanisms through which the host-microbiome-pathogen triad interact, and how we can leverage this knowledge to develop new strategies that mitigate disease, while not contributing to antimicrobial resistance.

肠道是一个独特的器官系统。除了消化和吸收营养物质的关键功能外，它还拥有丰富多样的微生物群。在猪肉生产中，肠道感染是影响最佳动物生产性能和行业经济竞争力的主要障碍。肠道中发生的宿主-微生物组-病原体相互作用在健康和患病状态下都起作用。猪痢疾（SD）是当前养猪业面临的一个挑战，其特征是粘液和血性腹泻。由于没有可用的疫苗，抗生素成为治疗和控制这种疾病的唯一方法。它是由水痢短螺旋体引起的，在疫情期间，多达100%的畜群可能受到影响。尽管距SD首次被描述已有近100年，但我们仍然不了解病变是如何发展的。在此，我们建议明确导致SD的机制，为感染控制和预防策略提供依据。我们以前已经表明，短螺旋体感染导致高水平的一氧化氮（NO）副产物在结肠。NO刺激肠道血管舒张，粘液和氯化物分泌，这些都是SD的标志性临床症状：血性腹泻的原因。目的1将描述一氧化氮在结肠炎和血性腹泻发展过程中的作用和来源。我们将采用体外结肠培养模型，结合空间基因表达和组织学技术来了解NO对SD的影响。接下来，我们将探讨如何应用no抑制剂来预防临床症状。目的2将研究一种新型短螺旋体细菌素选择结肠微生物群的能力。其他研究表明，没有微生物群的猪不会出现SD的临床症状。我们将结合体外和动物试验、分子成像和高通量测序，阐明病原体如何积极调节结肠微生物群，最终导致严重疾病。目的3将介绍短螺旋体为避免宿主防御而采用的免疫抑制策略。利用从结肠中分离的免疫细胞，我们将通过分析这些细胞的转录组来探索病原体如何抑制初始免疫反应。这一目标将阐明以前疫苗开发工作失败的原因，并有助于今后的改进。在当前的后抗生素时代，面对多重耐药细菌，需要新的替代方法来控制肠道细菌感染。本文提出的工作将阐明宿主-微生物组-病原体三联体相互作用的机制，以及我们如何利用这些知识制定减轻疾病的新策略，同时不导致抗菌素耐药性。