Elucidation of Commensal Bacteria Mechanisms Required for Host Protection

阐明宿主保护所需的共生细菌机制

• 批准号: 8412902
• 负责人: Howard C Hang
• 金额: $ 33.9万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8412902
• 关键词: Animal Model; Animals; Antibiotic Resistance; Antibiotics; Attenuated; Bacteria; Bacterial Infections; Biochemical; Biochemical Genetics; Biological Models; Caenorhabditis elegans; Complex; Development; Disease; Enteral; Enterococcus faecium; Environment; Genes; Genetic; Genetic Screening; Health; Host resistance; Human; Image; Immune system; Immunity; In Vitro; Individual; Infection; Inflammation; Inflammatory disease of the intestine; Intestines; Invaded; Investigation; Left; Mammals; Metabolism; Modeling; Modern Medicine; Mus; Mutation Analysis; Pathogenesis; Phenotype; Population; Probiotics; Role; Salmonella; Salmonella enterica; Salmonella typhimurium; Study models; Symbiosis; System; Virulence; base; commensal microbes; enteric pathogen; falls; gut microbiota; human disease; improved; in vivo; in vivo Model; inhibitor/antagonist; member; microbiome; mouse model; mutant; pathogen; prevent; public health relevance; sortase

DESCRIPTION (provided by applicant): The intestinal microbiome is increasingly recognized as an important part of our immune system. Specific members of this consortium are thought to inhibit enteric disease, yet current in vivo models have confounded investigation of bacterial interactions in the intestine due to the complex interdependence between host and microbiota. C. elegans lacks many of these complicating factors and provides a tractable model for the mechanistic exploration of specific bacterial interactions in the intestine. We have identified Enterococcus faecium, a commensal member of the human intestinal microbiota, as an in vivo inhibitor of Salmonella virulence in C. elegans. We hypothesize that E. faecium is acting via a conserved mechanism in worms and mammals to attenuate Salmonella pathogenesis. We aim to identify and characterize the E. faecium factor(s) required for this effect in C. elegans, then analyze the role of these factor(s) in the mouse. Thus, our C. elegans model system provides a bridge between in vitro studies and complex mouse models to investigate the mechanism of a conserved commensal-pathogen interaction. Due to the diverse and considerable influence the intestinal microbiota exerts on host health, the development of probiotic approaches for preventing disease may provide an alternative to antibiotics. Although antibiotics are a mainstay of modern medicine, antibiotic use has fallen under scrutiny in recent years due to the spread of antibiotic resistance in bacterial populations. In addition, antibiotic use has been shown to cause dysbiosis, increasing host vulnerability to gut inflammation and enteric infection. Many members of our intestinal microbiota have been observed to improve host health in various ways. Further development of probiotic therapies, however, will require understanding the roles of individual bacterial species in the complex intestinal environment. The development of C. elegans as a general model for studying intestinal commensal-pathogen interactions could be an important step towards characterizing these interactions, providing an efficient in vivo model system to identify genetic components of commensalism that can then be analyzed in higher animal models.

描述（由申请人提供）：肠道微生物组越来越被认为是我们免疫系统的重要组成部分。该联合体的特定成员被认为抑制肠道疾病，但由于宿主和微生物群之间复杂的相互依赖性，目前的体内模型混淆了肠道中细菌相互作用的研究。C.秀丽线虫缺乏许多这些复杂的因素，并提供了一个易于处理的模型，用于肠道中特定细菌相互作用的机制探索。我们已经确定屎肠球菌，人类肠道微生物群的一个重要成员，作为沙门氏菌在C.优雅的。我们假设E.粪菌通过蠕虫和哺乳动物中的保守机制起作用以减弱沙门氏菌的致病性。我们的目的是确定和表征E。在C. elegans，然后分析这些因子在小鼠中的作用。因此，我们的C. elegans模型系统提供了体外研究和复杂小鼠模型之间的桥梁，以研究保守的病原体-病原体相互作用的机制。 由于肠道微生物群对宿主健康的影响多样且相当大，因此开发用于预防疾病的益生菌方法可能会提供抗生素的替代品。虽然抗生素是现代医学的支柱，但近年来由于细菌群体中抗生素耐药性的传播，抗生素的使用受到了严格的审查。此外，抗生素的使用已被证明会导致 生态失调，增加宿主对肠道炎症和肠道感染的脆弱性。我们的肠道微生物群的许多成员已被观察到以各种方式改善宿主健康。然而，益生菌疗法的进一步发展将需要了解单个细菌物种在复杂肠道环境中的作用。C.线虫作为研究肠道寄生虫-病原体相互作用的一般模型可能是表征这些相互作用的重要一步，提供有效的体内模型系统来鉴定寄生虫病的遗传组分，然后可以在高等动物模型中分析。