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）：肠道微生物群越来越被认为是我们免疫系统的重要组成部分。该联盟的特定成员被认为可以抑制肠道疾病，但由于宿主和微生物群之间复杂的相互依赖关系，目前的体内模型混淆了肠道细菌相互作用的研究。秀丽隐杆线虫缺乏许多这些复杂的因素，并为肠道中特定细菌相互作用的机制探索提供了一个易于处理的模型。我们已经鉴定出粪肠球菌（Enterococcus faecium），一种人类肠道微生物群的共栖成员，作为秀丽隐杆线虫沙门氏菌毒力的体内抑制剂。我们假设，在蠕虫和哺乳动物中，粪肠杆菌通过一种保守的机制来减弱沙门氏菌的发病机制。我们的目标是鉴定和表征秀丽隐杆线虫产生这种作用所需的粪肠因子，然后分析这些因子在小鼠中的作用。因此，我们的秀丽隐杆线虫模型系统在体外研究和复杂的小鼠模型之间提供了一座桥梁，以研究保守的共生-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，益生菌预防疾病的方法的发展可能提供抗生素的替代品。尽管抗生素是现代医学的支柱，但近年来，由于细菌种群中抗生素耐药性的蔓延，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