Commensal-dependent induction of protective immunity

共生依赖的保护性免疫诱导

• 批准号: 9244503
• 负责人: GRETCHEN E DIEHL
• 金额: $ 19.52万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244503
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Biological Assay; Candidate Disease Gene; Cells; Clinical; Colitis; Colon; Data; Development; Employee Strikes; Epithelial; Epithelial Cells; Equilibrium; Escherichia coli; Gene Cluster; Genome; Goals; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-10; Intestines; Knock-out; Lead; Mediating; Microbe; Microbial Genetics; Modeling; Mononuclear; Mus; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Phagocytes; Physiology; Population; Probiotics; Process; Production; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Symbiosis; System; Systems Development; Testing; Therapeutic Uses; Tissues; Work; antimicrobial; base; chemokine receptor; commensal microbes; comparative genomics; cytokine; gene product; genetic element; genome wide association study; healing; immune function; immune system function; in vivo; interest; intestinal homeostasis; member; microbial; microbiota; microorganism; mouse model; pathogen; protective effect; repaired; response; therapeutic target

Summary Over the millennia, humans and their microbiota have coevolved a mutually beneficial relationship. Many essential aspects of host physiology, including immune system development and intestinal homeostasis, depend on interactions between cells of the intestine, the intestinal immune system, and the microbiota. For the intestinal immune system, these interactions require that it strike a balance between providing robust anti- microbial responses to pathogenic microbes while limiting inflammatory responses against the microbiota. To understand how this balance is achieved and maintained, it is critical to understand the intestinal microbes, immune cell populations, and signaling pathways involved. Data from our work and others suggest that CX3CR1 expressing mononuclear phagocytes (MNPs) detect signals from the microbiota and coordinate intestinal immune responses to promote epithelial integrity and reduce intestinal inflammation. This population of MNPs is highly phagocytic and is known to secrete both pro- and anti-inflammatory cytokines. In addition, this cell population has been found to be expanded in the colon of inflammatory bowel disease (IBD) patients as well as in mouse models of colitis. We hypothesize that CX3CR1+ MNPs recognize specific members of the microbiota, which in turn dictates their ability to mediate either protective or pathological responses. Changes in the commensal microbes encountered by CX3CR1+ MNPs would therefore be predicted to impact the function of these MNPs. As a hallmark of inflammatory conditions such as IBD is dysbiosis, or a shift in the composition of the microbiota, changes in the commensal microbes encountered by CX3CR1+ MNPs would directly impact their function. We have identified E. coli that are normal members of the mouse microbiota and offer different degrees of protection in mouse models of colitis. We will utilize this mouse commensal as well as E. coli human clinical isolates to understand how colonization with these microbes impacts the effector function of CX3CR1+ MNPs. We will further determine how these isolates support immune protection in models of colitis. Finally, with the goal of identifying microbial genetic elements which induce immune protection, we will utilize comparative genomics-based analysis to identify and subsequently target microbial gene clusters in these E. coli isolates that correlate with protective immunity. Our overall objective is to determine how specific members of the microbiota impacts intestinal immunity as the first step in understanding the regulation of intestinal homeostasis by the microbiota.

总结 几千年来，人类和他们的微生物群共同进化出了一种互利的关系。许多 宿主生理学的基本方面，包括免疫系统发育和肠道稳态， 取决于肠道细胞、肠道免疫系统和微生物群之间的相互作用。为 肠道免疫系统，这些相互作用需要它在提供强大的抗 这一过程可以抑制微生物对病原微生物的反应，同时限制针对微生物群的炎症反应。到 了解这种平衡是如何实现和维持的，了解肠道微生物是至关重要的， 免疫细胞群和相关的信号通路。我们的工作和其他人的数据表明， 表达CX 3CR 1的单核吞噬细胞（MNP）检测来自微生物群的信号并进行协调 肠道免疫反应，以促进上皮完整性和减少肠道炎症。该人群 MNP具有高度的吞噬作用，并且已知可分泌促炎细胞因子和抗炎细胞因子。此外，本发明还提供了一种方法， 已经发现该细胞群在炎症性肠病（IBD）患者的结肠中扩增 以及在结肠炎小鼠模型中。我们假设CX3CR1+ MNP识别细胞内的特定成员。 微生物群，这反过来又决定了它们介导保护或病理反应的能力。变化 因此，预测CX3CR1+ MNP遇到的微生物中的微生物会影响 这些MNP的功能。炎症性疾病如IBD的标志是生态失调，或者是细胞内环境的改变。 微生物群的组成，CX3CR1+ MNP遇到的肠道微生物的变化将 直接影响其功能。我们已经确定了E。大肠杆菌是小鼠微生物群的正常成员， 在小鼠结肠炎模型中提供不同程度的保护。我们将利用这种鼠标， E.大肠杆菌人类临床分离株，以了解这些微生物的定植如何影响效应子功能 CX3CR1+ MNP。我们将进一步确定这些分离株如何支持免疫保护的模型， 结肠炎最后，为了鉴定诱导免疫保护的微生物遗传元件，我们将 利用基于比较基因组学的分析来识别并随后靶向微生物基因簇， 这些E.与保护性免疫相关的大肠杆菌分离株。我们的总体目标是确定 微生物群的成员影响肠道免疫力，这是理解肠道免疫调节的第一步。 通过微生物群来维持肠道内稳态。