Mechanisms of Interleukin-17 Inflammation Induced by Bacteroides fragilis

脆弱拟杆菌诱导IL-17炎症的机制

• 批准号: 7779422
• 负责人: CYNTHIA SEARS
• 金额: $ 34.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7779422
• 关键词: Acute; Address; Adhesions; Adult; Affect; Anaerobic Bacteria; Bacteria; Bacteroides fragilis; Bangladesh; Binding; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cancer Etiology; Cell secretion; Cells; Cellular Structures; Child; Chronic; Clinical; Cognitive; Colitis; Colon; Colorectal Cancer; Complement; Complement Factor B; Crohn' s disease; Data; Dendritic Cells; Development; Diarrhea; Disease; Dysentery; E-Cadherin; Effector Cell; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Etiology; Exhibits; Feces; Goals; Human; Human Pathology; Hyperplasia; Immune; Immune response; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Infiltrate; Inflammatory Response; Interferons; Interleukin-17; Interleukin-4; Interleukin-8; Intestines; Irritable Bowel Syndrome; Leukocytes; Malnutrition; Mediating; Metalloproteases; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morbidity - disease rate; Mus; Neoplastic Cell Transformation; Nuclear; Outcome; Pathway interactions; Permeability; Phenotype; Protein Tyrosine Kinase; Proteins; Public Health; Recombinants; Regulatory T-Lymphocyte; Resistance; Rodent; Role; STAT protein; Signal Transduction; Signal Transduction Pathway; Source; Stat3 protein; T cell response; T-Lymphocyte; Therapeutic; Time; Toll-like receptors; Toxin; Ulcerative Colitis; United States; Virulence Factors; Woman; Work; Zinc; Zonula Adherens; burden of illness; c-myc Genes; cytokine; defined contribution; human disease; in vitro Model; in vivo; insight; mortality; mouse model; prospective; protein E; public health relevance; receptor; response

DESCRIPTION (provided by applicant): Bacteroides fragilis are common colonic commensals, known to occupy a mucosal niche in the colon and the leading anaerobe in human disease. One class of B. fragilis, enterotoxigenic Bacteroides fragilis (ETBF), is recently recognized as an etiology of inflammatory diarrheal disease and may incite active inflammatory bowel disease. Up to 30% of individuals, however, may be colonized, seemingly asymptomatically, with ETBF. The primary virulence factor of ETBF is a 20 kDa zinc-dependent metalloprotease toxin termed B. fragilis toxin (BFT). Our new ETBF-infected conventional C57BL/6 mouse model reveals that mice colonized with ETBF develop rapid onset symptomatic colitis (within 3 days) with marked colitis at 1 to 2 weeks. The colonic inflammatory infiltrates at 1 week are composed of increased CD4+ T cells that produce interleukin-17 (IL-17) but not ?-interferon or IL-4. Both the colonic epithelial cells and a subset of mucosal inflammatory cells display phosphorylated signal transducer and activator of transcription-3 (Stat3). Over time ETBF acute colitis subsides yielding chronic colitis that persists at least 8 months. Using matched isogenic B. fragilis strains differing only in their secretion of biologically active BFT, the colitis can be ascribed, at least in part, to BFT. In vitro BFT increases intestinal epithelial permeability at least, in part, by cleavage of the zonula adherens protein, E-cadherin, and activates Nuclear Factor-?B signaling resulting in secretion of the proinflammatory cytokine, interleukin-8. Our data support the hypothesis that ETBF colonization stimulates acute colitis mediated by induction of innate responses that direct adaptive responses along a Th17 pathway dependent on Stat3 signaling. We postulate that ETBF induce a continuum of human pathology from `asymptomatic' colonization, potentially associated with colonic hyperplasia and inflammation (precursor conditions to neoplastic transformation), to inflammatory diarrhea and colitis. The goals of this proposal are to identify the innate and adaptive host immune mechanisms associated with initiation and persistence of ETBF-induced colitis in C57BL/6 mice. We will define the contribution of Th17 effector cells and Stat signaling to the inflammatory response in ETBF-induced colitis. Our results allow us to use a common human colonic bacterium, ETBF, to begin to understand the newly recognized Th17-dependent colonic inflammation, potentially providing insights into therapeutic approaches for a common clinical problem, colitis. PUBLIC HEALTH RELEVANCE Colonic inflammation (colitis) contributes to a large burden of disease including two major public health concerns. The first is infectious diarrheal diseases, a global cause of morbidity and mortality that is associated with malnutrition and delayed cognitive development in children; and the second is colorectal cancer, the second leading cause of cancer-related mortality in the United States. Understanding colonic inflammation may also help in identifying treatments for individuals afflicted by inflammatory bowel disease (Crohn's disease and ulcerative colitis) and irritable bowel syndrome, an illness disproportionately affecting women.

描述（由申请人提供）：脆弱拟杆菌是常见的结肠寄生菌，已知占据结肠粘膜生态位，是人类疾病中的主要厌氧菌。一个B类。脆弱类杆菌（Bacteroides fragilis，ETBF）是近年来发现的引起炎症性肠病的病原菌，可引起活动性炎症性肠病。然而，高达30%的个体可能被ETBF定植，似乎无症状。ETBF的主要毒力因子是一种20 kDa的锌依赖性金属蛋白酶毒素，称为B。脆壁毒素（BFT）。我们的新的ETBF感染的常规C57 BL/6小鼠模型显示，ETBF定殖的小鼠在1至2周时发生快速发作的症状性结肠炎（3天内）和显著的结肠炎。1周时结肠炎性浸润由增加的CD 4 + T细胞组成，其产生白细胞介素-17（IL-17），但不产生？干扰素或IL-4。结肠上皮细胞和粘膜炎性细胞亚群均显示磷酸化的信号转导子和转录激活子-3（Stat 3）。随着时间的推移，ETBF急性结肠炎消退，产生持续至少8个月的慢性结肠炎。使用匹配的同基因B。fragilis菌株的差异仅在于它们分泌生物活性BFT，因此结肠炎可以至少部分地归因于BFT。体外BFT至少部分通过切割粘附小带蛋白E-钙粘蛋白来增加肠上皮渗透性，并激活核因子-？B信号传导导致促炎细胞因子白细胞介素-8的分泌。我们的数据支持ETBF定植刺激急性结肠炎的假设，诱导先天性反应，直接适应性反应沿着依赖于Stat 3信号转导的Th 17通路。我们假设ETBF诱导了从“无症状”定植（可能与结肠增生和炎症（肿瘤转化的前体条件）相关）到炎性腹泻和结肠炎的一系列人类病理学。本提案的目的是确定与C57 BL/6小鼠中ETBF诱导的结肠炎的起始和持续相关的先天性和适应性宿主免疫机制。我们将确定的贡献，Th 17效应细胞和Stat信号的炎症反应ETBF诱导的结肠炎。我们的研究结果使我们能够使用一种常见的人类结肠细菌ETBF来开始了解新认识到的Th 17依赖性结肠炎症，可能为常见的临床问题结肠炎的治疗方法提供见解。公共卫生相关性结肠炎（结肠炎）是一个巨大的疾病负担，包括两个主要的公共卫生问题。第一个是传染性结肠炎，这是一个全球性的发病和死亡原因，与儿童营养不良和认知发育迟缓有关;第二个是结肠直肠癌，这是美国癌症相关死亡的第二大原因。了解结肠炎症也可能有助于确定炎症性肠病（克罗恩病和溃疡性结肠炎）和肠易激综合征（一种不成比例地影响女性的疾病）患者的治疗方法。