Intestinal lysozyme controls mucosal immune response to microbiota

肠道溶菌酶控制对微生物群的粘膜免疫反应

• 批准号: 10640221
• 负责人: Nan Gao
• 金额: $ 35.85万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640221
• 关键词: Acceleration; Acute; Affect; Animal Model; Bacteria; Biology; Cell Differentiation process; Cell Wall; Cell secretion; Chromosomes; Clinical; Colitis; Colon; Crohn' s disease; Data; Defect; Development; Disease; Disease model; Enzymes; Epithelial Cells; Epithelium; Exhibits; Gene Mutation; Genes; Genetic; Genetically Engineered Mouse; Glycoside Hydrolases; Gnotobiotic; Goals; Gut Mucosa; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Immune; Immune response; Immune signaling; Immunologics; Immunology; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Innate Immune Response; Intestinal Mucosa; Intestines; Investigation; Knowledge; Literature; Microbe; Modeling; Mucolytics; Mucosal Immune Responses; Mucosal Immune System; Mucositis; Mucous Membrane; Muramidase; Mus; Myeloid Cells; Paneth Cells; Pathogenesis; Patients; Peptidoglycan; Phase; Physiological; Population; Predisposition; Process; Production; Recovery; Regulation; Research; Resolution; Role; Signal Transduction; Symptoms; Testing; Th2 Cells; Time; Ulcerative Colitis; adaptive immune response; antimicrobial peptide; bactericide; commensal microbes; defined contribution; dysbiosis; experimental study; feeding; functional disability; gain of function; genetic approach; gut inflammation; gut microbiota; healing; host-microbe interactions; in vivo; innovation; insight; intestinal epithelium; loss of function; microbial; microbiota; mouse model; novel strategies; pathobiont; prevent; response; risk variant

PROJECT SUMMARY: Intestinal Paneth cells and some myeloid cells secrete lysozyme, a glycoside hydrolase that catalytically cleaves bacterial cell-wall as well as exerts bactericidal activity through a non-enzymatic domain. This feature uniquely distinguishes lysozyme from other antimicrobial peptides. Elevated levels of intestinal lysozyme and its ectopic production by colonic mucosa are observed in clinically active intestinal inflammation conditions. Recent studies described defective lysozyme packaging and secretion in Paneth cells of Crohn’s disease (CD) patients. Unfortunately, existing literature suggested both a colitis-promoting and a colitis-protective role of lysozyme. The human LYZ gene is located in the vicinity of an Ulcerative Colitis (UC) risk locus, and patients with LYZ mutations exhibit IBD symptoms. Despite of these strong associations of intestinal lysozyme with UC and CD, surprisingly little is known about its exact physiological functions in regulating gut microbiota and mucosal immune response. This knowledge gap exists due to a lack of models for direct study of lysozyme in vivo function. This gap prevents us from fully understanding the clinical implication of lysozyme in the progression and management of distinct IBD forms. We have developed several mouse models to facilitate functional investigation of intestinal lysozyme under its deficient or over production conditions. Preliminary data suggest that lysozyme deficiency leads to a dysbiosis with an expansion in certain IBD-related bacterial species. When barrier function is acutely compromised, there is an enhanced translocation of opportunistic pathobionts and exacerbated colitis in these mice. Further analyses uncovered lysozyme sensitive microbes, an unexpected impact on epithelial cell differentiation and composition, as well as an influence on the mucosal immune response. This innovative project will investigate how lysozyme defects affect the colonization of IBD-related bacteria, how lysozyme-sensitive species modulate gut mucosa, and how lysozyme and bacterial interaction influences the progression and resolution of different experimental IBDs with distinct inflammatory profiles. The central hypothesis is that intestinal lysozyme modulates gut microbial community and its impact on mucosal immune responses to regulate inflammatory tone and the susceptibility of IBD. This hypothesis is formulated on the basis of preliminary data and existing literature. Two highly cohesive aims will first delineate the impact of lysozyme on gut microbiota, the regulation of mucosal homeostasis and inflammation by the lysozyme-sensitive microbiota, and will then examine the contribution of lysozyme defects to distinct forms of experimental colitis of different immunological profiles, with a particular effort devoted to understanding the role of type 2 immune signaling in these processes. This MPI project is constructed on complementary and indispensable expertise of the two PIs in experimental colitis, mucosal immunology, gnotobiotics study, genetics, and intestinal epithelial biology. The project utilizes rigorous genetic approaches and is expected to produce unique and disease-relevant insights into intestinal lysozyme and its impact on microbiota, mucosal immunology, and IBDs.

项目摘要： 肠道细胞和某些髓样细胞秘密溶菌酶，糖苷水解酶，催化裂解 细菌细胞壁以及通过非酶结构域发挥细菌活性。此功能独特 将溶菌酶与其他抗菌胡椒粉区分开。肠道溶菌酶及其生态的水平升高 在临床活跃的肠道感染条件下观察到结肠粘膜的产生。最近的研究 描述了克罗恩氏病（CD）患者的泛细胞中有缺陷的溶菌酶包装和分泌。 不幸的是，现有文献提出了促淋巴结结肠炎和结肠炎的作用。 人Lyz基因位于溃疡性结肠炎（UC）风险基因座的附近，患有LYZ突变的患者 展示IBD症状。尽管肠道溶菌酶与UC和CD有着强烈的关联，但令人惊讶的是 关于其在调节肠道微生物群和粘膜免疫响应中的确切生理功能知之甚少。 由于缺乏直接研究体内溶菌酶的模型，因此存在这种知识差距。这个差距可防止 我们完全了解溶菌酶在不同的临床意义中的临床意义 IBD表格。我们已经开发了几种小鼠模型，以促进肠溶菌酶的功能投资 在其不足或过于生产条件下。初步数据表明溶菌酶缺乏导致 某些与IBD相关细菌的营养不良膨胀。当屏障功能急剧 受损，这些机会病病原体的易位加剧了，这些病原体和恶化的结肠炎 老鼠。进一步分析发现的溶菌酶敏感微生物，这是对上皮细胞的意外影响 分化和组成以及对粘膜免疫反应的影响。这个创新的项目 将研究溶菌酶缺陷如何影响IBD相关细菌的定殖，溶菌酶敏感 物种调节肠粘膜，以及溶菌酶和细菌相互作用如何影响进展和 分辨出具有不同炎症特征的不同实验IBD。中心假设是 肠道溶菌酶调节肠道微生物群落及其对粘膜免疫的影响以调节 炎症性语调和IBD的敏感性。该假设是根据初步数据提出的 和现有文献。两个高度凝聚力的目标将首先描述溶菌酶对肠道微生物群的影响， 调节粘膜稳态和对溶菌酶敏感的菌群的炎症，然后将 检查溶菌酶缺陷对不同免疫学实验性结肠炎的不同形式的贡献 概况，特定的努力致力于了解2型免疫信号在这些过程中的作用。 这个MPI项目是基于实验中两个PI的完整性和必不可少的专业知识的构建 结肠炎，粘膜免疫学，gnotobiotics研究，遗传学和肠上皮生物学。项目利用 严格的遗传方法，有望产生与肠道有关的独特和疾病的见解 溶菌酶及其对微生物群，粘膜免疫学和IBD的影响。