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: 10427239
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427239
• 关键词: Acute; Affect; Animal Model; Bacteria; Biology; Cell Differentiation process; Cell Wall; Chromosomes; Clinical; Colitis; Colon; Conflict (Psychology); Crohn' s disease; Data; Defect; Development; Disease; Disease model; Enzymes; Epithelial; Epithelial Cells; Exhibits; Gene Mutation; Genes; Genetic; Genetically Engineered Mouse; Glycoside Hydrolases; Gnotobiotic; Goals; Gut Mucosa; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Immune; Immune signaling; Immunologics; Immunology; Inflammation; Inflammatory; Inflammatory Bowel Diseases; 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; Pathologic; 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; base; cohesion; 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; 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.

项目概要： 肠潘氏细胞和一些髓样细胞分泌溶菌酶，一种糖苷水解酶， 细菌细胞壁，并通过非酶结构域发挥杀菌活性。这一特点独特 将溶菌酶与其他抗菌肽区分开来。肠溶酶水平升高及其异位 在临床上活跃的肠道炎症条件下观察到结肠粘膜产生。最近的研究 描述了克罗恩病（CD）患者潘氏细胞中有缺陷的溶菌酶包装和分泌。 不幸的是，现有的文献表明，既有结肠炎促进和结肠炎保护作用的溶菌酶。的 人LYZ基因位于溃疡性结肠炎（UC）风险基因座附近，具有LYZ突变的患者 出现IBD症状。尽管肠溶菌酶与UC和CD有很强的关联，但令人惊讶的是， 关于其在调节肠道微生物群和粘膜免疫应答中的确切生理功能知之甚少。 这种知识差距的存在是由于缺乏直接研究溶菌酶体内功能的模型。这一差距防止 我们从充分理解溶菌酶在不同的进展和管理的临床意义， IBD形式。我们已经建立了几种小鼠模型，以促进肠道溶菌酶的功能研究 在生产不足或过剩的条件下。初步数据表明，溶菌酶缺乏导致 在某些IBD相关细菌物种中存在扩张的生态失调。当屏障功能严重受损时， 在这些疾病中，机会性致病菌的易位和结肠炎的加重是一个增强的过程。 小鼠进一步的分析发现了溶菌酶敏感的微生物，对上皮细胞的意外影响 分化和组成，以及对粘膜免疫应答的影响。这一创新项目 将研究溶菌酶缺陷如何影响IBD相关细菌的定植， 种调节肠粘膜，以及溶菌酶和细菌的相互作用如何影响进展和 具有不同炎症特征的不同实验IBD的消退。核心假设是， 肠溶菌酶调节肠道微生物群落及其对粘膜免疫应答的影响 炎症紧张度和IBD的易感性。这一假设是根据初步数据提出的 现有的文学。两个高度一致的目标将首先描述溶菌酶对肠道微生物群的影响， 通过溶菌酶敏感的微生物群调节粘膜稳态和炎症，然后将 检查溶菌酶缺陷对不同免疫学特性的实验性结肠炎的不同形式的贡献。 概况，特别致力于了解2型免疫信号在这些过程中的作用。 这个MPI项目是建立在实验中两个PI的互补和不可或缺的专业知识之上的。 结肠炎、粘膜免疫学、细菌学研究、遗传学和肠上皮生物学。该项目利用 严格的遗传学方法，预计将产生独特的和疾病相关的见解，肠道 溶菌酶及其对微生物群、粘膜免疫学和IBD的影响。