Mucosal Immune Defense Mechanisms of the Urinary Bladder

膀胱粘膜免疫防御机制

• 批准号: 10587639
• 负责人: MARCO COLONNA
• 金额: $ 62.28万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587639
• 关键词: ATAC-seq; Acute; Adult; Antibiotic Resistance; Antibiotic Therapy; Antibody-mediated protection; Antigens; Apoptosis; B-Cell Activation; B-Lymphocytes; Bacteria; Bacterial Infections; Binding; Binding Proteins; Bladder; Bladder Urothelium; Bladder mucosa; C3H/HeN Mouse; CD8-Positive T-Lymphocytes; Cell Culture System; Cell Line; Cell Separation; Cells; Chronic; Clostridium difficile; Complex; DNA Methylation; Data Analyses; Data Set; Defense Mechanisms; Disease; Disease Outcome; Dose; Enzymes; Epigenetic Process; Epithelium; Escherichia coli Infections; Exposure to; Female; Functional disorder; Future; Gastrointestinal tract structure; Gene Expression; Genes; Gut Mucosa; Health; Immune; Immune System Diseases; Immune response; Immunity; Infection; Infective cystitis; Inflammation; Inflammatory; Inflammatory Response; Inherited; Lead; Lymphoid Cell; Medical; Memory; Microbe; Modeling; Modification; Morphology; Mouse Cell Line; Mouse Strains; Mucins; Mucosal Immunity; Mucous Membrane; Mucous body substance; Mus; Nature; Opportunistic Infections; Oral; Organism; Outcome; Pathway interactions; Patients; Phenotype; Predisposition; Primary Cell Cultures; Process; Production; Prostaglandins; Protein Deficiency; Recording of previous events; Recurrence; Resistance; Resolution; Risk; Risk Factors; Role; Shapes; Signal Transduction; Streptomycin; TNF gene; Training; United States; Urinary tract infection; Urine; Uropathogenic E. coli; Urothelial Cell; Urothelium; Visit; Volatile Fatty Acids; Woman; Work; Writing; adaptive immune response; adaptive immunity; antimicrobial; bisulfite sequencing; chromatin modification; chronic infection; cyclooxygenase 2; cytokine; draining lymph node; dysbiosis; epithelial stem cell; experience; extracellular; gut colonization; gut dysbiosis; gut homeostasis; gut microbiota; histone modification; immune function; immunopathology; imprint; inhibitor; interleukin-22; methylation pattern; microbial; microbiome; microbiota; mouse model; neutrophil; new therapeutic target; pathogen; prevent; programs; recurrent infection; resistant strain; response; stem cells; therapy development; trait; whole genome

ABSTRACT: Complex mucosal networks impact the outcome of a urinary tract infection (UTI). UTIs caused mostly by uropathogenic E. coli (UPEC) are common, highly recurrent, and a leading cause of antibiotic therapy for otherwise healthy adult women. Thus, with dire predictions of antibiotic resistance reaching a tipping point, it is imperative to better understand the mechanisms of recurrent UTIs (rUTIs) to avoid a future where ordinarily treatable infections become unmanageable. 20-30% of women have a recurrence within 6 months of their initial infection. In fact, history of UTI is an independent risk factor for subsequent UTI. Mouse models have shown that upon UPEC infection of the bladder, a long-term remodeling of the bladder mucosa occurs, the nature of which depends upon the inflammatory and infection history, which alters susceptibility to subsequent infection. This remodeling, or “memory” of a prior infection, can include i) “trained immunity” of the bladder epithelium through epigenetic reprogramming; ii) an adaptive immune response, which is sometimes protective; and iii) disruptions of the gut microbiota due to oral antibiotic therapy leading to dysbiosis. Primary epithelial stem cells cultured from bladders of mice with a history of infection recapitulate many of the reprogrammed morphologic and gene expression features present in the convalescent mouse bladder. In addition, depletion of CD4+ and CD8+ T- cells alters susceptibility to same-strain recurrence. UPEC also interact with the gastrointestinal tract (GIT) microbiota, which is directly influenced by immune functions in the GIT, such as production of the cytokine interleukin 22 (IL-22), which regulates mucin production and induces the expression of antimicrobial factors that prevent invasive colonization. The GIT microbiota in turn shapes the composition of mucus. Understanding how the GIT microbiota and mucosa work in concert to restrict UPEC colonization is therefore key to understanding UPEC's relationship with the host. This proposal seeks to investigate how a prior infection leads to trained immunity that alters the response and outcome of subsequent infections by: i) using robust mouse infection models as well as cultured primary cells to probe chromatin modifications between cell lines derived from mice with differential UTI disease histories and susceptibilities to rUTI, with particular focus on Programmed Cell Death-associated genes, as well as tumor necrosis factor alpha and cyclooxygenase-2 (Aim 1); ii) probing how prior infection shapes the formation of adaptive immunity at the bladder mucosa and how that modulates susceptibility to recurrent infection (Aim 2); and iii) identifying microbial and mucosal immune mechanisms by which the gut mucosa restricts UPEC colonization in health and dysbiosis and the roles of IL-22 and its binding partner IL-22 binding protein in regulating the microbiota and mucus quantity and quality (Aim 3). The strength of this proposal is that it seeks to understand different forms of infection memory that develop in response to an initial infection including: i) trained immunity; ii) adaptive immunity; and iii) gut dysbiosis and how these host- pathogen interactions lead to epigenetic imprints that predispose to future infections.

摘要：复杂的粘膜网络影响尿路感染（UTI）的结果。乌蒂斯引起的 大多由肝癌大肠杆菌（UPEC）是常见的，高度复发，是抗生素治疗的主要原因 对于健康的成年女性。这是抗生素耐药性的方向预测到达临界点 必须更好地理解经常性UTI（RUTIS）的机制，以避免未来 可治疗感染变得难以管理。 20-30％的妇女在首次初期的6个月内复发 实际上，UTI的历史是随后的UTI的独立危险因素。鼠标模型表明 膀胱感染UPEC感染后，发生了膀胱粘膜的长期重塑，其性质的性质 取决于炎症和感染病史，这种病史会改变随后感染的敏感性。这 重塑或先前感染的“记忆”可以包括i）膀胱上皮的“受过训练的免疫” 表观遗传重编程； ii）一种自适应免疫响应，有时受到保护；和iii）破坏 由于口服抗生素疗法而导致营养不良的肠道菌群。原代上皮干细胞培养 来自感染史的小鼠的膀胱概括了许多重编程的形态和基因 疗养小鼠膀胱中存在的表达特征。此外，CD4+和CD8+ T-的耗竭 细胞改变对同一复发的敏感性。 UPEC还与胃肠道（GIT）相互作用 微生物群，直接受到GIT中免疫功能的影响，例如细胞因子的产生 白介素22（IL-22），调节粘蛋白的产生并诱导抗菌因子的表达 防止侵入性殖民化。 GIT菌群又塑造了粘液的组成。了解如何 因此，GIT微生物群和粘膜协同工作以限制UPEC殖民化是理解的关键 UPEC与主持人的关系。该建议旨在调查先前的感染如何导致训练 通过以下方式改变后续感染的反应和结果的免疫力：i）使用强大的小鼠感染 模型以及培养的原代细胞以探测从小鼠衍生的细胞系之间的染色质修饰 具有差异性UTI疾病史和对RUTI的敏感性，特别关注编程细胞 与死亡相关的基因以及肿瘤坏死因子α和环氧合酶-2（AIM 1）； ii）探测如何 先前的感染形成了膀胱粘膜自适应免疫的形成，以及如何调节 反复感染的敏感性（AIM 2）； iii）通过 肠粘膜在健康和营养不良中限制了UPEC殖民化以及IL-22的作用及其结合 伴侣IL-22结合蛋白在调查微生物群和粘液量和质量方面（AIM 3）。力量 该提议的是，它试图理解以响应一个人而发展的不同形式的感染记忆 最初感染包括：i）受过训​​练的免疫学； ii）适应性免疫学； iii）肠道营养不良以及这些宿主如何 病原体相互作用导致表观遗传印记，易受未来感染的影响。