Mucosal Immune Defense Mechanisms of the Urinary Bladder

膀胱粘膜免疫防御机制

基本信息

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
项目类别：
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

项目摘要

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。主要由尿路致病性大肠杆菌 (UPEC) 引起，很常见、高度复发，也是抗生素治疗的主要原因因此，对于其他健康的成年女性来说，抗生素耐药性的可怕预测已达到临界点。必须更好地了解复发性尿路感染 (rUTI) 的机制，以避免未来出现通常情况下的情况。 20-30% 的女性在初次感染后 6 个月内会出现复发。事实上，尿路感染史是后续尿路感染的独立危险因素。膀胱 UPEC 感染后，膀胱粘膜会发生长期重塑，其性质取决于炎症和感染史，这会改变对后续感染的易感性。重塑，或对先前感染的“记忆”，可以包括i）膀胱上皮的“训练有素的免疫力” 表观遗传重编程；ii) 适应性免疫反应，有时具有保护性；以及 iii) 破坏；由于口服抗生素治疗导致培养的原代上皮干细胞菌群失调，肠道微生物群受到影响。来自有感染史的小鼠膀胱的数据概括了许多重新编程的形态和基因此外，恢复期小鼠膀胱中存在 CD4+ 和 CD8+ T- 的表达特征。 UPEC 细胞会改变同株复发的易感性，并且还会与胃肠道 (GIT) 相互作用。微生物群，直接受到胃肠道免疫功能的影响，例如细胞因子的产生白细胞介素 22 (IL-22)，调节粘蛋白的产生并诱导抗菌因子的表达，防止侵入性定植。胃肠道微生物群反过来又塑造了粘液的组成。因此，胃肠道微生物群和粘膜协同作用限制 UPEC 定植是理解的关键 UPEC 与宿主的关系该提案旨在调查先前的感染如何导致受过训练。通过以下方式改变后续感染的反应和结果的免疫力：i) 使用强效小鼠感染模型以及培养的原代细胞来探测小鼠细胞系之间的染色质修饰具有不同的 UTI 病史和对 rUTI 的敏感性，特别关注 Programmed Cell 死亡相关基因，以及肿瘤坏死因子 α 和环氧合酶 2（目标 ii）探讨如何先前的感染塑造了膀胱粘膜适应性免疫的形成及其如何调节对反复感染的易感性（目标 2）；以及 iii) 通过以下方式识别微生物和粘膜免疫机制：肠道粘膜在健康和生态失调中限制 UPEC 定植以及 IL-22 及其结合的作用伙伴 IL-22 结合蛋白调节微生物群和粘液数量和质量（目标 3）。该提案的目的是试图了解不同形式的感染记忆，这些记忆是针对某种病毒而发展起来的。初始感染包括：i) 训练有素的免疫力；ii) 适应性免疫；以及 iii) 肠道菌群失调以及这些宿主如何- 病原体相互作用会导致表观遗传印记，从而导致未来感染。