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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）的预后。引起尿路