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:
  • 金额:
    $ 62.28万
  • 依托单位:
  • 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

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

项目成果

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会议论文数量(0)
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MARCO COLONNA其他文献

MARCO COLONNA的其他文献

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{{ truncateString('MARCO COLONNA', 18)}}的其他基金

Soluble TREM2 regulation of microglial function in Alzheimer disease
可溶性 TREM2 对阿尔茨海默病小胶质细胞功能的调节
  • 批准号:
    10432584
  • 财政年份:
    2022
  • 资助金额:
    $ 62.28万
  • 项目类别:
Impact of polyamines on ILC3 function at steady state and in preclinical model of colitis
多胺对稳态和结肠炎临床前模型中 ILC3 功能的影响
  • 批准号:
    10528082
  • 财政年份:
    2022
  • 资助金额:
    $ 62.28万
  • 项目类别:
The protein tyrosine kinase SYK drives innate immune responses against Alzheimer's Disease
蛋白质酪氨酸激酶 SYK 驱动针对阿尔茨海默病的先天免疫反应
  • 批准号:
    10674689
  • 财政年份:
    2022
  • 资助金额:
    $ 62.28万
  • 项目类别:
Impact of polyamines on ILC3 function at steady state and in preclinical model of colitis
多胺对稳态和结肠炎临床前模型中 ILC3 功能的影响
  • 批准号:
    10623342
  • 财政年份:
    2022
  • 资助金额:
    $ 62.28万
  • 项目类别:
Ontogenetic niche of B cells at the CNS borders in homeostasis, aging and autoimmunity
CNS 边界 B 细胞在稳态、衰老和自身免疫中的个体发育生态位
  • 批准号:
    10446266
  • 财政年份:
    2022
  • 资助金额:
    $ 62.28万
  • 项目类别:
Ontogenetic niche of B cells at the CNS borders in homeostasis, aging and autoimmunity
CNS 边界 B 细胞在稳态、衰老和自身免疫中的个体发育生态位
  • 批准号:
    10557870
  • 财政年份:
    2022
  • 资助金额:
    $ 62.28万
  • 项目类别:
MICROBIOTA-DEPENDENT CONTROL OF CLOSTRIDIUM DIFFICILE: THE ROLE OF ACETATE AND IL-22 BINDING PROTEIN
艰难梭菌的微生物群依赖性控制:乙酸盐和 IL-22 结合蛋白的作用
  • 批准号:
    10321553
  • 财政年份:
    2021
  • 资助金额:
    $ 62.28万
  • 项目类别:
Targeting TREM2 to boost anti-cancer therapy
靶向 TREM2 促进抗癌治疗
  • 批准号:
    10477296
  • 财政年份:
    2021
  • 资助金额:
    $ 62.28万
  • 项目类别:
Targeting TREM2 to boost anti-cancer therapy
靶向 TREM2 促进抗癌治疗
  • 批准号:
    10279674
  • 财政年份:
    2021
  • 资助金额:
    $ 62.28万
  • 项目类别:
MICROBIOTA-DEPENDENT CONTROL OF CLOSTRIDIUM DIFFICILE: THE ROLE OF ACETATE AND IL-22 BINDING PROTEIN
艰难梭菌的微生物群依赖性控制:乙酸盐和 IL-22 结合蛋白的作用
  • 批准号:
    10539270
  • 财政年份:
    2021
  • 资助金额:
    $ 62.28万
  • 项目类别:

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