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)的结局。UTI引起的 主要由尿路致病性E.大肠杆菌(UPEC)是常见的,高度复发,是抗生素治疗的主要原因 健康的成年女性因此,随着抗生素耐药性达到临界点的可怕预测, 必须更好地了解复发性UTI(rUTI)的机制,以避免未来通常 可治疗的感染变得无法控制。20%-30%的女性在首次发病后6个月内复发 感染事实上,UTI病史是随后UTI的独立危险因素。小鼠模型显示, 当膀胱的UPEC感染时,发生膀胱粘膜的长期重塑,其性质是 取决于炎症和感染史,这改变了对后续感染的易感性。这 先前感染的重塑或“记忆”可包括i)膀胱上皮的“训练免疫”, 表观遗传重编程; ii)适应性免疫反应,有时具有保护性; iii)破坏 由于口服抗生素治疗导致肠道微生物群失调。原代培养的上皮干细胞 从有感染史的小鼠膀胱中, 表达特征存在于恢复期小鼠膀胱中。此外,CD 4+和CD 8 + T细胞的耗竭 细胞改变了对相同菌株复发的敏感性。UPEC还与胃肠道(GIT)相互作用 微生物群,其直接受到GIT中的免疫功能的影响,例如细胞因子的产生 白细胞介素22(IL-22),其调节粘蛋白的产生并诱导抗微生物因子的表达, 防止入侵殖民。GIT微生物群反过来塑造粘液的组成。了解如何 因此,GIT微生物群和粘膜协同工作以限制UPEC定殖是理解的关键 UPEC与宿主的关系。该提案旨在调查先前的感染如何导致训练有素的 通过以下方式改变后续感染的应答和结果的免疫:i)使用强小鼠感染 模型以及培养的原代细胞来探测来自小鼠的细胞系之间的染色质修饰 有不同的UTI病史和对鲁蒂的易感性,特别关注程序化细胞 死亡相关基因,以及肿瘤坏死因子α和环氧合酶-2(Aim 1); ii)探索如何 先前的感染塑造了膀胱粘膜适应性免疫的形成, 对复发感染的易感性(目的2);和iii)通过以下方法鉴定微生物和粘膜免疫机制: 肠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 伴侣IL-22结合蛋白在调节微生物群和粘液数量和质量中的作用(目的3)。强度 这项建议的一个重要方面是,它试图了解不同形式的感染记忆,这些记忆是在对一种病毒的反应中发展起来的。 初始感染包括:i)训练的免疫; ii)适应性免疫;和iii)肠道生态失调以及这些宿主- 病原体相互作用导致表观遗传印记,使其易于发生未来的感染。

项目成果

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MARCO COLONNA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:
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:
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:
    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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