Regulation of C. difficile colitis by host genetic and immune factors

宿主遗传和免疫因素对艰难梭菌结肠炎的调节

基本信息

  • 批准号:
    10683220
  • 负责人:
  • 金额:
    $ 40.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-17 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

Project Summary: Clostridium difficile is the leading nosocomial infection in the U.S. Host factors are a key predictor of disease outcomes after C. difficile infection (CDI). We have discovered a key role for leptin receptor (LEPR) pathway and the pro-inflammatory cytokine Macrophage Inhibitory Factor (MIF) in CDI pathogenesis. Our data reveal that a common single nucleotide polymorphism (SNP) in the gene for LEPR (Q223R; present in up to 50% of humans) is associated with exaggerated MIF production after CDI in humans. CDI in mice homozygous for the mutant SNP (RR) resulted in higher MIF production, more colonic neutrophilia and tissue damage, without effects on pathogen. We reported that neutralizing MIF using antibody resulted in reduced tissue injury and improved survival in mice, without effects on C. difficile pathogen. Finally, blocking a key receptor for MIF, CXC chemokine receptor 2 (CXCR2) also reduced CDI-induced neutrophil accrual in tissue. This proposal is based on these published results and new preliminary data which indicate that LEPR Q to R change augments Bcl-2 like protein 11 (Bim) expression which controls MIF release by modulating pathways of autophagy/mitophagy/apoptosis. The overall hypothesis of our studies is that: LEPR Q to R substitution exaggerates CDI-induced, Bim-dependent MIF release that augments CXCR2-dependent tissue neutrophil accrual and worsens disease severity. To test this hypothesis, we propose three specific aims. Aim 1 will define the key pathogen-associated drivers of MIF and the main cellular sources of MIF production in CDI. We will use WT and toxin-deficient C. difficile strains to determine the role of toxins and non-toxin factors in driving MIF expression. Cellular sources of MIF will be defined after CDI in WT mice by intracellular staining and immunohistochemistry and their role in CDI will be tested by using selective MIF deletion in intestinal epithelial cells and in hematopoietic cells. Aim 2 will examine the mechanism of CDI-induced MIF release. We will determine the role of LEPR Q to R substitution in regulating Bim expression and subsequent autophagy, mitophagy and apoptosis pathways. Studies will use Bim-reporter and Bim-deficient mice, and Bim+/+ and Bim-/- human intestinal organoids generated from induced pluripotent stem cells in both QQ and RR background. Aim 3 will investigate the role of MIF-CXCR2 axis in CDI-induced tissue neutrophilia in QQ and RR mice. We will compare the effect of MIF on neutrophil trafficking and on their lifespan. We will utilize neutrophils derived from WT and CXCR2-/- mice in in vitro (migration assays) and in vivo (after depletion of endogenous neutrophils and reconstitution with labeled neutrophils prior to infection) experiments. We expect these studies to provide a greater understanding of the role of host genetics in regulating MIF during CDI pathogenesis. Our studies have the potential to identify new host-based targets that can be used in the design of novel CDI therapies.
项目总结: 艰难梭菌是美国主要的医院感染。宿主因素是疾病的关键预测因素 艰难梭菌感染(CDI)的预后。我们已经发现瘦素受体(LEPR)途径的关键作用和 促炎症细胞因子巨噬细胞抑制因子在CDI发病机制中的作用我们的数据显示, LEPR基因的常见单核苷酸多态(SNP)(Q223R;存在于多达50%的人类) 与人类CDI后MIF的夸大产生有关。CDI在突变纯合子小鼠中的应用 SNP(RR)导致MIF产生增加,结肠中性粒细胞增多和组织损伤,但不影响 病原体。我们报告说,使用抗体中和MIF可以减少组织损伤并改善 在小鼠体内存活,对艰难梭菌病原体没有影响。最后,阻断MIF的关键受体CXC趋化因子 受体2(CXCR2)也减少了CDI诱导的组织中性粒细胞的增加。这项建议是基于以下几点 已发表的结果和新的初步数据表明,LEPR从Q到R的变化增加了Bcl2样蛋白 11(Bim)的表达,通过调节自噬/有丝分裂/凋亡途径来控制MIF的释放。 我们研究的总体假设是:Lepr Q到R的替换夸大了CDI诱导的Bim依赖 MIF的释放增加了依赖CXCR2的组织中性粒细胞的增加,并加重了疾病的严重性。为了测试 在这一假设下,我们提出了三个具体目标。AIM 1将定义MIF的关键病原体相关驱动因素 CDI产生MIF的主要细胞来源。我们将使用WT和毒素缺乏的艰难梭菌菌株来 确定毒素和非毒素因素在驱动MIF表达中的作用。MIF的蜂窝来源将是 WT小鼠CDI后的细胞内染色和免疫组织化学定义及其在CDI中的作用 在肠上皮细胞和造血细胞中使用选择性MIF缺失进行检测。Aim 2将检查 CDI诱导MIF释放的机制。我们将确定LEPR Q到R的替换在调节中的作用 BIM表达与随后的自噬、有丝分裂吞噬和凋亡途径。研究将使用BIM-REPORTER 和Bim缺陷小鼠,以及诱导多能性产生的Bim+/+和Bim-/-人肠道器官 QQ和RR背景下的干细胞。目的3研究MIF-CXCR2轴在CDI诱导中的作用 QQ和RR小鼠的组织中性粒细胞。我们将比较MIF对中性粒细胞转运的影响以及对它们的影响 寿命。我们将在体外(迁移试验)和体内利用来自WT和CXCR2-/-小鼠的中性粒细胞 (在内源性中性粒细胞耗尽并在感染前用标记的中性粒细胞重建之后) 实验。我们期望这些研究能更好地理解寄主遗传学在调节 MIF在CDI发病机制中的作用我们的研究有可能确定新的基于主机的目标,可以使用 在设计新的CDI疗法方面。

项目成果

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Rajat Madan其他文献

Rajat Madan的其他文献

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{{ truncateString('Rajat Madan', 18)}}的其他基金

Regulation of C. difficile colitis by host genetic and immune factors
宿主遗传和免疫因素对艰难梭菌结肠炎的调节
  • 批准号:
    10362805
  • 财政年份:
    2021
  • 资助金额:
    $ 40.78万
  • 项目类别:
Regulation of C. difficile colitis by host genetic and immune factors
宿主遗传和免疫因素对艰难梭菌结肠炎的调节
  • 批准号:
    10490905
  • 财政年份:
    2021
  • 资助金额:
    $ 40.78万
  • 项目类别:
Role of a common leptin receptor polymorphism in regulating neutrophil heterogeneity after C. difficile infection
常见瘦素受体多态性在艰难梭菌感染后调节中性粒细胞异质性中的作用
  • 批准号:
    10266039
  • 财政年份:
    2019
  • 资助金额:
    $ 40.78万
  • 项目类别:
Role of a common leptin receptor polymorphism in regulating neutrophil heterogeneity after C. difficile infection
常见瘦素受体多态性在艰难梭菌感染后调节中性粒细胞异质性中的作用
  • 批准号:
    9974287
  • 财政年份:
    2019
  • 资助金额:
    $ 40.78万
  • 项目类别:
Role of a common leptin receptor polymorphism in regulating neutrophil heterogeneity after C. difficile infection
常见瘦素受体多态性在艰难梭菌感染后调节中性粒细胞异质性中的作用
  • 批准号:
    10852810
  • 财政年份:
    2019
  • 资助金额:
    $ 40.78万
  • 项目类别:
Role of leptin in mucosal protection during Clostridium difficile infection
瘦素在艰难梭菌感染期间粘膜保护中的作用
  • 批准号:
    8767529
  • 财政年份:
    2014
  • 资助金额:
    $ 40.78万
  • 项目类别:
Role of leptin in mucosal protection during Clostridium difficile infection
瘦素在艰难梭菌感染期间粘膜保护中的作用
  • 批准号:
    9113497
  • 财政年份:
    2014
  • 资助金额:
    $ 40.78万
  • 项目类别:

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