Impact of hyperglycemia on the pathogenesis of chronic bacterial lung infection

高血糖对慢性细菌性肺部感染发病机制的影响

基本信息

  • 批准号:
    10741890
  • 负责人:
  • 金额:
    $ 18.78万
  • 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:
    2023-06-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Abstract Muco-obstructive airway diseases (MADs) are chronic, life-threatening conditions that cause more than 3 million annual deaths worldwide. MADs are characterized by excess mucus accumulation in the airways, inflammation, chronic infection, and progressive respiratory failure. Pseudomonas aeruginosa (Pa) is the primary bacterial pathogen associated with MADs infections. Pa colonization leads to declining lung function, reduced quality of life, and decreased life expectancy in people with MADs. Diabetes is a frequent comorbidity affecting 18-50% of individuals with underlying MADs. Diabetes is associated with worse MADs clinical outcomes and increased susceptibility to severe pulmonary infections. In addition, diabetes is associated with increased antibiotic treatment failure in individuals with MADs. Utilizing novel in vitro and in vivo model systems, we have observed increased virulence potential and higher tolerance to antibiotic treatments in Pa under diabetic MADs-like conditions. These observations raise several questions such as how the diabetic microenvironment in MADs induces Pa virulence and how it leads to higher rates of antibiotic tolerance. We hypothesize that diabetic hyperglycemia in the lung microenvironment enhances bacterial fitness and potentiates bacterial virulence. We further hypothesize that hyperglycemia alters bacterial metabolism towards increased tolerance to antibiotic therapies. We will address these questions in both in vitro systems that reflect the MADs and diabetes lung environment and in a diabetic murine chronic infection model of MADs. This proposal will address key research areas including the influence of diabetes comorbidities in Pa virulence and antibiotic treatment failure in MADs.
摘要 粘液阻塞性呼吸道疾病(MADs)是一种慢性的、危及生命的疾病,导致300多万人死亡。 全球每年的死亡人数。MADS的特征是呼吸道粘液过度堆积,炎症, 慢性感染和进行性呼吸衰竭。铜绿假单胞菌(PA)是主要致病菌 与MADS感染相关的病原体。PA定植导致肺功能下降,肺质量下降 寿命,以及患有MADS的人的预期寿命减少。糖尿病是一种常见的共病,影响到18%-50%的 有潜在MAD的个体。糖尿病与较差的MADS临床结局和增加 对严重肺部感染的易感性。此外,糖尿病与抗生素的增加有关。 MADS患者的治疗失败。利用新的体外和体内模型系统,我们观察到 糖尿病MADS样下PA毒力增强和对抗生素治疗的耐受性增强 条件。这些观察提出了几个问题,如MADS中的糖尿病微环境如何 诱导巴氏杆菌的毒力以及它如何导致更高的抗生素耐药率。我们假设糖尿病患者 肺微环境中的高血糖可增强细菌的适合性并增强细菌 致命性。我们进一步假设,高血糖改变了细菌的新陈代谢 对抗生素治疗的耐受性。我们将在两个反映MADS的体外系统中解决这些问题 以及糖尿病肺环境和糖尿病小鼠慢性感染MADS模型。这项提议将 解决关键研究领域,包括糖尿病合并症对PA毒力和抗生素的影响 MADS治疗失败。

项目成果

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Lance R. Thurlow其他文献

Partial characterization of a Saccharopolyspora isolated from a preserved lab dissection specimen
从保存的实验室解剖标本中分离出的糖多孢菌的部分特征
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    0
  • 作者:
    S. Stawinski;Lance R. Thurlow;Amanda Robben;E. Gillock
  • 通讯作者:
    E. Gillock
Characterization of two environmental bacterial isolates by 16S rRNA sequence analysis, fatty acid methyl ester analysis, and scanning electron microscopy
通过 16S rRNA 序列分析、脂肪酸甲酯分析和扫描电子显微镜表征两种环境细菌分离株
  • DOI:
  • 发表时间:
    2005
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Lance R. Thurlow;E. Gillock
  • 通讯作者:
    E. Gillock
mTOR signaling is required for phagocyte free radical production, GLUT1 expression, and control of emStaphylococcus aureus/em infection
mTOR 信号通路对于吞噬细胞自由基的产生、GLUT1 表达以及金黄色葡萄球菌感染的控制是必需的
  • DOI:
    10.1128/mbio.00862-24
  • 发表时间:
    2024-04-29
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Christopher J. Genito;Benjamin P. Darwitz;Callista P. Reber;Nathaniel J. Moorman;Christina L. Graves;Andrew J. Monteith;Lance R. Thurlow;Kimberly A. Kline;Thomas E. Kehl-Fie
  • 通讯作者:
    Thomas E. Kehl-Fie

Lance R. Thurlow的其他文献

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{{ truncateString('Lance R. Thurlow', 18)}}的其他基金

A novel diabetic co-infection model to study pathogen interaction during coinfection
一种新型糖尿病合并感染模型,用于研究合并感染期间病原体相互作用
  • 批准号:
    10377244
  • 财政年份:
    2020
  • 资助金额:
    $ 18.78万
  • 项目类别:

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