Impact of hyperglycemia on the pathogenesis of chronic bacterial lung infection

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。

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.