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

• 批准号: 10741890
• 负责人: Lance R. Thurlow
• 金额: $ 18.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10741890
• 关键词: Acceleration; Address; Adolescent; Adult; Affect; Amino Acids; Antibiotic Therapy; Antibiotics; Area; Automobile Driving; Bacterial Infections; Behavior; Biological Models; Bronchiectasis; Carbon; Cause of Death; Cessation of life; Chemicals; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Citric Acid Cycle; Clinical; Complex; Cystic Fibrosis; Data; Dehydration; Detection; Diabetes Mellitus; Disease; Disease model; Environment; Failure; Fluorescence Microscopy; Genetic; Glucose; Healthcare; Hyperglycemia; Immune response; Immunosuppression; In Vitro; Incidence; Individual; Infection; Inflammation; Life; Life Expectancy; Lung; Lung diseases; Lung infections; Measures; Metabolic; Metabolic Pathway; Metabolism; Modeling; Morbidity - disease rate; Mucous body substance; Mus; Nutritional; Outcome; Pathogenesis; Persons; Phenotype; Predisposition; Primary Ciliary Dyskinesias; Production; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Quality of life; Quantitative Reverse Transcriptase PCR; Recurrence; Research; Respiratory Failure; Respiratory Tract Infections; Role; Source; System; Treatment Failure; Virulence; antibiotic tolerance; bacterial fitness; bacterial metabolism; care burden; chronic infection; chronic respiratory disease; comorbidity; cystic fibrosis infection; cystic fibrosis related diabetes; diabetic; fitness; in vivo; in vivo Model; lung injury; mortality; mouse model; muco-obstructive airway diseases; mutant; novel; pathogen; pathogenic bacteria; pulmonary function; pulmonary function decline; therapeutically effective

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.

抽象的 粘液阻塞性气道疾病 (MAD) 是一种慢性、危及生命的疾病，导致超过 300 万人罹患粘膜阻塞性气道疾病 (MAD) 全球每年的死亡人数。 MAD 的特点是呼吸道粘液过多、炎症、 慢性感染和进行性呼吸衰竭。铜绿假单胞菌 (Pa) 是主要细菌 与 MAD 感染相关的病原体。 Pa定植导致肺功能下降、呼吸质量下降 MAD 患者的寿命缩短，预期寿命缩短。糖尿病是一种常见的合并症，影响 18-50% 的人 具有潜在 MAD 的个体。糖尿病与较差的 MAD 临床结果相关，并且增加 易患严重肺部感染。此外，糖尿病与抗生素增加有关。 MAD 患者的治疗失败。利用新颖的体外和体内模型系统，我们观察到 在糖尿病 MAD 样情况下，Pa 患者的毒力潜力增加，对抗生素治疗的耐受性更高 状况。这些观察结果提出了几个问题，例如 MAD 中的糖尿病微环境如何 诱导 Pa 毒力以及它如何导致更高的抗生素耐受率。我们假设糖尿病 肺部微环境中的高血糖增强了细菌的适应性并增强了细菌的活性 毒力。我们进一步假设高血糖会改变细菌代谢，从而增加 对抗生素治疗的耐受性。我们将在反映 MAD 的体外系统中解决这些问题 和糖尿病肺环境以及糖尿病小鼠 MAD 慢性感染模型。该提案将 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 MAD 治疗失败。