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：
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
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

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

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.

抽象的粘膜刺激性气道疾病（MAD）是慢性，威胁生命的疾病，造成超过300万全球年度死亡。疯狂的特征是粘液在气道中积累过多，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定殖导致肺功能下降，质量降低生命，降低疯狂的人的预期寿命。糖尿病是一种常见的合并症，影响了18-50％有潜在疯狂的人。糖尿病与恶化的MAD临床结局有关，并增加对严重肺部感染的敏感性。此外，糖尿病与抗生素增加有关疯狂的人的治疗失败。利用新颖的体外和体内模型系统，我们已经观察到在类似糖尿病的疯狂状态下，PA的毒力潜力增加和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毒力及其如何导致抗生素耐受性较高。我们假设糖尿病肺微环境中的高血糖增强了细菌健康并增强细菌毒力。我们进一步假设高血糖会改变细菌代谢，以增加对抗生素疗法的耐受性。我们将在反映疯狂的两个体外系统中解决这些问题和糖尿病环境以及MAD的糖尿病鼠慢性感染模型。该提议将解决关键研究领域，包括糖尿病合并症在PA毒力和抗生素中的影响疯狂的治疗失败。