Bacteriophage as a predictive biomarker in chronic Pseudomonas airway disease

噬菌体作为慢性假单胞菌气道疾病的预测生物标志物

• 批准号: 10723956
• 负责人: Elizabeth Bendig Burgener
• 金额: $ 19.9万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-22 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723956
• 关键词: Acute; Address; Adult; Advisory Committees; Airway Disease; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Antimicrobial susceptibility; Aztreonam; Bacterial Chromosomes; Bacteriophages; Biological Markers; Biological Testing; Biology; Biometry; Bronchiectasis; Caring; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cystic Fibrosis; Cystic Fibrosis sputum; Data; Denmark; Development; Development Plans; Disease; Disease Management; Environment; Evolution; Foundations; Future; Genomics; Growth; Human; Impairment; In Vitro; Infection; Inhalation; Inovirus; Longitudinal cohort; Lung; Lung diseases; Lung infections; Measures; Mediating; Mentors; Microbial Biofilms; Microbiology; Minimum Inhibitory Concentration measurement; Nonlytic; Organism; Patient Care; Patients; Phenotype; Phylogeny; Physicians; Polysaccharides; Population; Prophages; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Publishing; Pulmonary Cystic Fibrosis; Pulmonology; Recurrence; Research; Resistance; Respiratory Disease; Respiratory Failure; Respiratory Tract Infections; Retrospective cohort; Sampling; Scientist; Serial Passage; Sputum; Testing; Therapeutic; Time; Tobramycin; Tracheostomy procedure; Training; Translational Research; Virion; Virus Integration; antibiotic tolerance; biobank; career; career development; chronic infection; clinical care; cohort; cystic fibrosis airway; cystic fibrosis infection; cystic fibrosis patients; emerging antibiotic resistance; experience; experimental study; gene function; genome sequencing; improved outcome; in vivo; insight; mucoid; novel; novel therapeutics; pathogen; personalized approach; predicting response; predictive marker; prospective; pulmonary function; resistance gene; respiratory; response; response biomarker; skills; translational medicine; treatment strategy; whole genome

PROJECT SUMMARY / ABSTRACT Despite major advances in therapy, pulmonary disease continues to dominate the clinical course of patients with cystic fibrosis (CF). All patients with CF develop chronic lung infections, with Pseudomonas aeruginosa (Pa) becoming a predominant organism in adulthood. Even in the face of chronic inhalational antibiotic therapy to target Pa in the lungs, CF patients experience intermittent pulmonary exacerbations with stepwise decline in lung function leading to eventual respiratory failure. Novel treatment strategies are urgently needed to address the damaging effects of chronic Pa in the lungs of CF patients. This will allow for all patients with CF to fully benefit of an evolving therapeutic landscape to address their defective CF gene function. I discovered the presence of the Pa filamentous (Pf) bacteriophage, in cohorts of patients with CF in Stanford and Denmark. Pf was associated with chronicity of Pa and more severe exacerbations (Burgener et al, Science Translational Medicine 2019). This constituted the first demonstration of the involvement of bacteriophage in human lung disease. This proposal aims to delve into the mechanisms behind these associations. Given the known shortcomings of chronic inhalational antibiotic therapy, I will test the hypothesis that in the lung Pf provides antibiotic tolerance and is a predictive biomarker to guide in choosing effective inhalational therapeutics. The first aim utilizes banked respiratory Pa isolates to (1a), assess antibiotic tolerance under conditions present in the lung, (1b) perform whole genome sequencing to assess for presence of antibiotic resistance genes and (1c) perform evolutionary experiments to investigate acquisition of resistance as a function of Pf. The second aim will assess Pf as a lung disease predictive biomarker in (2a) a retrospective cohort evaluating response to exacerbations therapy and (2b) perform a cross-over clinical trial to assess for differential effects of Pf on lung function. This proposal, supported by exciting and novel preliminary data, promises to provide rationale and mechanistic foundation for Pf to be used as a predictive biomarker to guide inhalational antibiotic choices in CF airway disease management. The proposed research draws upon my prior experience in clinical pulmonary medicine and growing expertise in translational research. Along with my mentors and advisory committee, I present a comprehensive career development plan for didactics and technical training in microbiology, genomics, and clinical trial design and biostatistics. This training, along with the clinical studies and experiments outlined, will allow me to develop skills crucial for my transition to an independent translational research career focused on bringing new therapies and treatment strategies for transformative management of CF lung disease.

项目总结/摘要 尽管在治疗方面取得了重大进展，但肺部疾病仍在临床病程中占主导地位 囊性纤维化（CF）患者。所有CF患者均发生慢性肺部感染， 铜绿假单胞菌（Pa）在成年期成为优势微生物。即使面对 慢性吸入性抗生素治疗以靶向肺部Pa，CF患者经历间歇性 肺部恶化伴肺功能逐步下降，最终导致呼吸衰竭。 迫切需要新的治疗策略来解决慢性Pa在肺动脉中的损害作用。 CF患者的肺部。这将使所有CF患者能够充分受益于不断发展的治疗方法 景观，以解决他们的缺陷CF基因功能。 我在CF患者队列中发现了Pa丝状噬菌体的存在 在斯坦福大学和丹麦。Pf与Pa的慢性化和更严重的急性加重相关 （Burgener et al，Science Translational Medicine 2019）。这是第一次展示 噬菌体与人类肺部疾病关系这项建议的目的是深入探讨机制， 这些协会的背后。鉴于慢性吸入抗生素治疗的已知缺点，我 将检验肺中Pf提供抗生素耐受性并且是预测性生物标志物的假设， 指导选择有效的吸入疗法。第一个目标利用储存的呼吸道Pa 分离株，以（1a），评估肺中存在的条件下的抗生素耐受性，（1b）进行整体 基因组测序以评估抗生素抗性基因的存在，以及（1c）进行进化分析， 第二个目标是评估Pf 作为肺部疾病预测生物标志物，在（2a）回顾性队列中评估对 急性加重治疗和（2b）进行交叉临床试验，以评估Pf的差异效应 对肺功能的影响这一提议得到了令人兴奋和新颖的初步数据的支持，有望提供 将Pf用作指导吸入给药的预测性生物标志物的原理和机制基础 CF气道疾病管理中的抗生素选择。 本研究基于我之前在临床肺医学方面的经验， 在翻译研究中不断增长的专业知识。沿着我的导师和顾问委员会， 微生物学教学和技术培训的全面职业发展计划， 基因组学、临床试验设计和生物统计学。这项培训，沿着临床研究， 概述的实验，将使我能够发展对我过渡到一个独立的关键技能， 翻译研究职业生涯的重点是带来新的疗法和治疗策略， CF肺病的变革管理。