The role of anaerobic microbiota in cystic fibrosis airway disease trajectory

厌氧微生物群在囊性纤维化气道疾病轨迹中的作用

• 批准号: 10716654
• 负责人: Ryan Coulson Hunter
• 金额: $ 20.65万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2023-11-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10716654
• 关键词: Acute Disease; Address; Aerobic; Aerobic Bacteria; Affect; Age; Airway Disease; Anaerobic Bacteria; Anoxia; Antibiotic susceptibility; Antimicrobial Resistance; Bacteria; Biological Models; Bronchoalveolar Lavage Fluid; Cells; Childbirth; Chronic; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Research; Coculture Techniques; Complex; Coupled; Cystic Fibrosis; Data; Development; Disease; Disease Management; Disparate; Environment; Epidemiology; Epithelial Cells; Etiology; Evolution; Flare; Fluorescent in Situ Hybridization; Functional disorder; Future; Growth; Image; Immune response; Immunologics; Immunology; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Laboratories; Lung; Lung diseases; Lung infections; Mediating; Metabolism; Microbiology; Modeling; Morbidity - disease rate; Mucins; Mutation; Nutritional; Organism; Outcome; Oxygen; Pathogenicity; Patient-Focused Outcomes; Patients; Population; Prevalence; Prevotella; Process; Pseudomonas aeruginosa; Publishing; Pulmonary Cystic Fibrosis; Reporting; Respiratory Tract Infections; Role; Shapes; Sinusitis; Staphylococcus aureus; Streptococcus; Structure; System; Testing; Therapeutic; Veillonella; Virulence; Work; acute infection; age group; airway epithelium; bacterial community; bronchial epithelium; cell type; children with cystic fibrosis; chronic respiratory disease; cystic fibrosis airway; cystic fibrosis patients; density; early cystic fibrosis; experimental study; feeding; genome sequencing; improved; in vitro Model; in vivo; innovation; insight; interdisciplinary approach; microbial; microbiome; microbiota; novel therapeutic intervention; pathogen; polymicrobial disease; pulmonary function; respiratory colonization; respiratory microbiota; single-cell RNA sequencing; targeted treatment; ventilator-associated pneumonia; whole genome

PROJECT SUMMARY / ABSTRACT Despite the recent surge in studies reporting on the prevalence and abundance of anaerobic microbiota in the airways of individuals with cystic fibrosis (CF), their mechanistic contributions, if any, to disease pathophysiology remain controversial and poorly understood. This knowledge gap is driven, in part, by conflicting epidemiological and in vitro experimental data, a lack of suitable model systems to study their interactions with the host, and the dearth of laboratory expertise in host-associated anaerobic microbiology. Studies that generate greater insight into the role of anaerobes in CF lung infection, particularly at early stages, are necessary to determine if, when, and how to target this group of organisms therapeutically. Our team has shown that (i) anaerobes are early colonizers of the pediatric CF airways prior to the acquisition of canonical pathogens, (ii) anaerobe bacterial communities elicit pro-inflammatory response when co-cultured with bronchial epithelial cells, and (iii) anaerobe-mediated mucin degradation and cross- feeding can shape the growth, virulence, and antibiotic susceptibility of canonical CF pathogens. Building on these data, this project proposes to use a multi-disciplinary approach to investigate how individual anaerobes interact with one another, the airway epithelium, and traditional pathogens (e.g., P. aeruginosa, S. aureus) in the context of early CF airway disease. First, using an experimental microbiome model system composed of 10 CF anaerobic species, we will determine how CF bacterial communities assemble and how their assembly dynamics are shaped by host and microbial processes. Second, using an innovative dual oxic-anoxic system that enables co-culture of anaerobic bacteria and airway epithelial cells, we will use single-cell RNA sequencing to determine how anaerobes interact with the airway epithelium, and how the host response varies by epithelial cell type. Finally, given that P. aeruginosa, S. aureus, and other aerobic pathogens co-colonize with anaerobic microbiota and rapidly adapt to the airways as patients age, we will use an in vitro experimental evolution approach to test whether early CF microbiota are sufficient to drive the adaptation of canonical pathogens to the nutritional milieu of the CF airways. At the completion of these aims, we will have defined how individual anaerobes interact with one another, the host, and traditional CF pathogens. In doing so, these studies will have a meaningful impact on our mechanistic understanding of the role of airway microbiota in chronic airway disease and may motivate future studies targeting specific anaerobic bacteria, or even promoting their growth, as a means of improving clinical outcomes. Finally, we use CF as our model system, but this work is broadly applicable to other acute and airway infections (e.g., COPD, sinusitis, ventilator associated pneumonias) in which anaerobes have been implicated but their mechanistic contributions remain undefined.

项目摘要 /摘要 尽管最近的研究激增，报告了厌氧的患病率和丰度 囊性纤维化（CF）的气道中的微生物群，其机械贡献（如果有的话） 疾病的病理生理学仍然存在争议性和知名度不佳。这种知识差距是驱动的 一部分，通过冲突的流行病学和体外实验数据，缺乏合适的模型系统来研究 他们与宿主的互动以及缺乏与宿主相关的厌氧方面的实验室专业知识 微生物学。对厌氧菌在CF肺部感染中的作用有更深入地了解的研究， 特别是在早期阶段，必须确定该群体是否，何时以及如何靶向这组生物 在治疗上。 我们的团队表明（i）厌氧是儿科CF气道的早期殖民者 获得规范病原体，（ii）厌氧菌细菌群落引起促炎反应 当与支气管上皮细胞共培养时，（iii）厌氧菌介导的粘蛋白降解和交叉 喂养可以影响规范CF病原体的生长，毒力和抗生素敏感性。建筑 在这些数据上，该项目建议使用多学科的方法来研究个人 厌氧菌相互作用，气道上皮和传统病原体（例如，P。铜绿假单胞菌， S.金黄色葡萄球菌）在早期CF气道疾病的背景下。首先，使用实验微生物组模型 由10个CF厌氧物种组成的系统，我们将确定CF细菌群落如何组装 以及如何通过宿主和微生物过程塑造其组装动力学。第二，使用一个 创新的双重毒性动物系统，可以使厌氧菌和气道上皮细胞共同培养 我们将使用单细胞RNA测序来确定Anaerobes如何与气道上皮相互作用， 以及宿主响应如何随上皮细胞类型而变化。最后，鉴于铜绿假单胞菌，金黄色葡萄球菌和 其他有氧病原体与厌氧菌群共同殖民，并在患者中迅速适应气道 年龄，我们将使用一种体外实验进化方法来测试早期CF微生物群是否是 足以将规范病原体适应CF气道营养环境。 这些目的完成时，我们将定义单个厌氧与一个人相互作用 另一个，宿主和传统的CF病原体。这样，这些研究将产生有意义的影响 关于我们对气道微生物群在慢性气道疾病中的作用的理解，可能 激励未来针对特定厌氧细菌甚至促进其生长的研究，以此作为一种手段 改善临床结果。最后，我们将CF用作模型系统，但是这项工作广泛适用 到其他急性和气道感染（例如COPD，鼻窦炎，相关肺炎） 厌氧菌已被暗示，但其机械贡献仍然不确定。