Bacterial mucin degradation in cystic fibrosis airway disease.

囊性纤维化气道疾病中的细菌粘蛋白降解。

基本信息

批准号：
9398656
负责人：
Ryan Coulson Hunter
金额：
$ 37.49万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9398656
关键词：
Address Amino Acids Anaerobic Bacteria Antibiotic Therapy Antibiotics Bacteria Bacterial Infections Bioavailable Carbon Cell Line Cells Chronic Chronic Obstructive Airway Disease Chronic Sinusitis Chronic lung disease Clinical Coculture Techniques Communities Complex Coupled Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Development Diet Disease Disease Progression Ecology Environment Epithelial Cells Epithelium Fermentation Future Glycoproteins Goals Growth Health Hereditary Disease Histologic Human Immunoassay Impairment In Vitro Individual Infection Inflammatory Response Knowledge Label Link Lung Lung diseases Metabolic Modeling Mucins Mucous body substance Mus Nutrient Nutritional Oral Oral cavity Organism Outcome Pathogenicity Patients Population Prevention Prevotella Process Pseudomonas Pseudomonas aeruginosa Pulmonary Cystic Fibrosis Pulmonary Fibrosis Respiratory Failure Respiratory Mucin Respiratory Tract Infections Role Saliva Site Source Sputum Stable Isotope Labeling Structure of respiratory epithelium Symbiosis Tissues Translating Treatment Efficacy Veillonella Virulence base co-infection commensal microbes cystic fibrosis airway cystic fibrosis patients density feeding improved in vivo in vivo imaging system insight interdisciplinary approach microbial microbiome microbiota mortality novel therapeutic intervention oral anaerobes oral bacteria pathogen respiratory salivary mucins stable isotope therapeutic development ventilator-associated pneumonia

Address Amino Acids Anaerobic Bacteria Antibiotic Therapy Antibiotics Bacteria Bacterial Infections Bioavailable Carbon Cell Line Cells Chronic Chronic Obstructive Airway Disease Chronic Sinusitis Chronic lung disease Clinical Coculture Techniques Communities Complex Coupled Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Development Diet Disease Disease Progression Ecology Environment Epithelial Cells Epithelium Fermentation Future Glycoproteins Goals Growth Health Hereditary Disease Histologic Human Immunoassay Impairment In Vitro Individual Infection Inflammatory Response Knowledge Label Link Lung Lung diseases Metabolic Modeling Mucins Mucous body substance Mus Nutrient Nutritional Oral Oral cavity Organism Outcome Pathogenicity Patients Population Prevention Prevotella Process Pseudomonas Pseudomonas aeruginosa Pulmonary Cystic Fibrosis Pulmonary Fibrosis Respiratory Failure Respiratory Mucin Respiratory Tract Infections Role Saliva Site Source Sputum Stable Isotope Labeling Structure of respiratory epithelium Symbiosis Tissues Translating Treatment Efficacy Veillonella Virulence base co-infection commensal microbes cystic fibrosis airway cystic fibrosis patients density feeding improved in vivo in vivo imaging system insight interdisciplinary approach microbial microbiome microbiota mortality novel therapeutic intervention oral anaerobes oral bacteria pathogen respiratory salivary mucins stable isotope therapeutic development ventilator-associated pneumonia

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项目摘要

PROJECT SUMMARY / ABSTRACT Despite extensive studies of cystic fibrosis (CF) bacterial pathogens, the efficacy of antibiotics achieved in vitro seldom translates to successful clinical outcomes. This limitation is partially driven by our lack of understanding of the host environments to which bacteria adapt, and the metabolic strategies that sustain community growth in vivo. Studies that generate greater insight into what CF pathogens are doing within the cystic fibrosis airways are necessary to inform more effective therapeutic strategies. This proposal addresses how CF pathogens obtain nutrients within the lung. Despite the presence of bacterial cells at high densities, the nutrient source(s) that sustains their growth is not apparent; the predominant carbon reservoir, mucins, are recalcitrant to degradation by the canonical pathogen Pseudomonas aeruginosa. Given their abundance in the lung and their ability to degrade salivary mucins, we propose that anaerobes typically associated with the oral cavity, facilitate carbon acquisition by Pseudomonas, which in turn drives disease. More specifically, commensal bacteria (e.g. Prevotella, Veillonella) are able to thrive off respiratory mucin secretions, releasing mixed fermentation byproducts. We hypothesize that if allowed to accumulate (due to impaired mucus clearance), fermentation-derived metabolites can support the growth of other organisms. We have recently shown that saliva-derived bacterial communities stimulate the growth of P. aeruginosa when provided mucin as the sole carbon source. This suggests that mucin-degrading anaerobes may support pathogens during infection. Based on these data, this project will use a multi-disciplinary approach to (1) identify the anaerobic bacteria and the mucin-derived metabolites they generate that can support P. aeruginosa growth, (2) Use a stable isotope labeling approach to track the flow of mucin-derived carbon throughout CF sputum, (3) Use a mucin-overproducing cell line to assess Pseudomonas-epithelium interactions in the presence of mucin-degrading anaerobes, and (4) use a murine chronic lung infection model to assess the growth and pathogenicity of Pseudomonas in vivo when co-infected with oral-derived anaerobes. At the completion of this study, we will have defined a pathogenic role for oral-associated bacteria in the lower airways and provide a detailed characterization of carbon flow within the CF lung. Altogether, these studies will have a meaningful impact on our understanding of the functional role of the CF microbiota and the potential development of therapeutic strategies. While the CF microbiome will serve as a starting point to investigate mucin-derived cross-feeding interactions, our approach is equally applicable to the prevention of other respiratory diseases – COPD, chronic sinusitis, and ventilator- associated pneumonias – where a viscous mucus environment harbors complex bacterial infections.

项目摘要 /摘要尽管大量研究囊性纤维化（CF）细菌病原体，但抗生素的效率在体外实现的很少转化为成功的临床结果。该限制部分由我们对细菌适应的宿主环境缺乏了解以及代谢策略在体内维持社区的增长。对CF病原体的洞察力产生更深入的研究在囊性纤维化气道中进行操作是为了告知更有效的治疗策略。该建议介绍了CF病原体如何在肺内获得营养。尽管有在高密度下存在细菌细胞，维持其生长的养分来源不是显而易见；主要的碳储库粘液是顽固的，被规范降解病原体铜绿假单胞菌。鉴于它们在肺中的丰富和降解能力唾液粘液蛋白，我们建议厌氧菌通常与口腔相关，促进碳假单胞菌的收购又驱动了疾病。更具体地，共生细菌（例如 Prevotella，Veillonella）能够脱离呼吸道粘蛋白分泌物，释放混合发酵副产品。我们假设如果允许积累（由于粘液清除受损），发酵衍生的代谢产物可以支持其他生物的生长。我们最近显示了当提供粘蛋白为唯一的碳源。这表明降解粘蛋白厌氧菌可能会在感染。基于这些数据，该项目将使用多学科的方法来（1）确定它们产生的厌氧菌细菌和粘蛋白衍生的代谢产物可以支持铜绿假单胞菌生长，（2）使用稳定的同位素标记方法来跟踪粘蛋白衍生的碳的流动 CF痰，（3）使用粘蛋白超过产生的细胞系评估假单胞菌 - 上皮相互作用粘液降解厌氧菌的存在，（4）使用鼠类慢性肺部感染模型与口服衍生的同时感染时，评估体内假单胞菌的生长和致病性厌氧。这项研究完成时，我们将定义口腔相关细菌的致病作用在下部气道中，提供了CF肺内碳流的详细表征。共，这些研究将对我们对CF的功能作用的理解产生有意义的影响微生物群和治疗策略的潜在发展。而CF微生物组将服务作为研究粘蛋白衍生的交叉进食相互作用的起点，我们的方法同样是适用于预防其他呼吸道疾病 - COPD，慢性鼻窦炎和呼吸机 - 相关的肺炎 - 粘性粘液环境具有复杂细菌感染。