The Role of Anaerobic Bacterial Infection in Cystic Fibrosis

描述(由申请人提供)：囊性纤维性肺疾病反映了针对慢性细菌感染的先天肺防御机制的失败。最近，有一件事变得很明显，即CF的气道腔充满了相对低氧的粘液。目前的建议验证了这样的假设，即CF呼吸道的低氧环境促进了专性厌氧菌作为对CF肺部致病的混合感染的感染。因此，来自北爱尔兰(Stuart Elborne)、爱尔兰共和国(Gerald McElvaney)和美国(Richard Boucher)的研究人员组成的财团探索了这一假设，并产生了下列初步数据：1)严格的培养和分子诊断技术显示，CF肺中存在厌氧菌；2)在CF肺中检测到的厌氧菌并不反映口腔污染；以及3)高密度(相当于假单胞菌)以及随着急性加重而发生的变化支持在CF肺中存在厌氧细菌是致病的概念。该联盟将测试与厌氧菌在CF肺部疾病发病机制中的作用相关的三个假设：1)特定目标1将测试CF中是否存在厌氧菌但不是正常肺，厌氧菌和铜绿假单胞菌是在相似的时间间隔内获得的，以及厌氧菌是病原体而不是无辜的旁观者。2)特殊目的2将验证临床研究中鉴定的厌氧菌是致病的假说，研究体外厌氧菌生长和致病的分子机制。3)特殊目标3将检验这样的假设，即在体内患病的小鼠肺中需要一个复杂的环境来支持厌氧生长/感染，并且如果在肺中建立生长，厌氧菌是致病的。该项目的长期目标是验证厌氧菌在CF肺中致病的假说，确定它们何时产生这种致病效应，并确定介导发病的机制。这些研究的结果将对设计改进CF肺部疾病治疗的策略至关重要，重点关注以下关键问题：厌氧菌是否应该接受治疗，如果是的话，在PS之前或之后对年轻患者进行治疗。收购铜绿假病毒？这项研究将产生一组来自慢性肺病患者的厌氧菌临床分离库，用于测试抗菌药物的敏感性，并为未来的抗生素试验选择抗生素，以临床测试厌氧菌在慢性肺病发病机制中的作用。 与公共卫生相关：这项提议旨在测试专性厌氧菌是CF肺中的病原体的假设。如果是这样的话，这一观察结果将增加它们是其他主要呼吸道疾病的病原体的可能性，例如慢性支气管炎。这样的观察可能会改变医生对呼吸道疾病患者进行抗生素治疗的方式。

DESCRIPTION (provided by applicant): Cystic fibrosis lung disease reflects a failure of innate lung defense mechanisms against chronic bacterial infection. Recently, it has become apparent that the CF airway lumen is filled with adherent mucus that is relatively hypoxic. The present proposal tests the hypothesis that the hypoxic environment of the CF airways promotes infection by obligate anaerobes as mixed infections that are pathogenic for the CF lung. Accordingly, a consortium of investigators from Northern Ireland (Stuart Elborn), the Irish Republic (Gerald McElvaney), and the U.S. (Richard Boucher) have explored this hypothesis and produced the following preliminary data: 1) anaerobes are present in the CF lung, as revealed by rigorous culture and molecular diagnostic techniques; 2) the anaerobes detected in CF lung do not reflect oral contamination; and 3) the high density (equal to Pseudomonas), and changes with acute exacerbation support the notion that anaerobic bacteria are pathogenic in the CF lung. The consortium will test three hypotheses that relate to the role of anaerobes in the pathogenesis of CF lung disease: 1) Specific Aim 1 will test whether there are anaerobes in the CF but not normal lung, that anaerobes and P. aeruginosa are acquired over similar time intervals, and that anaerobes are pathogens and not innocent bystanders. 2) Specific Aim 2 will test the hypothesis that anaerobes identified in the clinical study are pathogenic, investigating the molecular mechanisms underlying anaerobe growth and pathogenesis in vitro. 3) Specific Aim 3 will test the hypothesis that a complex environment is required in the diseased mouse lung in vivo to support anaerobic growth/infection, and that anaerobes are pathogenic if growth is established in the lung. The long-term goals of this project are to test the hypothesis that anaerobes are pathogenic in the CF lung, identify when they produce this pathogenic effect, and identify the mechanisms mediating pathogenesis. The outcome of these studies will be critical in designing strategies to improve therapy of CF lung disease, focused on such key issues as: should anaerobes be treated at all, and if so, treated in young patients prior to or after Ps. aeruginosa acquisition? This study will generate a bank of clinical isolates of anaerobes from CF patients that will serve for testing antimicrobial sensitivities and selecting antibiotics for future antibiotic trials to clinically test the role of anaerobes in the pathogenesis of CF lung disease. PUBLIC HEALTH RELEVANCE: This proposal is designed to test the hypothesis that obligate anaerobic bacteria are pathogens in the CF lung. If so, this observation would raise the possibility that they are pathogens in other major airways diseases, e.g., chronic bronchitis. Such observations might change the way physicians approach antibiotic therapy of patients with airways disease.