The Role of Anaerobic Bacterial Infection in Cystic Fibrosis

描述（由申请人提供）：囊性纤维化肺疾病反映了先天肺防御机制对慢性细菌感染的失败。最近，CF气道腔内明显充满黏附性黏液，黏附性黏液相对缺氧。目前的建议验证了CF气道的缺氧环境促进专性厌氧菌感染的假设，这是CF肺致病性的混合感染。因此，来自北爱尔兰（Stuart Elborn）、爱尔兰共和国（Gerald McElvaney）和美国（Richard Boucher）的一组研究人员对这一假设进行了探索，并得出了以下初步数据：1)通过严格的培养和分子诊断技术显示，CF肺中存在厌氧菌；2) CF肺中检测到的厌氧菌不反映口腔污染；3)高密度（相当于假单胞菌）和随急性加重的变化支持厌氧细菌在CF肺中致病的观点。该联盟将测试与厌氧菌在CF肺部疾病发病机制中的作用有关的三个假设：1)Specific Aim 1将测试CF中是否存在厌氧菌而不是正常肺，厌氧菌和铜绿假单胞菌在相似的时间间隔内获得，厌氧菌是病原体而不是无辜的旁观者。2) Specific Aim 2将验证临床研究中发现的厌氧菌具有致病性的假设，探讨厌氧菌体外生长和发病的分子机制。3)特异性目标3将验证一个假设，即患病小鼠肺中需要一个复杂的环境来支持厌氧生长/感染，如果厌氧菌在肺中生长，则厌氧菌是致病的。该项目的长期目标是验证厌氧菌在CF肺中致病的假设，确定它们何时产生这种致病作用，并确定介导发病的机制。这些研究的结果将对设计改善CF肺病治疗的策略至关重要，重点关注以下关键问题：厌氧菌是否应该治疗，如果应该治疗，在获得铜绿假单胞菌之前或之后治疗年轻患者？本研究将产生CF患者厌氧菌临床分离库，用于抗菌药物敏感性测试和未来抗生素试验选择抗生素，以临床测试厌氧菌在CF肺部疾病发病机制中的作用。

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.