The Role of Anaerobic Bacterial Infection in Cystic Fibrosis

描述（由申请人提供）：囊性纤维化肺病反映了先天性肺防御机制对慢性细菌感染的失败。最近，已经变得明显的是，CF气道腔充满了相对缺氧的粘附粘液。本提案测试了CF气道的低氧环境促进专性厌氧菌作为CF肺致病性的混合感染的感染的假设。因此，一个来自北方爱尔兰的调查人员联合会（Stuart Elborn），爱尔兰共和国（Gerald McElvaney），美国（RichardBoucher）已经探索了这一假设并产生了以下初步数据：1）如通过严格的培养和分子诊断技术所揭示的，厌氧菌存在于CF肺中; 2）在CF肺中检测到的厌氧菌不反映口腔污染;高密度（等于假单胞菌）和急性加重的变化支持厌氧菌在CF肺中是致病性的观点。该联盟将测试与厌氧菌在CF肺病发病机制中的作用有关的三个假设：1）特定目标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，以及厌氧菌是病原体而不是无辜的旁观者。2)具体目标2将检验临床研究中鉴定的厌氧菌具有致病性的假设，研究厌氧菌体外生长和发病机制的分子机制。3)具体目标3将检验以下假设：患病小鼠肺体内需要复杂环境以支持厌氧菌生长/感染，如果在肺中建立生长，则厌氧菌是致病性的。本项目的长期目标是检验厌氧菌在CF肺中致病的假设，确定它们何时产生这种致病作用，并确定介导发病机制的机制。这些研究的结果将是至关重要的，在设计策略，以改善治疗CF肺疾病，重点是这样的关键问题：厌氧菌是否应在所有的治疗，如果是这样，治疗年轻患者之前或之后Ps。收购铜绿假单胞菌？本研究将从CF患者中产生一个厌氧菌临床分离株库，用于测试抗菌药物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CF肺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.