H. influenzae genes associated with COPD

项目总结：慢性阻塞性肺疾病的结果是一个复杂的相互作用， 环境因素、宿主免疫反应和微生物因素。嗜血杆菌 流感病毒在人呼吸道定植，是与COPD相关的重要病原体。的 本研究的总体目标是确定H.流感因子是导致COPD发病的重要因素。的 在这个建议中利用的基本原则是H。流感在遗传上是高度可变的， 自然选择在特定的细菌种群中保留了必要的基因。具体目标1 已知H.流感病毒毒力基因将在H.流感病毒株 来自COPD患者和非COPD成人。在特定目标2中，分离 不同的H。将从COPD患者和非COPD成人中分离的流感病毒， 鉴定这项基因发现工作将利用消减基因组杂交来鉴定H。流感 对应于代表性COPD H中存在的基因的DNA片段。流感病毒株，但不存在 在一个代表性菌株中。COPD和COPD患者中产生的DNA片段的患病率 非COPD H.将使用细菌基因组微阵列技术评估流感菌株。在 此外，还将定义并绘制COPD相关DNA片段的相应基因 螺杆流感病毒染色体，以及在Escherosal株的侧翼区域中的缺失程度 评估。在特定目标3中，潜在的COPD相关毒力基因在 将描述COPD菌株，并将描述每个基因对“COPD病理型”的相对贡献 使用分类树分析确定。在具体目标4中，通过免疫调节剂的表达， 人上皮细胞对H.将使用ELISA测量“COPD病理型”的流感。 项目相关性：本项目的结果将确定H。流感病毒相关基因 COPD将描述它们在刺激人类上皮细胞免疫反应中的作用。这些结果将 从而更好地理解H。与COPD相关的流感毒力途径，并导致 预防和管理COPD的新策略。

PROJECT SUMMARY: Chronic obstructive pulmonary disease results from a complex interplay of environmental factors, host immune responses, and microbial factors. The bacterium Haemophilus influenzae colonizes the human respiratory tract and is an important pathogen associated with COPD. The overall goal of this study is to identify H. influenzae factors that contribute to the pathogenesis of COPD. The underlying principles exploited in this proposal are that H. influenzae are genetically highly variable and that natural selection preserves necessary genes among specific populations of bacteria. In Specific Aim 1 the prevalence of known H. influenzae virulence genes will be described among H. influenzae strains isolated form patients with COPD and from adults without COPD. In Specific Aim 2 additional genes that segregate differentially among H. influenzae isolated from patients with COPD and from adults without COPD will be identified. This gene discovery effort will utilize subtractive genomic hybridization to identify H. influenzae DNA fragments that correspond to genes present in a representative COPD H. influenzae strain but absent in a representative commensal strain. The prevalence of the resultant DNA fragments among COPD and non-COPD H. influenzae strains will be assessed using a bacterial genomic microarray technique. In addition, the corresponding genes of the COPD-associated DNA fragments will be defined and mapped on the H. influenzae chromosome, and the extent of the deletion in flanking regions of the commensal strain assessed. In Specific Aim 3, the co-occurrence of the potential COPD-associated virulence genes among COPD strains will be described and the relative contribution of each gene to the "COPD pathotype" will be determined using a classification tree analysis. In Specific Aim 4, the expression of immune mediators by human epithelial cells in response to H. influenzae of the "COPD pathotypes" will be measured using ELISA. PROJECT RELEVANCE: The results of this project will identify H. influenzae genes that are associated with COPD will describe their role in stimulating immune responses by human epithelial cells. These results will lead to a better understanding of the H. influenzae virulence pathways associated with COPD and lead to novel new strategies for prevention and management of COPD.