H. influenzae genes associated with COPD

项目摘要：慢性阻塞性肺疾病是由 环境因素、宿主免疫反应和微生物因素。嗜血杆菌 流感病毒在人类呼吸道中定植，是与慢性阻塞性肺疾病相关的重要病原体。这个 这项研究的总体目标是确定与COPD发病相关的流感嗜血杆菌因子。这个 这项提案中采用的基本原理是，流感嗜血杆菌在遗传上高度可变，而且 自然选择在特定的细菌种群中保留了必要的基因。在具体目标1中 已知的流感嗜血杆菌毒力基因在分离的流感嗜血杆菌菌株中的流行情况将被描述。 来自COPD患者和没有COPD的成年人。在特定的目标中，另外两个分离的基因 从COPD患者和非COPD成人分离的流感嗜血杆菌之间的区别将是 已确认身份。这项基因发现工作将利用消减基因组杂交来鉴定流感嗜血杆菌。 与典型的COPD流感嗜血杆菌菌株中存在但不存在的基因相对应的DNA片段 以一种典型的共生品系。所产生的DNA片段在慢性阻塞性肺疾病和慢性阻塞性肺疾病中的发生率 将使用细菌基因组微阵列技术对非COPD流感嗜血杆菌菌株进行评估。在……里面 此外，COPD相关DNA片段的相应基因将被定义并绘制在 流感嗜血杆菌染色体和共生菌株侧翼区域的缺失程度 评估过了。在特定目标3中，潜在的COPD相关毒力基因在 将描述COPD菌株，并且每个基因对“COPD致病类型”的相对贡献如下 使用分类树分析确定。在特定的目标4中，免疫介质的表达通过 人类上皮细胞对“COPD致病类型”的流感嗜血杆菌的反应将用酶联免疫吸附试验进行测定。 项目相关性：该项目的结果将确定与流感嗜血杆菌相关的基因 COPD将描述它们在刺激人类上皮细胞免疫反应方面的作用。这些结果将 更好地了解与慢性阻塞性肺疾病相关的流感嗜血杆菌毒力途径，并导致 预防和管理慢性阻塞性肺病的新策略。

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.