Field Study to Understand Progression of Chronic Airway Infection

摘要 慢性感染的一个关键问题是受感染器官的进行性功能障碍。重要的是，病人 有相似危险因素的患者和个体一样，疾病进展速度也有显著差异。 患者在不同的时间。囊性肺炎患者慢性铜绿假单胞菌肺部感染的研究 纤维化(CF)就是一个很好的例子。肺功能下降率的显著变异性在各个地区都可以看到 患者就算宿主CFTR型和呼吸道微生物学也是相似的。 虽然细菌和宿主因素都可能导致疾病变异，但几项新发现导致了我们 重点关注在感染PA过程中进化的遗传变异。首先，已经发现CFPA菌株在遗传上 在体内多样化，产生与克隆相关的变异，这些变异在毒力上明显不同，这些变异可以 在肺内同时共存。其次，我们的数据显示，遗传变异的分布 随着时间的变化和高致病性基因变异的出现可以在时间上与 疾病的变化。最后，许多研究小组调查了宿主的遗传和环境因素 影响疾病，但细菌遗传变异对疾病进展的影响相对较少。 在这里，我们利用独特的临床和技术资源，以及我们对PA发病机制的知识来测试 假设在感染CF患者的PA人群中进化的某些基因变异会增加肺 受伤。我们将分三步检验这一假设。首先，我们会检测痰中的PA基因变异吗 根据肺部疾病表型在特定时间点收集。第二，我们将进行遗传 关联分析，以描绘哪些变种/变异组与 表型。第三，我们将研究基因变异对PA毒力、寄主伤害、 和炎症。这项工作可以识别潜在的因果关系，并提供证据 疾病进展机制的原则，该机制可能在许多慢性感染中起作用。

Abstract A key problem in chronic infections is progressive dysfunction of the infected organ. Importantly, patients with similar risk factors often exhibit marked variation in the rate of disease progression, as do individual patients at different times. The chronic Pseudomonas aeruginosa (Pa) lung infections in people with cystic fibrosis (CF) are a prime example. Pronounced variability in the rate of lung function decline is seen across patients even when host CFTR genotype and airway microbiology are similar. While both bacterial and host factors likely contribute to disease variation, several new findings lead us to focus on genetic variation that evolves in infecting Pa. First, CF Pa strains have been found to genetically diversify in vivo, producing clonally-related variants that differ markedly in virulence, and these variants can co-exist simultaneously inside lungs. Second, our data show that the distribution of genetic variants changes over time and the emergence of highly virulent genetic variants can be temporally associated with changes in disease. Finally, many groups have investigated host genetic and environmental factors that affect disease, but the effects of bacterial genetic variants on disease progression are relatively unexplored Here we exploit unique clinical and technical resources, and our knowledge of Pa pathogenesis to test the hypothesis that some gene variants that evolve in the Pa populations infecting CF patients increase lung injury. We will test this hypothesis in three steps. First, will we measure Pa gene variants in sputum collected at specific time points based on the lung disease phenotypes. Second, we will perform genetic association analysis to delineate which variants/variant groups are most strongly associated with the phenotypes. Third, we will investigate the functional effects of gene variants on Pa virulence, host injury, and inflammation. This work could identify potential cause and effect relationships and provide proof of principle for a disease progression mechanism that may operate in many chronic infections.