Pseudomonas Genomic Signatures Associated With Persistence in Cystic Fibrosis

 描述(申请人提供)：囊性纤维化(CF)是美国最常见的缩短寿命的遗传性疾病。囊性纤维化的大部分发病率和死亡率是由铜绿假单胞菌引起的。虽然一些铜绿假单胞菌菌株从CF患者的呼吸道中被根除，但其他菌株仍然存在，并最终导致慢性感染。一旦铜绿假单胞菌感染确立了慢性化，即使在体外测试时是敏感的，并暴露在长时间的静脉注射抗生素中，也无法用抗生素清除细菌。最终结果是肺功能缓慢进行性恶化，最终往往导致死亡或肺移植。鉴于严重的临床后果，需要新的方法来识别导致慢性感染的高风险菌株。哪些细菌因素导致铜绿假单胞菌在慢性阻塞性肺疾病中的不同持久性？大约15%的铜绿假单胞菌基因组因菌株而异。这些基因赋予菌株特有的特征，统称为“辅助基因组”。我们推测，在某些铜绿假单胞菌菌株中存在或不存在特定的辅助基因，这是它们抵抗根治和进展为慢性感染的能力的原因。为了检验我们的假设，我们将利用由早期假单胞菌感染控制(EPIC)临床试验和观察性研究产生的独特资源，该研究由来自多个地点的249名患者组成，自试验开始以来对其进行了近七年的中位数跟踪调查。我们建议使用EPIC队列来验证我们的假设，以完成以下具体目标：(1)在新感染铜绿假单胞菌的儿童中，我们将识别辅助基因，以区分随后被根除的分离株和持续存在的分离株。(2)在间歇性感染铜绿假单胞菌的儿童中，我们将识别辅助基因，以区分导致慢性感染进展的菌株和未进展为慢性感染的菌株。

 DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is the most common life-shortening genetic disorder in the U.S. Much of the morbidity and mortality in CF is caused by the bacterium Pseudomonas aeruginosa. While some strains of P. aeruginosa are eradicated from the airways of CF patients, others persist and ultimately lead to chronic infections. Once P. aeruginosa infection establishes chronicity, the bacterium cannot be cleared with antibiotics even if it is sensitive when tested ex vivo and exposed to prolonged courses of intravenous antibiotics. The net result is a slowly progressive deterioration of lung function that frequently culminates in death or lung transplantation. Given the severe clinical consequences, new approaches are needed for identifying strains at high risk for causing chronic infections. Which bacterial factors account for the differential persistence of P. aeruginosa in CF airways? Approximately 15% of the P. aeruginosa genome varies from strain to strain. These genes, which confer strain-specific traits, are together referred to as the "accessory genome." We hypothesize that the presence or absence of specific accessory genes in some P. aeruginosa strains accounts for their ability to resist eradication and progress to chronic infection in CF. T test our hypothesis, we will utilize unique resources generated by the Early Pseudomonas Infection Control (EPIC) Clinical Trial and Observational Study, which consist of 249 patients from multiple sites followed over a median of almost seven years since initiation of the trial. We propose to use the EPIC cohort to test our hypothesis by completing the following specific aims: (1) In children with CF newly infected with P. aeruginosa, we will identify accessory genes that distinguish isolates that were subsequently eradicated from those that persisted. (2) In children with CF intermittently infected with P. aeruginosa, we will identify accessory genes that distinguish isolates that caused progression to chronic infection from those that did not.