Pseudomonas aeruginosa Adaptation During Early CF Airway Infection and Treatment

描述(由申请人提供)： 肺部疾病是遗传性囊性纤维化患者预期寿命和生活质量的主要决定因素。机会革兰氏阴性杆菌铜绿假单胞菌感染大多数CF患者的呼吸道，这种病原体的感染显然与较差的呼吸结局有关。铜绿假单胞菌在生命早期感染慢性支气管炎。多年来，细菌适应了CF的呼吸道环境，并刺激了炎症反应，这些反应在根除感染方面无效，但会损害呼吸道。制定预防铜绿假单胞菌定植和消除慢性感染的策略将需要了解细菌对慢性肺病的自然历史贡献。这项辅助性拨款提案描述了一个包括囊性纤维化临床医生、微生物学家和流行病学家在内的合作项目，该项目将利用两项大型、相互关联的、正在进行的CF微生物学多中心研究产生的独特资源，称为囊性纤维化研究的早期抗假瘤疗法(EPIC)。我们建议使用EPIC试验提供的铜绿假单胞菌临床分离株、相关的临床数据和独特的临床研究指导机会来研究铜绿假单胞菌适应CF呼吸道的自然历史。具体地说，拟议的项目将定义感染携带新发现的适应性变化的铜绿假单胞菌的临床相关性：编码主要转录调节因子LasR的基因的失活突变。在最近的一项单中心横断面研究中，我们发现这种突变发生在CF慢性呼吸道感染的早期，平均比粘液样改变(最好地描述铜绿假单胞菌CF适应性变化)早两年，但患病率相似。此外，LasR突变感染与肺功能加速下降有关。可能与这一发现有关，初步证据表明，LasR突变导致对CF治疗中最常用的三类抗生素：内酰胺类、氨基糖苷类和氟喹诺酮类药物的耐药性增加。相反，LasR突变株在体外对至少两类代谢抑制剂更敏感，这为感染这些菌株的患者提供了替代治疗策略。因此，在慢性铜绿假单胞菌Cf呼吸道感染过程中LasR突变的出现可能作为疾病进展的标志，并且可以为携带这些适应性突变的患者开发新的治疗方法。然而，为了解决这些方法的有效性，我们的初步流行病学发现必须在更大的多中心人群中得到验证。我们建议确定在EPIC试验中登记的幼儿中LasR突变铜绿假单胞菌感染的患病率和相关的临床特征，以检验LasR突变在铜绿假单胞菌感染期间相对常见和早期发生的假设，并与先前的抗生素暴露、肺功能加速下降和更频繁的呼吸恶化有关。这项研究的结果将阐明慢性肺病的自然病史，并可能导致目前的慢性肺病治疗方案的改进。公共卫生相关性：囊性纤维化(CF)是高加索人最常见的遗传病。患有慢性肺病的人死于慢性肺部感染的平均年龄为37岁，这些感染限制了他们的生命质量和寿命。这个项目将研究引起肺部感染的细菌之间的差异，以及这些细菌特征和肺部疾病进展之间的关系。这个项目的目的是为了更好地了解CF肺部疾病的发病机制，以便开发更好的治疗方法。

DESCRIPTION (provided by applicant): Lung disease is the primary determinant of life expectancy and quality of life among people with the genetic disease cystic fibrosis (CF). The opportunistic Gram-negative bacterium Pseudomonas aeruginosa infects the respiratory tracts of most patients with CF, and infection with this pathogen is clearly associated with worse respiratory outcomes. P. aeruginosa infects CF airways early in life. Over many years, bacteria adapt to the CF airway environment and stimulate inflammatory responses that are ineffective in eradicating the infection, yet damage airways. The development of strategies to prevent P. aeruginosa colonization and eliminate chronic infection will require an understanding of the natural history of the bacterial contribution to CF lung disease. This ancillary grant proposal describes a collaborative project including CF clinicians, microbiologists, and epidemiologists that will make use of the unique resources generated from two large, interrelated, ongoing multicenter studies of CF microbiology, known as the Early Antipseudomonal Therapy in Cystic Fibrosis studies (EPIC). We propose to use the P. aeruginosa clinical isolates, linked clinical data, and unique clinical research mentorship opportunities available from the EPIC trials to study the natural history of P. aeruginosa adaptation to the CF airway. Specifically, the proposed project will define the clinical relevance of infection with P. aeruginosa carrying a newly-identified adaptive change: inactivating mutation in the gene encoding the major transcriptional regulator LasR. In a recent single-center, cross-sectional study, we found this mutation to occur early during CF chronic airway infection, on average two years earlier than mucoidy (the best-described P. aeruginosa CF adaptive change), yet with a similar prevalence. Furthermore, LasR mutant infection was associated with accelerated lung function decline. Perhaps related to this finding, preliminary evidence suggests that LasR mutation leads to increased resistance to the three classes of antibiotic used most often in CF therapy: ¿lactams, aminoglycosides, and fluoroquinolones. Conversely, LasR mutants are more susceptible in vitro to at least two classes of metabolic inhibitors, suggesting alternative therapeutic strategies for patients infected with these isolates. Thus, the emergence of LasR mutation during chronic P. aeruginosa CF airway infections may serve as a marker for advancing disease, and novel therapies could be developed for patients carrying these adaptive mutants. However, to address the utility of these approaches, our preliminary epidemiologic findings must be validated in a larger, multicenter population. We propose to define the prevalence and associated clinical features of LasR mutant P. aeruginosa infection among the young children enrolled in the EPIC trials, to test the hypothesis that LasR mutation occurs relatively commonly and early during P. aeruginosa CF infections, and is associated with preceding antibiotic exposure, accelerated decline in lung function, and more frequent respiratory exacerbations. The results of this study will clarify the natural history of CF lung disease, and may lead to improvements in current CF therapeutic regimens. PUBLIC HEALTH RELEVANCE: Cystic fibrosis (CF) is the most common genetic disease of Caucasians. People with CF die at a median age of 37 years from chronic lung infections that limit their quality and length of life. This project will examine the differences among the bacteria that cause CF lung infections, and the relationship between these bacterial characteristics and lung disease progression. The goal of this project is to better understand the pathogenesis of CF lung disease so that better treatments can be developed.