Pseudomonas Aeruginosa Early CF Adaptive Changes: A Translational Study

描述（由申请人提供）：肺部疾病是遗传性疾病囊性纤维化（CF）患者预期寿命和生活质量的主要决定因素。机会性革兰氏阴性菌铜绿假单胞菌感染大多数CF患者的呼吸道，感染这种病原体显然与更差的呼吸结局相关。铜绿假单胞菌在生命早期感染CF气道。多年来，细菌适应CF气道环境并刺激炎症反应，这些炎症反应在根除感染方面无效，但会损害气道。预防铜绿假单胞菌定植和消除慢性感染的策略的发展将需要了解细菌对CF肺病的自然史。该提案描述了一个为期四年的计划，以进一步建立独立的，转化研究的候选人的职业生涯。特别是，候选人，训练有素的医生和微生物学家，将继续他的临床研究培训，并将他的时间集中在他资助的合作项目，以确定早期CF气道感染期间铜绿假单胞菌变化的自然史。该项目使用铜绿假单胞菌临床分离株、相关临床数据和独特的临床研究指导机会，这些机会来自两项当地主导的CF微生物学国家研究，即囊性纤维化研究中的早期抗假单胞菌治疗（EPIC）。具体而言，该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的基因中的失活突变。在我们的初步研究中，这种突变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治疗中最常用抗生素的耐药性增加。相反，LasR突变体在体外对至少两类代谢抑制剂更敏感，这表明感染这些分离株的患者的替代治疗策略。因此，在慢性铜绿假单胞菌CF气道感染期间LasR突变的出现可以作为疾病进展的标志物，并且可以为携带这些适应性突变体的患者开发新的疗法。然而，为了解决这些方法的效用，我们的初步流行病学研究结果必须在一个更大的，多中心的人口验证。我们的目的是确定EPIC试验中招募的幼儿中LasR突变铜绿假单胞菌感染的患病率和相关临床特征，以检验LasR突变在铜绿假单胞菌CF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道加重相关。在这里，我们还建议将有关LasR突变的结果与该人群中其他常见的铜绿假单胞菌CF适应性变化的结果进行比较。这项研究的结果将澄清CF肺病的自然史，并可能导致目前CF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性疾病，CF患者死于慢性肺部感染的中位年龄为37岁，这限制了他们的生活质量和寿命。该提案描述了一个为期四年的计划，以进一步建立候选人的转化研究生涯，重点是慢性CF肺部感染的病理生理学，长期目标是确定和开发更好的治疗方法。这里描述的项目将定义导致CF肺部感染的细菌之间的差异，以及这些细菌特征与肺部疾病进展之间的关系，作为实现这些目标的关键下一步。

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 proposal describes a four-year plan to further establish the independent, translational research career for the candidate. In particular, the candidate, a trained physician and microbiologist, will continue his clinical research training and focus his time on his funded, collaborative project to define the natural history of P. aeruginosa changes during early CF airway infection. This project uses the P. aeruginosa clinical isolates, linked clinical data, and unique clinical research mentorship opportunities available from two locally-led, national studies of CF microbiology, the Early Antipseudomonal Therapy in Cystic Fibrosis studies (EPIC). Specifically, this 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. This mutation was associated in our preliminary studies with accelerated lung function decline. Perhaps related to this finding, preliminary evidence suggests that LasR mutation leads to increased resistance to the antibiotics used most often in CF therapy. 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 aim 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. Here, we also propose to compare results concerning LasR mutation with those for other common P. aeruginosa CF adaptive changes in this population. 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, and people with CF die at a median age of 37 years from chronic lung infections that limit their quality and length of life. This proposal describes a four-year plan to further establish the translational research career of the candidate, focused on the pathophysiology of chronic CF lung infections with the long-term goals of identifying and developing better treatments for this devastating disease. The project described here will define the differences among the bacteria that cause CF lung infections, and the relationship between these bacterial characteristics and lung disease progression, as a critical next step towards these goals.