Pseudomonas Aeruginosa Early CF Adaptive Changes: A Translational Study

描述（由申请人提供）：肺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，这种病原体的感染显然与更差的呼吸系统结局相关。铜绿假单胞菌在生命早期就感染 CF 气道。多年来，细菌适应 CF 气道环境并刺激炎症反应，这些反应无法有效根除感染，但却会损害气道。制定预防铜绿假单胞菌定植和消除慢性感染的策略需要了解细菌导致 CF 肺病的自然史。该提案描述了一个四年计划，旨在进一步为候选人建立独立的转化研究生涯。特别是，候选人是一名训练有素的医生和微生物学家，他将继续接受临床研究培训，并将时间集中在他资助的合作项目上，以定义早期 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、关联的临床数据以及独特的临床研究指导机会，这些机会来自两项当地主导的国家 CF 微生物学研究，即囊性纤维化早期抗假单胞菌治疗研究 (EPIC)。具体来说，该项目将定义铜绿假单胞菌感染的临床相关性，该感染携带新发现的适应性变化：编码主要转录调节因子 LasR 的基因失活突变。在我们的初步研究中，这种突变与肺功能加速衰退有关。也许与这一发现有关，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，这为感染这些分离株的患者提出了替代治疗策略。因此，慢性铜绿假单胞菌CF气道感染期间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体的患者开发新的疗法。然而，为了解决这些方法的实用性，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。我们的目的是确定参加 EPIC 试验的幼儿中 LasR 突变型铜绿假单胞菌感染的患病率和相关临床特征，以检验以下假设：LasR 突变在铜绿假单胞菌 CF 感染过程中相对较常见且较早发生，并且与之前的抗生素暴露、肺功能加速下降和更频繁的呼吸系统恶化有关。在这里，我们还建议将 LasR 突变的结果与该群体中其他常见铜绿假单胞菌 CF 适应性变化的结果进行比较。这项研究的结果将阐明 CF 肺部疾病的自然史，并可能导致当前 CF 治疗方案的改进。 公共卫生相关性：囊性纤维化 (CF) 是白种人最常见的遗传病，患有 CF 的人死于慢性肺部感染，中位年龄为 37 岁，慢性肺部感染限制了他们的质量和寿命。该提案描述了一项为期四年的计划，旨在进一步建立候选人的转化研究生涯，重点关注慢性 CF 肺部感染的病理生理学，长期目标是确定和开发针对这种毁灭性疾病的更好的治疗方法。这里描述的项目将定义引起 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.