Viral Pathogenesis of Early Cystic Fibrosis Lung Disease

描述（由申请人提供）：CF肺病的发展和演变可能是可变的，但从我们先前的研究中可以清楚地看出，生理和结构缺陷开始于婴儿期，并且经常在检测到细菌感染之前存在，涉及其他病因或感染性损伤。关于病毒对CF肺中细菌定植、气道炎症、生理指标和结构变化的影响知之甚少。在这个建议中，我们将定义病毒感染在早期CF肺部疾病起源中的作用。结合印第安纳州大学（印第安纳波利斯，印第安纳州）、华盛顿大学（圣路易斯，密苏里州）和澳大利亚囊性纤维化早期监测小组（AREST CF）（澳大利亚墨尔本和珀斯）的专业知识和可用资源，我们将确定CF婴儿病毒感染的发病率和类型。将在婴儿期的预定时间收集支气管肺泡灌洗液和咽部分泌物，并将使用高度灵敏的基于核酸的检测和强大的微生物组学测定来表征下呼吸道感染。此外，我们将系统地定义CF肺的最早生理变化，结合灌洗液中的炎症标志物分析，肺功能测量和计算机X射线断层成像，在新生儿筛查后不久诊断的婴儿的监测计划中。创新的气道建模技术将被应用于更好地检测和测量支气管扩张之前的气道疾病。我们将研究病毒感染和CF肺的初始病理生理变化之间的关系，并检验早期呼吸道病毒感染改变气道细菌植物群和炎症特征并加速CF婴儿肺部疾病进展的假设。该建议有三个具体目标，即（i）确定呼吸道病毒感染的频率及其对CF婴儿支气管内细菌感染和炎症演变的影响;（ii）研究早期病毒感染对CF婴儿呼吸道症状发展和肺部生理变化的影响;（iii）研究早期病毒感染对CF婴儿呼吸道症状发展和肺部生理变化的影响。以及（iii）评估如通过结构和气道建模技术所定义的病毒感染和气道疾病之间的关系。如果成功，这些研究将为CF肺病的发病机制提供新的见解，帮助设计治疗策略以减少病毒诱导的肺部发病率，并可能预防不可逆气道疾病的发展。(End摘要）

DESCRIPTION (provided by applicant): The development and evolution of CF lung disease can be variable, but it is clear from our previous research that physiological and structural defects begin in infancy and are frequently present prior to the detection of bacterial infection, implicating other etiologies or infectious insults. Little is known about the impact of viruses on bacterial colonization, airway inflammation, physiological measures, and structural changes in the CF lung. In this proposal, we will define the role(s) of viral infections in the origins of eary CF pulmonary disease. Combining the expertise and resources available at the University of Indiana (Indianapolis, Indiana), Washington University (St. Louis, Missouri), and the Australian Early Surveillance Team for Cystic Fibrosis (AREST CF) (Melbourne and Perth, Australia), we will define the incidence and type of viral infections in CF infants. Bronchoalveolar lavage fluid and pharyngeal secretions will be collected at predetermined times during infancy, and highly sensitive nucleic acid-based detection and powerful microbiomic assays will be used to characterize lower respiratory tract infections. Also, we will systematically define the earliest physiological changes in the CF lung, combining analyses for inflammatory markers in lavage fluid, pulmonary function measurements, and computerized x-ray tomographic imaging, in a surveillance program for infants diagnosed shortly after newborn screening. Innovative airway modeling techniques will be applied to better detect and measure airway disease that precedes bronchiectasis. We will examine the relationship between viral infections and initial pathophysiological changes in the CF lung, and test the hypothesis that early respiratory viral infections alter the bacterial flora and inflammatory profile in the airway and accelerate progression of pulmonary disease in CF infants. The proposal has three Specific Aims, which will (i) define the frequency of respiratory virus infections and their impact on the evolution of endobronchial bacterial infection and inflammation in CF infants; (ii) examine the impact of early virus infections on the development of respiratory symptoms and physiological changes in the lungs of CF infants; and (iii) evaluate the relationship between virus infections and airway disease as de- fined by structural and airway modeling techniques. If successful, these studies will provide new insights into the pathogenesis of CF lung disease, aid the design of therapeutic strategies to reduce virus-induced pulmonary morbidity, and potentially prevent the development of irreversible airway disease. (End of Abstract)