Viral Pathogenesis of Early Cystic Fibrosis Lung Disease

描述(申请人提供)：CF肺部疾病的发展和演变可能是可变的，但从我们之前的研究中可以清楚地看到，生理和结构缺陷始于婴儿期，经常出现在细菌感染检测之前，涉及其他病因或感染性侮辱。病毒对肺细菌定植、呼吸道炎症、生理指标和肺组织结构变化的影响知之甚少。在这项提案中，我们将定义病毒感染在早期CF肺部疾病发生中的作用(S)。结合印第安纳大学(印第安纳州印第安纳波利斯)、华盛顿大学(密苏里州圣路易斯)和澳大利亚囊性纤维化早期监测小组(澳大利亚墨尔本和珀斯)提供的专业知识和资源，我们将确定囊性纤维化婴儿的病毒感染发生率和类型。在婴儿期，将在预定的时间收集支气管肺泡灌洗液和咽分泌物，并将使用高灵敏度的核酸检测和强大的微生物组分析来确定下呼吸道感染的特征。此外，在新生儿筛查后不久诊断的婴儿监测项目中，我们将结合灌洗液中炎症标志物的分析、肺功能测量和计算机化的X射线断层成像，系统地定义CF肺最早的生理变化。创新的呼吸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呼吸道疾病。我们将研究病毒感染与CF肺最初的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CF婴儿呼吸道细菌菌群和炎症特征并加速肺部疾病进展的假说。该提案有三个具体目标，这将(I)确定呼吸道病毒感染的频率及其对CF婴儿呼吸道细菌感染和炎症演变的影响；(Ii)检查早期病毒感染对CF婴儿呼吸道症状和肺部生理变化的影响；以及(Iii)评估通过结构和呼吸道建模技术定义的病毒感染和呼吸道疾病之间的关系。如果成功，这些研究将为CF肺部疾病的发病机制提供新的见解，有助于设计治疗策略以减少病毒诱导的肺部发病率，并有可能防止不可逆转的呼吸道疾病的发展。(摘要结束)

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)