The Microbiota of the Pediatric CF Airway: What role does it play?

项目摘要/摘要 进行性阻塞性肺病仍然是囊性肺炎发病率和早期死亡的最大原因。 纤维化(CF)。早期发现和治疗肺功能下降是获得最佳长期结果的关键； 然而，肺功能和放射学结果的生理学测量未能捕捉到炎症和 从婴儿期开始的感染，通常是无症状的。粘液淤积与细菌杀灭功能受损 为慢性呼吸道细菌感染提供最佳环境。独立于文化 使用下一代测序技术的方法揭示了一种更复杂的、多菌的 与之前使用传统文化确定的相比，在CF呼吸道中发现了更多的社区。有趣的是，大量的 这些群落是厌氧菌，已知存在于口腔中，被认为是非致病的。 最近发现，CF痰中的厌氧菌通过发酵产生营养环境 新陈代谢和粘蛋白降解，促进细菌病原体的生长和持续，如 铜绿假单胞菌，一种已知的导致CF肺功能下降的因素。令人惊讶的是，拉古纳博士 发现与传统的CF病原体相比，厌氧菌的相对丰度已经更高 然而，我们还不清楚它们在CFs的发病机制中的作用。 早期肺部疾病的发展。关键问题仍然是早期厌氧菌的存在 慢性阻塞性肺疾病婴儿下呼吸道中的细菌使他们的肺功能更快地下降， 经常出现肺部恶化或结构性肺损伤。因此，这一点的中心假设 认为婴幼儿下呼吸道厌氧菌与CF的发病有关 具有发酵代谢，并将具有独特的代谢和偏蛋白质组生物特征， 煽动炎症，促进早期慢性肺病的发展。这项研究花费了 利用团队的专业知识并与该领域的专家建立合作关系，以及独特的 宝贵的资源：收集患有/不患有哮喘的儿童的支气管肺泡灌洗液(BALF)样本 Cf可立即进行分析。该项目的目标有三个：第一，通过测量 发酵和粘蛋白产物，以确定BALF中的厌氧菌群是否与发酵剂有关 CF呼吸道内的环境。第二，确定下呼吸道微生物区系是否与 有/无CF儿童BALF中代谢谱的测定。第三，通过创新 代谢蛋白质组学技术，以鉴定代谢蛋白质组以确定其代谢活性 CF呼吸道中的微生物群落。这个项目完成后所获得的知识将使 医疗保健提供者考虑厌氧特定抗生素或鼓励开发新的 以细菌发酵过程为靶点的抗菌药作为治疗CF肺部疾病的新方法。

Project Summary/Abstract Progressive, obstructive lung disease remains the biggest cause of morbidity and early mortality in cystic fibrosis (CF). Early detection and treatment of pulmonary decline is key to optimal long-term outcome; however, physiologic measures of lung function and radiologic outcomes fail to capture the inflammation and infection that begin in infancy, which are often asymptomatic. Mucus stasis and impaired bacterial killing provide the optimal environment for chronic bacterial infection in the CF airway. Culture-independent approaches using next-generation sequencing techniques have revealed a more complex, polymicrobial community in the CF airway than previously identified using traditional culture. Interestingly, a large number of these communities are anaerobes, known to inhabit the oral cavity and thought to be non-pathogenic. Recently, anaerobes in CF sputum were found to generate a nutritional environment through fermentative metabolism and mucin degradation that facilitates the growth and persistence of bacterial pathogens like Pseudomonas aeruginosa, a known contributor to lung function decline in CF. Surprisingly, Dr. Laguna has found that anaerobes are already present in higher relative abundance compared to traditional CF pathogens in the lower airways of infants with CF; however, we do not yet understand their contribution in the development of early lung disease. The key question remains whether the early presence of anaerobic bacteria in the lower airways of CF infants predisposes them to a more rapid decline in lung function, more frequent pulmonary exacerbations or structural lung damage. Therefore, the central hypothesis of this proposal is that anaerobic bacteria in the lower airways of infants and children with CF is associated with fermentative metabolism and will have a unique metabolic and metaproteomic biosignature that incites inflammation and contributes to the development of early CF lung disease. This research takes advantage of the team's expertise and established collaborations with experts in the field as well as a unique and valuable resource: a collection of bronchoalveolar lavage fluid (BALF) samples from children with/without CF available for immediate analysis. The aims of this project are three-fold: First, through the measurement of fermentation and mucin products, to determine if anaerobic communities in BALF associate with a fermentative environment in the CF airway. Second, to determine if the lower airway microbiota is associated with the metabolomic profile measured in BALF from young children with/without CF. Third, through innovative metaproteomics technology, to characterize the metaproteome to determine the metabolic activity of the microbial communities in the CF airway. The knowledge gained upon completion of this project would allow healthcare providers to consider anaerobic specific antibiotics or encourage the development of new antimicrobials targeting bacterial fermentative processes as a new treatment for CF lung disease.