Host microbiota and airway mucus: a novel paradigm for lung defense and immune homeostasis during early post-natal development

宿主微生物群和气道粘液：产后早期发育期间肺防御和免疫稳态的新范例

• 批准号: 10305691
• 负责人: Alessandra Maria Livraghi-Butrico
• 金额: $ 38.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305691
• 关键词: 5 year old; Adult; Affect; Age; Animals; Antibiotic Therapy; Antibiotics; Asthma; Bacterial Infections; Bacterial Pneumonia; Biology; Bronchoalveolar Lavage; Cell Differentiation process; Cells; Child; Congenic Mice; Cystic Fibrosis; Data; Defense Mechanisms; Dehydration; Development; Disease; Elements; Epithelial Cells; Exhibits; Gene Expression; Germ-Free; Harvest; Homeostasis; Human; Immune; Infant; Inflammatory; Inhalation; Knockout Mice; Knowledge; Life; Link; Lung; Lung immune response; MUC5AC gene; Mediating; Messenger RNA; Modeling; Mucins; Mucociliary Clearance; Mucous body substance; Mus; Neonatal; Operative Surgical Procedures; Outcome; Pathogenesis; Pattern; Perinatal; Phenotype; Predisposition; Proteins; Publications; Pulmonary Cystic Fibrosis; Recording of previous events; Respiratory Disease; Respiratory Signs and Symptoms; Respiratory System; Sampling; Secretory Cell; Shapes; Signal Transduction; Surface; Syndrome; System; Testing; Therapeutic; Tube; Wild Type Mouse; age related; biobank; congenic; cystic fibrosis mouse; dysbiosis; early onset; endotracheal; germ free condition; gut dysbiosis; gut microbiota; gut-lung axis; histological specimens; host microbiome; host microbiota; interleukin-22; lung health; lung microbiota; mRNA Expression; mRNA sequencing; mucus clearance; mucus-associated lung diseases; neonatal mice; neonatal period; neonate; novel; pediatric patients; postnatal development; postnatal period; protein expression; rRNA Genes; transcriptome

Airway mucus clearance is a primary lung defense mechanism and the early neonatal period represents a critical “window of susceptibility” for lung health. Perinatal changes in key components of the mucus clearance system have been qualitatively described, but the details and functional significance of these changes are unknown. Our preliminary data in mice and humans indicate that: 1) airway mucus composition is developmentally regulated; and 2) components of the mucus clearance system are affected by the status of the host microbiota in early life. We have identified a testable mechanism to link the host microbiota with neonatal airway mucus biology and lung homeostasis, i.e., the IL-22+ILC3-mediated gut-lung axis. We also posit that humans exhibit age-dependent changes in key elements contributing to airway mucus clearance, e.g., MUC5AC levels. To test these hypotheses, we propose the following aims: 1) To test whether host microbiota dysbiosis or blockade of the IL-22+ILC3-mediated gut-lung axis affect the abundance, composition, and function of airway mucus in neonatal vs. adult mice. Congenic mice raised in germ-free or specific-pathogen free conditions, either naïve or treated with antibiotics, will be assessed at post natal day (PND)10 and PND66 for: 1) bronchoalveolar lavage (BAL) protein composition, mucus concentration, and secreted mucins quantification; 2) airway mucociliary clearance; and 3) lung mRNA sequencing. Specific contributions of IL-22 signaling and outcomes in the context of airway surface dehydration will be assessed using IL-22 KO mice and Scnn1b-Tg mice, respectively. Changes in host microbiota will be determined by bacterial 16S ribosomal RNA gene quantification. 2) To test whether CF-like host microbiota dysbiosis affects the establishment of the normal, IL-22+ILC3-mediated gut-lung axis in neonatal mice. Congenic ∆F508 CF mice and WT littermates, either naïve or treated with antibiotics, will be used at PND10 to study the influx of IL22+ILC3 cells into the lung referenced to quantitative analysis of their gut microbiota. In parallel, lung and BAL samples will be collected to assess the effect of CF gut dysbiosis on the early lung transcriptome and the composition of neonatal airway secretions. Crosses with Scnn1b-Tg mice will be used to exacerbate the ∆F508 CF lung phenotype. 3) To test whether the composition of “healthy” airway mucus presents age- dependent, quantitative differences in humans. Airway mucus samples harvested from endotracheal tubes used in neonates/infants/children (0-5 years old) and adults (25-40 years old) with no history or symptoms of respiratory diseases will be analyzed for mucin and protein composition. Histologic specimens obtained from the LungMAP Biorepository (BRINDL) will be probed for mRNA and protein expression of specific mucus markers. Completion of these aims will establish a new conceptual framework and provide much needed experimental evidence to study the pathogenesis, develop therapeutic approaches, and account for host microbiota influences on “early” lung health and early onset muco-obstructive lung diseases.

气道粘液清除是新生儿早期肺部防御的主要机制