Lung Structural and Functional Alterations Following Early-life RSV Infection

早期 RSV 感染后肺结构和功能的改变

• 批准号: 10229146
• 负责人: Carrie-Anne Malinczak
• 金额: $ 3.3万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229146
• 关键词: Adoptive Transfer; Affect; Age; Alveolar; Animals; Appearance; Area; Asthma; Automobile Driving; Bioinformatics; Biology; Cells; Cellular Structures; Childhood Asthma; Collagen; Data; Defect; Dendritic Cells; Deposition; Development; Distal; Elastin; Environment; Epithelial Cells; Extracellular Matrix; Functional disorder; Image; Immune; Immunity; Infant; Infection; Inflammatory; Inflammatory Response; Interleukin-13; Knowledge; Lead; Life; Link; Lung; Measurement; Measures; Modeling; Modification; Mus; Myeloid Cells; Neonatal; Pathogenicity; Pathway interactions; Population; Predisposition; Production; Pulmonary Pathology; Pulmonary function tests; Research; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Role; Severities; Structure; Symptoms; TSLP gene; Techniques; Testing; Time; Training; Transcriptional Activation; Viral Respiratory Tract Infection; Virus Diseases; airway epithelium; airway remodeling; career development; cytokine; lung development; mouse model; neonatal mice; novel; programs; pulmonary function; response; transcriptome sequencing

Abstract Severe respiratory syncytial virus (RSV) infection has been associated with the development of childhood asthma. In this proposal, our hypothesis will test whether early-life viral infections lead to lung developmental and remodeling alterations that negatively impact lung function later in life. Our preliminary data demonstrate that early-life RSV infection modifies lung development leading to disorganized ECM and simplified alveolar spaces, that lead to decreased lung function by pulmonary function tests (PFT). At 5 weeks post-neonatal RSV infection, significant defects are observed in measured PFT parameters consistent with decreased lung function. The early-life lung has a specifically modified immune environment in order for proper lung development to occur and this predisposition may enhance the detrimental effects of respiratory viral infection by hijacking these programs leading to improper lung development. ILC2 have a known role for normal lung development early in life and provide IL-13 for proper alveolarization. During this period, the ECM is being organized, especially elastin and collagen deposition, as well as alveolarization needed for normal lung development. However inappropriate and/or overactivation of these programs have been linked to severe lung dysfunction. ILC2 as well dendritic cells (DC), have been implicated in detrimental lung remodeling along with IL-33 and TSLP which are upregulated following RSV infection. Previous studies from our lab have shown that “inflammatory” DC and ILC2 are persistently increased in the lungs of mice following early-life RSV infection and our preliminary data show that they correlate to the altered lung development and dysfunction later in life. Immunofluorescent imaging at 5 weeks post-infection showed increased elastin deposition and the appearance of disorganized ECM compared to naïve animals of the same age. We also observed increased expression of Il33 and Tslp in isolated airway epithelial cells from 5 week post-infection mice, demonstrating clear changes in lung structural cells that link to the accumulated innate immune cells, DC and ILC2. The transfer of DC isolated from 5 week post-neonatal RSV infected mice into neonatal naïve mice led to decreased lung function along with increased Il13 and elastin expression in the lungs at 5 weeks post-transfer. These latter studies link altered DC from early-life RSV infection to lung pathology associated with altered development. We hypothesize that early-life RSV infection promotes TSLP-driven DC modifications that alter ILC2 activity leading to dysregulated lung development, persistant pathogenic structural alterations and decreased lung function. Our studies will test and define the role of trained DC immunity after early-life RSV infection that leads to altered ILC2 activity during lung structural development. We will target the TSLP pathway that is known to affect DC and ILC2 cytokine production, leading to strong immunopathogenic responses. These studies will define how early-life respiratory viral infection leads to causative alterations in lung development with defined mechanisms linking activation of critical innate immune cells to long term sequelae predisposing infants to altered lung function later in life.

摘要