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.

抽象的 严重的呼吸道合胞病毒（RSV）感染与儿童的发展有关 哮喘。在该提议中，我们的假设将测试早期病毒感染是否导致肺发育 以及重塑改变后来对肺部功能产生负面影响的变化。我们的初步数据证明了 早期的RSV感染修饰了肺发育，导致ECM混乱并简化肺泡 空间，通过肺功能测试（PFT）导致肺功能下降。炎后RSV 5周 感染，在与肺功能降低一致的测得的PFT参数中观察到明显的缺陷。 早期生命的肺有特定修饰的免疫环境，以便发生适当的肺部发育 这种易感性可能通过劫持这些来增强呼吸道病毒感染的不利影响 导致肺部发展不当的计划。 ILC2在早期的正常肺发育中具有已知作用 生命并提供IL-13以进行适当的肺泡化。在此期间，ECM正在组织，尤其是弹性蛋白 正常肺发育所需的胶原蛋白沉积以及牙槽化。但是不合适 和/或这些程序过度激活与严重的肺功能障碍有关。 ILC2以及树突状细胞 （DC），已在有害的肺重塑中与IL-33和TSLP一起进行了暗示 RSV感染后。我们实验室的先前研究表明，“炎症” DC和ILC2是 早期RSV感染后，小鼠肺的持续增加，我们的初步数据表明 它们与肺部发育变化和生命后期的功能障碍相关。在5处免疫荧光成像 感染后几周显示弹性蛋白的沉积增加和混乱的ECM的出现 到同龄的天真动物。我们还观察到在孤立气道中IL33和TSLP的表达增加 感染后5周的上皮细胞，表明肺结构细胞的明显变化与 累积的先天免疫细胞DC和ILC2。在肿瘤后5周分离的直流RSV的转移 被感染的小鼠进入新生儿小鼠，导致肺功能降低，而IL13和弹性蛋白增加 转移后5周在肺中表达。这些后来的研究链接了从早期RSV感染中改变DC 肺部病理与发展的改变有关。我们假设早期生命的RSV感染 促进由TSLP驱动的直流修饰改变ILC2活性导致肺失调 发育，持续的致病结构改变和改善的肺功能。我们的研究将 测试并定义了训练有素的DC免疫在早期RSV感染后的作用，从而导致ILC2活性改变 在肺结构发育期间。我们将针对已知会影响DC和ILC2细胞因子的TSLP途径 产生，导致强烈的免疫病反应。这些研究将定义早期生活的呼吸道 病毒感染会导致肺发育的严重改变，并具有连接激活的机制 对长期后遗症的关键先天免疫细胞使婴儿在生命后期改变了肺功能。