Early Life Rhinovirus Infection and Childhood Asthma

生命早期鼻病毒感染和儿童哮喘

• 批准号: 10200651
• 负责人: Marc B. Hershenson
• 金额: $ 45.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10200651
• 关键词: 13 year old; Allergens; Allergic; Asthma; Attenuated; Biological Assay; Birth; Brush Cell; CASP1 gene; Canis familiaris; Cell physiology; Cells; Chemicals; Child; Childhood Asthma; Cohort Studies; Curettage procedure; Data; Development; Epithelial Cells; Equilibrium; Flow Cytometry; Genome; Hela Cells; House Dust; Human; Immune; Immunoblotting; Immunofluorescence Immunologic; Inbred BALB C Mice; Infant; Infection; Inflammasome; Inflammation; Interferon Type II; Interleukin-1 beta; Interleukin-13; Knockout Mice; Leukotriene E4; Life; Lower respiratory tract structure; Lung; Lymphoid Cell; Measures; Metaplasia; Mucous body substance; Mus; Netherlands; Neutralization Tests; Nose; Pathogenesis; Phenotype; Prevention; Production; Regulation; Respiratory Tract Infections; Respiratory syncytial virus; Rhinovirus; Rhinovirus infection; Risk; Risk Factors; Role; Shorthand; Signal Transduction; TSLP gene; Testing; Tissues; Viral; Viral Respiratory Tract Infection; Virus Diseases; Western Australia; Wheezing; Wisconsin; Work; Zileuton; airway epithelium; airway hyperresponsiveness; airway inflammation; asthma prevention; cohort; cytokine; eosinophilic inflammation; inhibitor/antagonist; insight; macrophage; mouse model; neutralizing antibody; new therapeutic target; response

Project Summary Birth cohort studies have found significant associations between early-life wheezing-associated respiratory tract infections and the development of asthma in children up to 13 years of age. These studies suggest that early life respiratory tract infections have a direct effect on lung and/or immune cell development and the risk of asthma. To determine possible mechanisms, we established a mouse model of early-life RV infection. Infection of 6 day-old mice, but not mature mice, induces long-lasting mucous metaplasia, eosinophilic inflammation and airways hyperresponsiveness (AHR) which is associated with type 2 innate lymphoid cell (ILC2) expansion and dependent on IL-13, IL-25 and IL-33. For this renewal application, we have developed preliminary data showing that early-life RV infection increases the number of airway IL-25+ DCLK1+ brush cells, providing a mechanism for a persistent ILC2-dependent asthma-like phenotype. In addition, we have found that, in immature mice, activation of the NLRP3 inflammasome and IL-1β maturation inhibits type 2 cytokine expression and mucous metaplasia. In this proposal, we will test the general hypothesis that, following early- life RV infection, development of ILC2-dependent type 2 airway inflammation and mucous metaplasia represents a balance between tuft cell RV-induced IL-25 signaling (promotes the phenotype) and NLRP3- dependent IL-1β signaling (suppresses the phenotype). To test this, we propose the following Aims: Specific Aim 1. Determine the contribution of airway brush (tuft) cells to viral-induced IL-25 production. We hypothesize that: 1) early-life RV infection stimulates a persistent increase in the number of IL-25-producing airway tuft cells; 2) tuft cells are required for RV-induced ILC2 expansion, mucous metaplasia and AHR; 3) RV-induced IL-25 and IL-13 production (by ILC2s and M2 polarized macrophages) constitute a feed-forward mechanism for tuft cell development. Specific Aim 2. Determine the role of IL-1β on the development of RV-induced mucous metaplasia and AHR. We hypothesize that: 1) in immature mice, RV-induced, NLRP3 inflammasome-dependent IL-1β production suppresses the asthma-like phenotype; 2) IL-1β inhibits epithelial cell innate cytokine expression; and 3) LPS and dog-associated house dust each attenuate development of the mucous metaplasia phenotype by stimulating inflammasome priming and activation. Specific Aim 3. Determine the effects of early-life RV-C infection. We hypothesize that: 1) compared to RV-A, RV-C infection of 6 day-old mice induces more type 2 inflammation, mucous metaplasia and AHR; 2) RV-C induces greater expansion of tuft cells; 3) RV-C elicits inflammasome priming but not activation, thereby permitting greater and more long-lasting type 2 cytokine expression and mucous metaplasia. Immature mice and infants with respiratory viral infections will be studied. Completion of the proposed work will provide new insight into the pathogenesis of asthma development, and identify new targets for prevention.

项目概要 出生队列研究发现，生命早期喘息相关的呼吸系统疾病之间存在显着关联。 这些研究表明，13 岁以下儿童的呼吸道感染和哮喘的发展。 生命早期呼吸道感染对肺和/或免疫细胞的发育有直接影响，并增加以下风险： 为了确定可能的机制，我们建立了早期 RV 感染的小鼠模型。 6 日龄小鼠（但不是成熟小鼠）会诱导持久的粘液化生、嗜酸性炎症和 气道高反应性 (AHR) 与 2 型先天淋巴细胞 (ILC2) 扩张和 依赖于 IL-13、IL-25 和 IL-33 对于此更新申请，我们已经开发了初步数据。 研究表明，生命早期 RV 感染会增加气道 IL-25+ DCLK1+ 刷状细胞的数量，从而提供 持续的ILC2依赖性哮喘样表型的机制此外，我们还发现，在 未成熟小鼠中，NLRP3 炎性体的激活和 IL-1β 的成熟抑制 2 型细胞因子 在本提案中，我们将测试以下一般假设： RV 感染、ILC2 依赖性 2 型气道炎症和粘膜化生的发展 代表簇细胞 RV 诱导的 IL-25 信号传导（促进表型）和 NLRP3- 之间的平衡 依赖性 IL-1β 信号传导（抑制表型） 为了测试这一点，我们提出以下目标： 具体目标 1. 确定气道刷（簇）细胞对病毒诱导的 IL-25 的贡献 我们认为：1）生命早期感染 RV 会刺激数量持续增加。 产生 IL-25 的气道簇细胞；2) 簇细胞是 RV 诱导的 ILC2 扩增、粘膜化生所必需的 和 AHR；3) RV 诱导的 IL-25 和 IL-13 产生（由 ILC2 和 M2 极化巨噬细胞）构成 簇细胞发育的前馈机制。 具体目标 2. 确定 IL-1β 在 RV 诱导的粘液化生发展中的作用 我们认为：1）在未成熟小鼠中，RV 诱导的 NLRP3 炎性体依赖性 IL-1β 2）IL-1β抑制上皮细胞固有细胞因子的表达； 3) LPS 和狗相关的室内灰尘都会减弱粘液化生表型的发展 通过刺激炎症小体启动和激活。 具体目标 3. 确定生命早期 RV-C 感染的影响 我们着迷于：1) 比较。 RV-A、RV-C 感染 6 日龄小鼠可诱发更多 2 型炎症、粘膜化生和 AHR 2) RV-C 诱导簇细胞更大的扩张；3) RV-C 从而引发炎症小体启动但不激活 允许更多、更持久的 2 型细胞因子表达和粘膜化生。 将研究患有呼吸道病毒感染的未成熟小鼠和婴儿，完成拟议的工作。 将为哮喘发展的发病机制提供新的见解，并确定新的预防目标。