Early Life Rhinovirus Infection and Childhood Asthma

生命早期鼻病毒感染和儿童哮喘

• 批准号: 9128143
• 负责人: Marc B. Hershenson
• 金额: $ 29.69万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128143
• 关键词: Acute; Allergens; Asthma; Attenuated; Cells; Childhood Asthma; DNA Methylation; Data; Development; Epigenetic Process; Epithelial Cells; Family history of; Flow Cytometry; Genetic; Genetic Transcription; Germ-Free; Human; Immune response; Inbred BALB C Mice; Individual; Infant; Infection; Interferon Type II; Interleukin-13; Irrigation; Knockout Mice; Lead; Life; Lung; Lymphoid Cell; Measures; Mechanical ventilation; Metaplasia; Mucous body substance; Mus; Neonatal; Nose; Orphan; Phenotype; Population; Production; Reporter; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Rhinovirus; Risk Factors; Role; Sampling; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; TSLP gene; Testing; Tretinoin; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Wheezing; Wisconsin; Work; acute bronchiolitis; airway hyperresponsiveness; base; cytokine; disorder prevention; eosinophil; high risk infant; in vivo; mature animal; microbiome; mouse model; novel; promoter; public health relevance; receptor; research study; respiratory; response; small molecule inhibitor

 DESCRIPTION (provided by applicant): In high risk infants, wheezing-associated illness with rhinovirus (RV) is a significant risk factor for asthma development. Thus, RV infection in early life, in combination with other factors such as genetic background, al- lergen exposure and microbiome, may modulate the immune response, increasing the likelihood of asthma development. To test this, we developed an immature mouse model of RV1B infection. In contrast to mature animals, 6 day-old mice infected with RV1B develop sustained airways hyperresponsiveness, mucous meta- plasia and IL-13 production. This asthma-like phenotype is dependent a population of IL-13-producing type 2 innate lymphoid cells (ILC2s). In this proposal, we will test the general hypothesis that, in susceptible individual- als, early-life RV infection contributes to childhood asthma development via the expansion of IL-13-producing ILC2s. To test this general hypothesis, three specific aims are proposed: Aim 1. Determine the roles of IL-25, IL-33 and TSLP in RV-induced mucous metaplasia and airways hyperresponsiveness in neonatal BALB/c mice. We hypothesize that, in immature 6 day-old mice: i) RV infection increases airway cell production of IL-33 and TSLP; (ii) IL-25, IL-33 and TSLP are required for maxi- mal mucous metaplasia and AHR; (iii) a deficient IFN-γ response allows RV-induced TSLP production; and iv) a permissive epigenetic state exists at the IL-25 promoter, allowing RV-induced transcription. Aim 2. Determine the contribution of ILC2s to RV-induced airway responses. We hypothesize that: i) in RV-infected immature mice, IL-25, IL-33 and TSLP function cooperatively to regulate expansion and IL-13 production by ILC2s; ii) ILC2s are required and sufficient for maximal RV-induced type 2 cytokine expression, mucous metaplasia and AHR; and iii) IFN-γ attenuates ILC2 expansion and IL-13 production. Aim 3. Determine the effects of neonatal RV infection on responses to subsequent heterologous re- infection. We hypothesize that: i) early-life RV1B infection alters the immune response to subsequent RV2 or RSV infection, leading to type 2 rather than type 1 responses; ii) synergistic type 2 responses are driven by ILC2s; and iii) RV directly stimulates IL-13 production from ILC2s ex vivo. For Aims 1-3, to determine whether ILC2s constitute a common cellular response to early-life respiratory viral infection, we will compare RV1B, RV2 and RSV-A infections in 6 day-old immature mice and 8 month-old mature mice. Also, to support Aims 1 and 2, we will analyze IL-25, IL-33 and IL-33 levels and ILC2s in nasal and tracheal lavage samples taken from infants hospitalized with acute respiratory viral infections. Finally, to begin to understand why only some infants exposed to early-life viral infection may develop asthma, we will perform "proof-of-concept" experiments examining mucous metaplasia, airways hyperresponsiveness and ILC2s in RV-infected A/J, C57BL/6 and germ-free mice.

 描述（由申请人提供）：在高危婴儿中，鼻病毒（RV）引起的喘息相关疾病是哮喘发生的一个重要危险因素。因此，生命早期的RV感染，与遗传背景、过敏原暴露和微生物组等其他因素相结合，可能会调节免疫反应，增加哮喘发生的可能性。为了测试这一点，我们开发了 RV1B 感染的未成熟小鼠模型。与成熟动物相比，感染 RV1B 的 6 日龄小鼠出现持续的气道高反应性、粘液化生和 IL-13 产生。这种哮喘样表型依赖于产生 IL-13 的 2 型先天淋巴细胞 (ILC2) 群体。在本提案中，我们将检验以下一般假设：在易感个体中，生命早期的 RV 感染通过产生 IL-13 的 ILC2 的扩增而导致儿童哮喘的发生。为了检验这一一般假设，提出了三个具体目标： 目标 1. 确定 IL-25、IL-33 和 TSLP 在 RV 诱导的新生 BALB/c 小鼠粘液化生和气道高反应性中的作用。我们假设，在未成熟的 6 日龄小鼠中： i) RV 感染增加气道细胞 IL-33 和 TSLP 的产生； (ii) 最大粘液化生和 AHR 需要 IL-25、IL-33 和 TSLP； (iii) IFN-γ反应缺陷导致 RV 诱导 TSLP 产生； iv) IL-25 启动子处存在允许的表观遗传状态，允许 RV 诱导转录。目标 2. 确定 ILC2 对 RV 诱导的气道反应的贡献。我们假设： i) 在 RV 感染的未成熟小鼠中，IL-25、IL-33 和 TSLP 协同发挥作用，调节 ILC2 的扩增和 IL-13 的产生； ii) ILC2 是 RV 诱导的 2 型细胞因子最大表达、粘膜化生和 AHR 所必需的且足够的； iii) IFN-γ 减弱 ILC2 扩增和 IL-13 产生。目标 3. 确定新生儿 RV 感染对随后异源再感染反应的影响。我们假设： i) 早期 RV1B 感染改变了对随后 RV2 或 RSV 感染的免疫反应，导致 2 型而不是 1 型反应； ii) 协同 2 型反应由 ILC2 驱动； iii) RV 直接刺激 ILC2 离体产生 IL-13。对于目标 1-3，为了确定 ILC2 是否构成对生命早期呼吸道病毒感染的常见细胞反应，我们将比较 6 日龄未成熟小鼠和 8 个月龄成熟小鼠中的 RV1B、RV2 和 RSV-A 感染。此外，为了支持目标 1 和 2，我们将分析因急性呼吸道病毒感染住院的婴儿的鼻腔和气管灌洗样本中的 IL-25、IL-33 和 IL-33 水平以及 ILC2。最后，为了开始了解为什么只有一些在生命早期接触病毒感染的婴儿可能会患上哮喘，我们将进行“概念验证”实验，检查感染 RV 的 A/J、C57BL/6 和无菌小鼠的粘液化生、气道高反应性和 ILC2。