Early Life Rhinovirus Infection and Childhood Asthma

生命早期鼻病毒感染和儿童哮喘

基本信息

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
项目类别：
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

项目摘要

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，与鼻病毒（RV）相关的喘息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，与遗传背景等其他因素相结合，都可能导致哮喘的发生。过敏原暴露和微生物组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，6 日龄的小鼠感染了 RV1B。 RV1B 产生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 小鼠粘膜化生和气道高反应性中的作用我们在未成熟的 6 日龄小鼠中发现：i) RV 增加气道感染。 (ii) IL-25、IL-33 和 TSLP 是最大粘液化生所必需的AHR；(iii) IFN-γ 反应缺陷允许 RV 诱导 TSLP 产生；和 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。我们勇敢地承认：i) 在 RV 感染的未成熟小鼠中，IL-25、IL-33 和 TSLP 协同作用，通过调节扩张和 IL-13 的产生。 ILC2；ii) ILC2 是 RV 诱导的最大 2 型细胞因子表达、粘膜化生和 AHR 所必需的；iii) IFN-γ 减弱 ILC2 扩增和 IL-13 产生。目标 3. 确定新生儿感染 RV 对的影响。对随后异源再感染的反应我们发现：i) 早期 RV1B 感染改变了对随后 RV2 或 RSV 感染的免疫反应，导致 RV1B 型感染。 2 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 体外产生 IL-13，以确定 ILC2 是否构成早期的常见细胞反应。 -终生呼吸道病毒感染，我们将比较 6 日龄未成熟小鼠和 8 个月龄成熟小鼠的 RV1B、RV2 和 RSV-A 感染。目标 1 和 2，我们将分析从因急性呼吸道病毒感染住院的婴儿身上采集的鼻腔和气管灌洗样本中的 IL-25、IL-33 和 IL-33 水平以及 ILC2，以了解为什么只有部分婴儿会接触到病毒。生命早期的病毒感染可能会发展为哮喘，我们将进行“概念验证”实验，检查 RV 感染者的粘液化生、气道高反应性和 ILC2 A/J、C57BL/6 和无菌小鼠。