Early Life Rhinovirus Infection and Childhood Asthma

生命早期鼻病毒感染和儿童哮喘

• 批准号: 9233004
• 负责人: Marc B. Hershenson
• 金额: $ 44.67万
• 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/9233004
• 关键词: Acute; Allergens; Asthma; Attenuated; Cell Maturation; 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; Salvelinus; 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; experimental study; high risk infant; in vivo; mature animal; microbiome; mouse model; novel; permissiveness; promoter; public health relevance; receptor; respiratory; response; small molecule inhibitor; Acute; Allergens; Asthma; Attenuated; Cell Maturation; 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; Salvelinus; 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; experimental study; high risk infant; in vivo; mature animal; microbiome; mouse model; novel; permissiveness; promoter; public health relevance; receptor; 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（由适用提供）：在高风险婴儿中，与鼻病毒相关疾病（RV）是哮喘发育的重要危险因素。这是早期生命中的RV感染与其他因素（例如遗传背景，暴露质量和微生物组）结合使用，可能会调节免疫激素，从而增加哮喘发育的可能性。为了测试这一点，我们开发了一种未成熟的RV1B感染的小鼠模型。与成熟的动物相反，感染RV1B的6天大小鼠会产生持续的气道高反应性，粘液元增生性和IL-13产生。这种类似哮喘的表型取决于产生IL-13型先天性淋巴样细胞（ILC2S）的群体。在该提案中，我们将检验以下一般假设，即在敏感的个体中，早期生命的RV感染通过扩大IL-13产生的ILC2S来促进儿童哮喘的发育。为了检验这一普遍的假设，提出了三个特定的目的：目标1。确定IL-25，IL-33和TSLP在RV诱导的粘膜化生和Airways在新生儿BALB/CICE中的过度反应性的作用。我们假设，在未成熟的6天大小鼠中：i）RV感染增加了IL-33和TSLP的气道细胞的产生； （ii）IL-25，IL-33和TSLP是Maxi-Mal Mucous Metaplasia和AHR所必需的； （iii）不足的IFN-γ响应允许RV诱导的TSLP产生； IV）在IL-25启动子处存在允许的表观遗传状态，允许RV诱导的转录。目标2。确定ILC2对RV诱导的气道响应的贡献。我们假设：i）在RV感染的未成熟小鼠中，IL-25，IL-33和TSLP合作起作用，以调节ILC2S的扩张和IL-13的产生； ii）需要ILC2，足以满足最大RV诱导的2型细胞因子表达，粘液化生和AHR； iii）IFN-γ减弱了ILC2的扩张和IL-13的产生。目标3。确定新生儿RV感染对随后异源再感染的反应的影响。我们假设：i）早期生命的RV1B感染改变了对随后的RV2或RSV感染的免疫响应，导致2型而不是1型反应； ii）由ILC2S驱动的2型响应； iii）RV直接刺激来自ILC2的IL-13产生。对于目标1-3，为了确定ILC2是否构成对早期呼吸道病毒感染的常见细胞反应，我们将在6天大的未成熟小鼠和8个月大的成熟小鼠中比较RV1B，RV2和RSV-A感染。此外，为了支持目标1和2，我们将在鼻和气管灌洗样品中分析IL-25，IL-33和IL-33水平以及ILC2，并从住院的婴儿中，急性呼吸道病毒感染。最后，为了开始理解为什么只有一些暴露于早期病毒感染的婴儿可能会发展哮喘，我们将进行“概念验证”实验，以检查RV感染的A/J，C57BL/6和细菌的RV感染的A/J，AIRWAINS AIRWAINS HYPER RESSPONSISION和ILC2S和ILC2。