IRAK-M in lung defense against rhinovirus infection

IRAK-M 在肺部防御鼻病毒感染中的作用

• 批准号: 8630524
• 负责人: Hong W Chu
• 金额: $ 41.9万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630524
• 关键词: Acute; Affect; Age; Allergic; Allergic inflammation; Alveolar Macrophages; American; Antiviral Response; Asthma; Autophagocytosis; Bone Marrow; Cessation of life; Chimera organism; Common Cold; Disease; Eotaxin; Epithelial; Epithelial Cells; Figs - dietary; Goals; Healthcare; Homeostasis; Host Defense; Human; IL8 gene; IRAK1 gene; IRAK3 gene; Infection; Inflammation; Inflammatory; Interferons; Interleukin-1; Interleukin-13; JUN gene; Knockout Mice; Lung; Lung diseases; Mediating; Modeling; Molecular; Mus; Natural Immunity; Pathway interactions; Patients; Phosphotransferases; Population; Prevention; Production; Relative (related person); Research; Respiratory Tract Infections; Rhinovirus; Role; TNF gene; Testing; Tissues; United States; Up-Regulation; Viral; Wild Type Mouse; Work; airway epithelium; airway inflammation; airway obstruction; allergic airway inflammation; asthmatic airway; cost; cytokine; high risk; macrophage; novel strategies; prevent; public health relevance; receptor

DESCRIPTION (provided by applicant): The goal of this proposal is to determine the function of an innate immunity regulator IL-1 receptor-associated kinase M (IRAK-M) during human rhinovirus (HRV) infection in the lung. HRVs are the most common viral infective agents in humans and the predominant cause of the common cold. Notably, HRVs are also the most common cause of exacerbations of several major respiratory diseases such as asthma. HRV primarily infects airway epithelium, but also affects lung macrophages. IRAK-M is critical to maintain tissue homeostasis, but excessive IRAK-M expression under diseased conditions likely predisposes patients to infections and disease exacerbations. We found increased IRAK-M in asthmatic airway epithelium and alveolar macrophages. Moreover, we discovered that Th2 cytokine IL-13 (a hallmark of allergic inflammation) increases IRAK-M. However, the role of IRAK-M in lung defense against HRV has not been explored. We found that baseline IRAK-M is pivotal in preventing excessive pro-inflammatory cytokine production upon HRV infection, but does not impair anti-viral responses. In contrast, IRAK-M up-regulation under a Th2 cytokine milieu enhances viral replication in part through autophagy. We hypothesize that IRAK-M up-regulation in allergic lungs (e.g., airway epithelial cells and alveolar macrophages) impairs anti-viral responses, predisposing the host to HRV infection and exacerbation of airway allergic inflammation. Three aims are proposed. Aim 1 will determine IRAK-M functions in normal lung defense against HRV infection. By using primary airway epithelial cells, macrophages, mouse bone marrow chimera models and conditional IRAK-M knockout mice, we will test if in normal lungs, IRAK-M prevents excessive inflammation during HRV infection, but does not impair the anti-viral mechanism. Aim 2 will define how IRAK-M up-regulation in a Th2 cytokine milieu promotes airway HRV infection. We propose that IRAK-M up-regulation by IL-13 inhibits type I and III interferon production, thus promoting autophagy and viral replication. We will perform mechanistic studies in airway epithelial cells and macrophages to determine if IRAK-M-mediated interferon inhibition promotes HRV replication via autophagy. Aim 3 will determine how HRV infection exaggerates airway allergic inflammation. We will test the hypothesis that IRAK-M/autophagy axis up-regulation in allergic lungs contributes to HRV-mediated exacerbation of airway allergic inflammation. We will define a critical role of IRAK-M/autophagy axis in HRV- mediated exaggeration of airway allergic inflammation in mice by targeting IRAK-M and autophagy. We then dissect the molecular mechanisms whereby IRAK-M/autophagy axis exaggerates airway allergic inflammation during HRV infection, which reciprocally up-regulates IRAK-M/autophagy axis. Defining the role of IRAK-M in HRV infection is likely to identify novel strategies for the prevention and treatment of acute asthma exacerbations, which afflict >18 million Americans, and cost >$28 billion/year.

描述（由申请人提供）：本提案的目的是确定先天免疫调节剂IL-1受体相关激酶M（IRAK-M）在肺中人鼻病毒（HRV）感染期间的功能。HRV是人类最常见的病毒感染因子，也是普通感冒的主要原因。值得注意的是，HRV也是几种主要呼吸道疾病（如哮喘）恶化的最常见原因。HRV主要感染气道上皮，但也影响肺巨噬细胞。IRAK-M对维持组织稳态至关重要，但在疾病条件下过度表达IRAK-M可能使患者易于感染和疾病恶化。我们发现哮喘气道上皮和肺泡巨噬细胞中IRAK-M增加。此外，我们发现Th 2细胞因子IL-13（过敏性炎症的标志）增加IRAK-M。然而，IRAK-M在肺防御HRV中的作用尚未被探索。我们发现，基线IRAK-M在防止HRV感染后过度的促炎细胞因子产生方面是关键的，但不损害抗病毒反应。相反，IRAK-M在Th 2细胞因子环境下的上调部分地通过自噬增强病毒复制。我们假设IRAK-M在过敏性肺中的上调（例如，气道上皮细胞和肺泡巨噬细胞）损害抗病毒应答，使宿主易受HRV感染和气道过敏性炎症的恶化。提出了三个目标。目的1将确定IRAK-M在正常肺防御HRV感染中的功能。通过使用原代气道上皮细胞、巨噬细胞、小鼠骨髓嵌合体模型和条件性IRAK-M敲除小鼠，我们将测试在正常肺中，IRAK-M是否在HRV感染期间防止过度炎症，但不损害抗病毒机制。目的2将定义IRAK-M在Th 2细胞因子环境中的上调如何促进气道HRV感染。我们认为IL-13上调IRAK-M抑制了I型和III型干扰素的产生，从而促进了自噬和病毒复制。我们将在气道上皮细胞和巨噬细胞中进行机制研究，以确定IRAK-M介导的干扰素抑制是否通过自噬促进HRV复制。目的3将确定HRV感染如何加重气道过敏性炎症。我们将检验过敏性肺中IRAK-M/自噬轴上调有助于HRV介导的气道过敏性炎症恶化的假设。我们将通过靶向IRAK-M和自噬来定义IRAK-M/自噬轴在小鼠中HRV介导的气道过敏性炎症加重中的关键作用。然后，我们剖析了IRAK-M/自噬轴在HRV感染期间夸大气道过敏性炎症的分子机制，其上调IRAK-M/自噬轴。 确定IRAK-M在HRV感染中的作用可能会确定预防和治疗急性哮喘急性发作的新策略，这些急性哮喘急性发作折磨着超过1800万美国人，每年花费超过280亿美元。