IRAK-M in lung defense against rhinovirus infection

描述(由申请人提供)：这项建议的目标是确定先天免疫调节剂IL-1受体相关激酶M(IRAK-M)在人鼻病毒(HRV)感染肺部过程中的功能。HRV是人类最常见的病毒感染物，也是普通感冒的主要原因。值得注意的是，心率变异性也是哮喘等几种主要呼吸道疾病恶化的最常见原因。HRV主要感染呼吸道上皮细胞，但也影响肺巨噬细胞。IRAK-M对维持组织动态平衡至关重要，但在疾病条件下过度表达IRAK-M可能会使患者容易感染和疾病恶化。我们发现哮喘患者的呼吸道上皮细胞和肺泡巨噬细胞中IRAK-M表达增加。此外，我们发现Th2细胞因子IL-13(过敏性炎症的标志)增加了IRAK-M。然而，IRAK-M在肺防御HRV中的作用还没有被探索。我们发现，基线IRAK-M在防止HRV感染时过度产生促炎细胞因子方面起着关键作用，但不会损害抗病毒反应。相反，IRAK-M在Th2细胞因子环境下上调，部分通过自噬增强病毒复制。我们假设，IRAK-M在过敏性肺(如呼吸道上皮细胞和肺泡巨噬细胞)中上调会损害抗病毒反应，使宿主容易受到HRV感染，并加剧呼吸道过敏性炎症。提出了三个目标。目的1确定IRAK-M在正常肺防御HRV感染中的功能。通过使用原代呼吸道上皮细胞、巨噬细胞、小鼠骨髓嵌合体模型和条件性IRAK-M基因敲除小鼠，我们将测试在正常肺中，IRAK-M是否可以防止HRV感染期间的过度炎症，但不会损害抗病毒机制。目标2将定义在Th2细胞因子环境中IRAK-M上调如何促进呼吸道HRV感染。我们认为IL-13上调IRAK-M可以抑制I型和III型干扰素的产生，从而促进自噬和病毒复制。我们将在呼吸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感染如何加重呼吸道过敏性炎症。我们将检验这一假设，即过敏肺中IRAK-M/自噬轴上调有助于HRV介导的呼吸道过敏性炎症的加重。我们将通过靶向IRAK-M和自噬来确定IRAK-M/自噬轴在HRV介导的小鼠呼吸道过敏性炎症的夸大中的关键作用。然后，我们剖析了在HRV感染过程中，IRAK-M/自噬轴夸大呼吸道变态反应性炎症的分子机制，从而相互上调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加重的新策略，这种疾病折磨着1800万美国人，每年耗资280亿美元。

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.