Role of immunoproteasome in airway viral infection

免疫蛋白酶体在气道病毒感染中的作用

基本信息

批准号：
10398121
负责人：
Hong W Chu
金额：
$ 55.59万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10398121
关键词：
Abbreviations Acute Address Air Allergens Anti-Inflammatory Agents Antiviral Agents Antiviral Response Antiviral Therapy Asthma Biological Response Modifiers CRISPR/Cas technology Cells Chronic Clinical Common Cold Data Disease Dose Eotaxin Epithelial Cells Exposure to Genes Goals Healthcare Host Defense Mechanism Human IFNAR1 gene Immune Impairment Infection Inflammation Inflammatory Interferon Receptor Interferons Interleukin-13 Investigation Knock-out Knockout Mice Liquid substance Lung Lung diseases Measures Mediating Molecular Weight Mus Oxidative Stress Pathologic Patients Peptide Hydrolases Production Proteins Pulmonary Inflammation Pyroglyphidae Regulation Research Resolution Respiratory Disease Rhinovirus Rhinovirus infection Role STAT1 gene STAT1 protein Scientist Signal Transduction Slice System T-Lymphocyte Testing Tracheobronchial Viral Viral Load result Viral Respiratory Tract Infection Virus Virus Diseases Wild Type Mouse Work airway epithelium airway hyperresponsiveness airway inflammation asthma exacerbation asthmatic asthmatic patient base chronic infection cytokine effective therapy eosinophil experimental study exposed human population improved in vivo innovation knockout gene multicatalytic endopeptidase complex multidisciplinary novel novel strategies novel therapeutics receptor

项目摘要

Project Summary/Abstract The goal of this proposal is to determine the regulation and functions of immunoproteasome (IP) during rhinovirus infection in airways with type 2 inflammation, a hallmark of the type 2 (e.g., interleukin 13 [IL-13]) high asthma. Rhinovirus (RV) infection remains a significant healthcare burden due to its contribution to exacerbations of asthma and other lung diseases. Because there is no effective therapy for airway RV infection, it is imperative to define novel mechanisms (e.g., IP) that clear RV from the infected airway cells (e.g., epithelial cells). We found reduced IP expression in airway epithelial cells of severe asthma patients with airway type 2 inflammation. Importantly, our preliminary data strongly suggest that IP expression in human primary airway epithelial cells was significantly up-regulated by RV (RV-A and RV-C) infection, and that knockout or inhibition of key IP components (e.g., LMP2 and LMP7) increased airway epithelial viral load. Type 2 cytokine IL-13 significantly reduced IP induction by RV. RV-infected LMP2 knockout (vs. wild-type) mice were unable to clear the viruses effectively, and increased lung inflammation. We will test the hypothesis that airway IP induction during RV infection serves as a critical host defense mechanism to eliminate viral infection, but is impaired in airways with type 2 inflammation, leading to persistent infection and excessive inflammation. In Aim 1, we will determine the role of the interferons (IFNs)/IFN receptor (IFNR)/STAT1 axis in IP regulation by RV and type 2 inflammation by performing gene knockout experiments in human primary airway epithelial cells, and using the human precision- cut lung slices or gene (e.g., IFNAR or STAT1) deficient mice exposed to IL-13, allergen and/or RV. In Aim 2, we will determine the role of IP in RV-mediated asthma exacerbation and underlying mechanisms by using IP deficient mice (whole body or airway epithelial conditional gene knockout) and human primary airway epithelial cells with IP gene knockout. We will test if IP’s antiviral and anti-inflammatory functions depend on its regulation of RV 3C protease and A20, a negative immune regulator. In Aim 3, we will determine the efficacy of IP as an antiviral agent in airways with type 2 inflammation. By delivering a single low-dose of IFN-l or a viral mimic (i.e., polyI:C) into cultured human airway epithelium or mouse airways with type 2 inflammation, we will test if enhancing IP expression promotes resolution of airway acute RV infection and inflammation. Research findings will significantly improve our understanding about host defense mechanisms against RV infection, and likely provide a new opportunity to treat RV infections in patients with asthma and other diseases.

项目概要/摘要该提案的目标是确定免疫蛋白酶体（IP）在过程中的调节和功能。气道中鼻病毒感染伴有 2 型炎症，这是 2 型炎症的标志（例如白细胞介素 13 [IL-13]）高鼻病毒（RV）感染由于会导致病情加重，因此仍然是一个重大的医疗负担。由于气道RV感染尚无有效治疗方法，因此势在必行。我们发现，定义从受感染的气道细胞（例如上皮细胞）中清除 RV 的新机制（例如 IP）。患有气道 2 型炎症的严重哮喘患者气道上皮细胞中 IP 表达减少。重要的是，我们的初步数据强烈表明 IP 在人原代气道上皮细胞中的表达 RV（RV-A 和 RV-C）感染显着上调，并且关键 IP 的敲除或抑制成分（例如 LMP2 和 LMP7）显着增加气道上皮病毒载量 2 型细胞因子 IL-13。 RV 感染的 LMP2 敲除小鼠（与野生型小鼠相比）减少了 IP 诱导，无法清除病毒。我们将检验 RV 期间气道 IP 诱导的假设。感染作为消除病毒感染的关键宿主防御机制，但在气道中受到损害 2 型炎症，导致持续感染和过度炎症。在目标 1 中，我们将确定干扰素 (IFN)/干扰素受体 (IFNR)/STAT1 轴在 RV 和 2 型炎症 IP 调节中的作用在人原代气道上皮细胞中进行基因敲除实验，并利用人体精准- 切割暴露于 IL-13、过敏原和/或 RV 的肺切片或基因（例如 IFNAR 或 STAT1）缺陷小鼠。我们将通过使用 IP 确定 IP 在 RV 介导的哮喘恶化中的作用及其潜在机制缺陷小鼠（全身或气道上皮条件性基因敲除）和人类初级气道上皮我们将测试IP的抗病毒和抗炎功能是否依赖于其调节。在目标 3 中，我们将确定 IP 作为一种免疫调节剂的功效。通过提供单次低剂量的 IFN-1 或病毒模拟物（即， PolyI:C) 进入培养的人气道上皮或患有 2 型炎症的小鼠气道，我们将测试是否增强 IP 表达可促进气道急性 RV 感染和炎症的消退。将显着提高我们对宿主针对 RV 感染的防御机制的理解，并且可能为治疗哮喘和其他疾病患者的 RV 感染提供了新的机会。