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

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

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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.

项目摘要/摘要该提案的目的是确定在 2型注射的气道中的鼻病毒感染，这是2型的标志（例如，白介素13 [IL-13]）高哮喘。鼻病毒（RV）感染仍然是严重的医疗保健烧伤，因为它对加剧的贡献哮喘和其他肺部疾病。因为没有有效的气道RV感染疗法定义从感染气道细胞（例如上皮细胞）清除RV的新型机制（例如IP）。我们发现严重哮喘患者2型炎症的严重哮喘患者的气道上皮细胞中的IP表达降低。重要的是，我们的初步数据强烈表明IP在人类原代气道上皮细胞中的表达由RV（RV-A和RV-C）感染显着上调，并敲除或抑制关键IP 组件（例如LMP2和LMP7）增加了气道上皮病毒负荷。 2型细胞因子IL-13显着 RV减少IP诱导。 RV感染的LMP2敲除（相对于野生型）小鼠无法清除病毒有效，并增加肺部注射。我们将测试RV期间气道IP诱导的假设感染是消除病毒感染的关键宿主防御机制，但在气道中受损 2型炎症，导致持续感染和过量炎症。在AIM 1中，我们将确定干扰素（IFNS）/IFN受体（IFNR）/STAT1轴在IP调节中通过RV和2型注射的作用在人类原代气道上皮细胞中进行基因敲除实验，并使用人类精确性 - 切割肺切片或基因（例如IFNAR或Stat1）缺乏暴露于IL-13，过敏原和/或RV的小鼠。在AIM 2中，我们将通过使用IP来确定IP在RV介导的哮喘加剧和基本机制中的作用缺乏小鼠（全身或气道上皮条件基因敲除）和人类原发性气道上皮具有IP基因敲除的细胞。我们将测试IP的抗病毒和抗炎功能是否取决于其调节 RV 3C蛋白酶和A20的负免疫调节剂。在AIM 3中，我们将确定IP的效率 2型注射的气道中的抗病毒剂。通过输送单剂量的IFN-L或病毒模拟物（即 polyi：c）进入具有2型注射的培养的人类气道上皮或小鼠气道，我们将测试是否增强IP表达可促进气道急性RV感染和注射的分辨率。研究结果将大大提高我们对针对RV感染的宿主防御机制的理解，并可能提供新的机会来治疗哮喘和其他疾病患者的RV感染。