Reversing Cigarette Smoke-Induced Antiviral Immunosuppression

逆转香烟烟雾引起的抗病毒免疫抑制

• 批准号: 10471578
• 负责人: JORDAN PATRICK METCALF
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471578
• 关键词: Address; Adverse effects; Agonist; Animal Model; Animals; Antiviral Response; Antiviral Therapy; Basic Science; Bioinformatics; Biological Models; Cell model; Chemicals; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Research; Cytochrome P450; Data; Defect; Epithelial; Epithelial Cells; Family; Genes; Genetic; Goals; Health; Human; Immune; Immune response; Immune system; Immunology; Immunosuppression; Impairment; In Vitro; Infection; Infection Control; Influenza A virus; Injury; Innate Immune Response; Innate Immune System; Innovative Therapy; Interferon Activation; Interferon-alpha; Interferons; Intervention; Ligands; Literature; Lung; Mediating; Methods; Modeling; Mus; Pathway interactions; Play; Population; Positioning Attribute; Predisposition; Production; Proteins; Public Health; Respiratory Tract Infections; Risk; Risk Factors; Role; Severities; Signal Transduction; Smoker; Smoking; Stress; Testing; Therapeutic; Time; Tretinoin; Veterans; Viral; Viral Respiratory Tract Infection; Virus Diseases; Work; base; bronchial epithelium; cigarette smoke; cigarette smoke-induced; cigarette smoke-induced lung disease; cigarette smoking; combustible cigarette; cytokine; design; experience; experimental study; exposure to cigarette smoke; genetic manipulation; human model; improved; improved outcome; in vivo; influenza infection; innovation; lung injury; member; mortality; mouse model; new therapeutic target; non-smoker; novel; overexpression; prevent; prophylactic; pulmonary function; receptor; response; restoration

The long-term goal of our work is to understand how the human innate immune system responds to Influenza A virus (IAV) infection and to find novel methods to control the infection. Cigarette smoking is a significant public health problem, particularly among veterans. Exposure to cigarette smoke (CS) significantly increases the risk for respiratory viral infections. Influenza infection is seven times more common and is much more severe in smokers than nonsmokers. The goal of our proposed studies is to determine the severity and mechanisms of CS-mediated innate immune suppression. Induction of interferon (IFN) is a critical component of the host response to influenza infection. IFNs are further divided into type I (mainly IFN-α and β), II (IFN-γ) and III (IFN-λ) subtypes, based in part on the differential use of unique receptors through which they mediate signal transduction to induce antiviral activity. Retinoic acid-inducible protein I (RIG-I) plays an important role in the recognition of, and IFN induction by, IAV. Our previous studies have shown that CS and cigarette smoke extract (CSE) suppress antiviral innate immune responses in IAV-infected human and mouse lung, especially immunosuppression due to RIG-I inhibition. This immunosuppressive effect of CS may play a critical role in the enhanced susceptibility of smokers to serious influenza infection. We have also shown that reversing the RIG-I defect prevents CS induced immunosuppression, restores all three types of IFN responses, and reduces mortality. We have also discovered a new mechanism whereby IAV and CS decreases barrier function and increases lung injury during infection through induction of cytochrome P450 family 1 subfamily B member 1 (CYP1B1). We have new preliminary data that demonstrates this effect, and that RIG-I activation appears to suppress CYP1B1 induction, and that partial loss of CYP1B1 decreases lung injury during infection. These novel findings support the idea that understanding the mechanisms of CS-induced immunosuppression may have significant therapeutic potential. Our overall hypothesis is that CS increases lung injury by suppressing RIG-I and upregulating CYP1B1. We further hypothesize that RIG-I overexpression or chemical RIG-I activation using SLR10 suppresses CYP1B1, decreases lung injury and mortality during IAV infection. We will use an in vitro human model and an in vivo mouse model to test these concepts to evaluate the role of CYP1B1-mediated lung injury and RIG-I- mediated immune restoration in smokers during IAV infection. We will test these hypotheses using the following integrated Specific Aims: AIM 1: Determine whether chemical activation of RIG-I alleviates CS-induced mortality and immunosuppression during IAV infection. AIM 2: Determine whether CYP1B1 induction by CS enhances lung injury and mortality during IAV infection. This proposal is conceptually innovative, as it addresses unanswered questions regarding whether specific stimulation of RIG-I has potential benefits in human and mouse CS models during IAV infection, and whether CS and IAV increase lung injury through induction of CYP1B1. We have extensive evidence that combustible cigarette smoking impairs antiviral responses and increases lung injury in human and mouse models. The experimental team combines experience in immunology, animal models, genetic manipulation of cell models, and bioinformatics. Our team is uniquely positioned to combine our basic and clinical research expertise and experience to determine basic mechanisms and clinical consequences of CS-mediated immunosuppression and enhanced lung injury to identify targets for new therapeutics.

我们工作的长期目标是了解人类先天免疫系统如何应对 流感病毒（IAV）感染并找到控制感染的新方法。吸烟是一种 重大的公共卫生问题，尤其是在退伍军人中。大量暴露于香烟烟雾（CS） 增加了呼吸道病毒感染的风险。流感感染是普遍的七倍，而且很大 吸烟者比非吸烟者更严重。我们提出的研究的目的是确定严重性和 CS介导的先天免疫抑制的机制。诱导干扰素（IFN）是关键成分 宿主对影响力感染的反应。 IFN进一步分为I型（主要是IFN-α和β），II（IFN-γ） 和III（IFN-λ）亚型，部分基于独特受体的差异使用，它们通过它们介导 信号转移以诱导抗病毒活性。视黄酸诱导蛋白I（RIG-I）在 IAV对IFN的识别和IFN诱导。我们以前的研究表明CS和香烟烟雾 提取物（CSE）抑制IAV感染的人和小鼠肺中的抗病毒先天免疫调查 由于rig-1抑制作用而引起的免疫抑制。 CS的这种免疫抑制作用可能在 吸烟者对严重影响力感染的敏感性增强了。我们还表明，逆转RIG-I 缺陷可防止CS诱导的免疫抑制，恢复所有三种类型的IFN反应，并减少 死亡。我们还发现了一种新机制，IAV和CS逐渐降低了障碍功能和 通过诱导细胞色素p450家族1亚家族B成员1，增加感染期间的肺损伤 （CYP1B1）。我们有新的初步数据证明了这种效果，并且RIG-I激活似乎正在 抑制CYP1B1诱导，CYP1B1的部分丧失会减少感染期间的肺损伤。这些 新发现支持理解CS诱导的免疫抑制的机制的观念。 具有巨大的治疗潜力。 我们的总体假设是，CS通过抑制RIG-I和上调CYP1B1来增加肺损伤。 我们进一步假设使用SLR10抑制RIG-I的过表达或化学RIG-I激活 CYP1B1，降低IAV感染期间的肺损伤和死亡率。我们将使用体外人类模型和 体内小鼠模型测试这些概念，以评估CYP1B1介导的肺损伤和RIG-I的作用 IAV感染期间吸烟者的免疫训练。 我们将使用以下集成特定目的来检验这些假设： 目标1：确定RIG-1的化学激活是否减轻了CS诱导的死亡率和 IAV感染期间的免疫抑制。 AIM 2：确定CS1B1通过CS诱导是否会增强IAV期间的肺损伤和死亡率 感染。 该提议在概念上是创新的，因为它解决了有关特定是否是否具体问题的问题 刺激RIG-I在IAV感染过程中对人和小鼠CS模型具有潜在的益处，以及是否是否 CS和IAV通过诱导CYP1B1增加肺损伤。我们有大量证据表明 吸烟会损害抗病毒反应并增加人和小鼠模型中的肺损伤。这 实验团队结合了免疫学，动物模型，细胞模型的基因操纵的经验， 和生物信息学。我们的团队具有独特的位置，可以将我们的基本和临床研究专业知识结合在一起 确定CS介导的免疫抑制的基本机制和临床后果的经验 并增强肺损伤以识别新疗法的靶标。