Reversing Cigarette Smoke-Induced Antiviral Immunosuppression

逆转香烟烟雾引起的抗病毒免疫抑制

基本信息

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
项目类别：
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

项目摘要

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甲型流感病毒（IAV）感染并找到控制吸烟的新方法是一项重要任务。严重的公共卫生问题，特别是在退伍军人中显着暴露于香烟烟雾（CS）。增加呼吸道病毒感染的风险，流感感染的发生率是其七倍，而且发病率要高得多。我们提出的研究的目的是确定吸烟者的严重程度和程度。 CS介导的先天免疫抑制机制是干扰素（IFN）诱导的关键组成部分。宿主对流感感染的反应又分为I型（主要是IFN-α和β）、II型（IFN-γ）。和 III (IFN-λ) 亚型，部分基于它们介导的独特受体的不同使用视黄酸诱导蛋白 I (RIG-I) 在诱导抗病毒活性的信号转导中发挥着重要作用。我们之前的研究表明，CS 和香烟烟雾对 IAV 的识别和 IFN 的诱导有关。提取物 (CSE) 抑制感染 IAV 的人和小鼠肺部的抗病毒先天免疫反应，尤其是由于 RIG-I 抑制而产生的免疫抑制作用可能在 CS 的免疫抑制作用中发挥关键作用。我们还表明，逆转 RIG-I 会增加吸烟者对严重流感感染的易感性。预防 CS 引起的免疫抑制缺陷，恢复所有三种类型的 IFN 反应，并减少我们还发现了 IAV 和 CS 降低屏障功能和死亡率的新机制。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应，并且 RIG-I 的激活似乎是这样的。抑制 CYP1B1 诱导，并且 CYP1B1 部分缺失可减少感染期间的肺损伤。新发现支持这样的观点：了解 CS 诱导的免疫抑制机制可能有助于具有显着的治疗潜力。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。我们进一步探究 RIG-I 过表达或使用 SLR10 的化学 RIG-I 激活抑制 CYP1B1 可减少 IAV 感染期间的肺损伤和死亡率。我们将使用体外人体模型和模型。体内小鼠模型来测试这些概念，以评估 CYP1B1 介导的肺损伤和 RIG-I- 的作用介导 IAV 感染期间吸烟者的免疫恢复。我们将使用以下综合具体目标来测试这些假设：目标 1：确定 RIG-I 的化学激活是否可以减轻 CS 引起的死亡率和 IAV 感染期间的免疫抑制。目标 2：确定 CS 诱导 CYP1B1 是否会增加 IAV 期间的肺损伤和死亡率感染。该提案在概念上具有创新性，因为它解决了有关具体是否刺激 RIG-I 在 IAV 感染期间的人类和小鼠 CS 模型中具有潜在的益处，以及是否 CS 和 IAV 通过诱导 CYP1B1 增加肺损伤我们有大量证据表明可燃。在人类和小鼠模型中，吸烟会损害抗病毒反应并增加肺损伤。实验团队结合了免疫学、动物模型、细胞模型基因操作的经验，我们的团队具有独特的优势，能够将我们的基础和临床研究专业知识与确定 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确定新疗法的靶点。