Antiviral Immunosuppression by Cigarette Smoke

香烟烟雾的抗病毒免疫抑制作用

• 批准号: 9275377
• 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: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275377
• 关键词: Acetylcysteine; Antioxidants; Antiviral Agents; Antiviral Response; Chronic Obstructive Airway Disease; Complex; Data; Development; Environmental Tobacco Smoke; Glutathione; Goals; Human; Immune; Immune response; Immune system; Immunosuppression; Impairment; Infection; Infection Control; Inflammation; Influenza; Influenza A virus; Influenza prevention; Innate Immune Response; Innate Immune System; Knock-out; Knockout Mice; Knowledge; Lung; Mediating; Methods; Modeling; Molecular; Mus; NADPH Oxidase; Organ Culture Techniques; Outcome; Oxidases; Pattern recognition receptor; Play; Predisposition; Prevention therapy; Process; Proteins; RNA Viruses; Respiratory Tract Infections; Risk; Risk Factors; Role; Smoker; Smoking; Testing; Therapeutic; Time; Transgenic Mice; Tretinoin; Veterans; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Work; cigarette smoking; cigarette smoking; cytokine; design; environmental tobacco smoke exposure; epidemiology study; experimental study; in vivo; influenzavirus; knock-down; mortality; mouse model; non-smoker; novel; overexpression; pathogen; prevent; public health relevance; response

DESCRIPTION (provided by applicant): Cigarette smoke (CS) suppresses the immune system, and smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). Exposure to cigarette smoke is associated with a significant increase in the risk for respiratory viral infections. Our work is to understand how CS compromises the human innate immune system's response to influenza virus infection, and to find novel methods to control the infection. Epidemiological studies show that influenza infection is seven times more common and is much more severe in smokers than nonsmokers. Retinoic acid-inducible protein I (RIG-I) plays an important role in the recognition of, and cytokine induction by, influenza virus and other RNA viruses. Our previous studies, using an ex vivo human organ culture model, have found that cigarette smoke extract (CSE) suppresses antiviral and innate immune responses in influenza virus infected human lung through oxidative inhibition of viral-mediated induction of the pattern recognition receptor, RIG-I. This immunosuppressive effect of CS may play a role in the enhanced susceptibility of smokers to serious influenza infection in the lung. We propose to use an in vivo mouse model to study the mechanism by which CS suppresses the expression and function of the RIG-I initiated innate response to influenza virus. The hypothesis of this proposal is that long-term CS impairs the protective RIG-I initiated antiviral response to influenza virus in vivo while RIG-I overexpression and antioxidants provide therapeutic inhibition of immunosuppression from smoking. To test the central hypothesis, we propose to pursue the following integrated specific aims: AIM 1: Is RIG-I knockdown by CS responsible for the suppression of the RIG-I initiated antiviral response in CS-exposed mice? AIM 2: Can RIG-I overexpression in mouse lung reverse the CS-mediated suppression of the antiviral response in CS-exposed mice? AIM 3: Can antioxidants restore the RIG-I initiated antiviral response in CS-exposed mice? These studies will significantly enhance our understanding of the mechanism whereby CS suppresses the human immune system and predisposes humans to worse outcomes of influenza virus infection. Determination of the molecular mechanisms of immunosuppression will be important in designing strategies for the development of new and novel treatments for cigarette smoke enhanced lung infections, particularly those due to influenza.

描述（由申请人提供）： 香烟烟雾（CS）抑制免疫系统，吸烟是慢性阻塞性肺部疾病（COPD）的主要危险因素。暴露于香烟烟雾与呼吸道病毒感染风险的显着增加有关。我们的工作是了解CS如何损害人类先天免疫系统对流感病毒感染的反应，并找到控制感染的新方法。流行病学研究表明，流感感染的常见七倍，吸烟者比非吸烟者高得多。视黄酸诱导的蛋白I（RIG-I）在流感病毒和其他RNA病毒的识别和细胞因子诱导的识别和细胞因子诱导中起重要作用。我们先前使用过体内器官培养模型的研究发现，香烟烟雾提取物（CSE）抑制了通过氧化抑制模式识别受体RIG-I的病毒介导诱导的氧化抑制氧化抑制人类肺部流感病毒中的抗病毒和先天免疫反应。 CS的这种免疫抑制作用可能在吸烟者对肺部严重流感感染的敏感性增强中发挥作用。我们建议使用体内小鼠模型来研究CS抑制RIG-1的表达和功能的机制，从而启动了对流感病毒的先天反应。该提议的假设是长期CS损害了保护性RIG-I对体内流感病毒的抗病毒反应，而RIG-I过表达 抗氧化剂可提供对吸烟免疫抑制的治疗性抑制作用。 为了检验中心假设，我们建议追求以下集成的特定目的：目标1：CS是否击倒了RIG-1负责抑制CS暴露的小鼠中RIG-I启动的抗病毒反应？ AIM 2：小鼠肺中的RIG-1过表达可以反向CS介导的抗病毒反应抑制CS暴露的小鼠吗？ AIM 3：抗氧化剂可以恢复CS暴露小鼠的RIG-I引发的抗病毒反应吗？ 这些研究将显着增强我们对CS抑制人类免疫系统的机制的理解，并使人类倾向于对流感病毒感染的更严重的预后。确定免疫抑制的分子机制对于设计用于开发用于香烟烟雾增强的新型和新型治疗方法的策略将很重要，尤其是由于流行性的肺部感染。