Cigarette Smoke and Susceptibility to Influenza Infection

香烟烟雾与流感感染的易感性

• 批准号: 8515504
• 负责人: ILONA JASPERS
• 金额: $ 40.32万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-12 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515504
• 关键词: Antioxidants; Antiviral Agents; Antiviral Response; Attenuated; Biopsy; CXCL10 gene; Cell Culture Techniques; Cell physiology; Cells; Chronic; Cohort Studies; Complex; DNA Methylation; Data; Disease; Enzymes; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Experimental Models; Exposure to; Gene Expression; Gene Silencing; Host Defense; Human; Human Volunteers; Immune; Immune response; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Influenza; Interferons; Intervention; Irrigation; Knowledge; Life; Link; Liquid substance; Measurable; Measures; Mediating; Modeling; Molecular; Mucositis; Nasal Epithelium; Nose; Nutritional; Outcome; Oxidants; Pathway interactions; Phase; Play; Population; Predisposition; Production; Protocols documentation; Research Design; Role; Sampling; Severities; Smoke; Smoker; Smoking; Structure of respiratory epithelium; Sulforaphane; Supplementation; Surface; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tobacco smoke; Translating; Translational Research; Up-Regulation; Viral; Virus; Virus Diseases; Virus Replication; airway epithelium; base; cell type; cigarette smoke-induced; cigarette smoking; defense response; design; environmental particulate; heme oxygenase-1; improved; in vitro Model; in vivo; in vivo Model; influenza virus vaccine; influenzavirus; insight; interest; non-smoker; non-smoking; novel; novel therapeutics; overexpression; pollutant; primary outcome; research study; respiratory; respiratory infection virus; respiratory virus; response; tool; volunteer

Previous studies have demonstrated that the incidence and severity of respiratory virus infections is greater in smokers than in non-smokers, but the mechanisms mediating these responses are currently not well understood. Our preliminary data demonstrate that cultured nasal epithelial cells from smokers are more susceptible to influenza virus infections, shed more virus, and have decreased expression of type 1 interferons. This in vitro model thus provides an important tool to investigate the cellular and molecular basis for enhanced susceptibility to influenza virus seen in smokers. In addition, our preliminary data demonstrate that nasal administration of live attenuated influenza virus (LAIV) offers the possibility of studying influenza virus infections safely in humans in vivo. Using tightly linked human in vitro and in vivo approaches, this proposal is designed to test the hypothesis that chronic exposure to cigarette smoke alters epithelial antiviral and inflammatory responses to influenza virus infection via two potentially related mechanisms: decreased expression of phase II (antioxidant) enzymes and suppression of type 1 interferon (antiviral) pathways. We further hypothesize that upregulation of phase II enzymes via nutritional supplementation with SFN is a potential therapeutic strategy to mitigate these effects. Specific aim 1 will use an in vitro model of differentiated human nasal epithelial cells to determine mechanisms that modify influenza-induced antiviral defense responses in smokers, initially focusing on the role of type I IFN antiviral defense responses and the potential role of cigarette smoke-induced gene silencing. Specific aim 2 will use our existing protocol of administration of LAIV vaccine as a model for influenza virus infections to confirm mechanisms that mediate enhanced susceptibility to influenza infections in smokers in vivo. LAIV-induced viral replication and antiviral defense responses will be assessed in smokers and non-smokers using endpoints measured in nasal biopsy tissue and lavage fluids. Outcomes within each study cohort will be grouped based on changes in innate immune defense gene expression found in specific aim 1. Specific aim 3 will use both the in vitro and in vivo models to determine the relationships between antioxidant gene expression, antiviral pathways, and virus-induced inflammation in smokers and non-smokers. We will assess how upregulation of HO-1 as a result of supplementation with SFN can improve key abnormalities in antiviral pathways and inflammatory/immune response changes associated with smokers, as identified in SA1+2. Data derived from these studies will yield insights into the mechanisms that enhance the susceptibility to influenza virus infections in smokers and explore potential therapeutic interventions using a translational research design.

先前的研究表明，呼吸道病毒感染的发生率和严重程度更高 吸烟者的反应比不吸烟者的反应要好，但目前介导这些反应的机制并不完善 明白了。我们的初步数据表明，培养的吸烟者鼻上皮细胞更 易受流感病毒感染，散发更多病毒，并且 1 型干扰素表达减少。 因此，该体外模型提供了一个重要的工具来研究增强的细胞和分子基础。 吸烟者对流感病毒的易感性。此外，我们的初步数据表明，鼻 减毒活流感病毒（LAIV）的施用为研究流感病毒提供了可能性 在人体体内安全感染。该提案使用紧密相连的人体体外和体内方法 旨在检验以下假设：长期接触香烟烟雾会改变上皮抗病毒和 通过两种潜在相关机制对流感病毒感染产生炎症反应： II 相（抗氧化）酶的表达和 1 型干扰素（抗病毒）途径的抑制。我们 进一步假设通过补充 SFN 来上调 II 相酶是一种 减轻这些影响的潜在治疗策略。具体目标1将使用分化的体外模型 人鼻上皮细胞以确定改变流感诱导的抗病毒防御的机制 吸烟者的反应，最初关注 I 型 IFN 抗病毒防御反应的作用以及潜在的 香烟烟雾诱导的基因沉默的作用。具体目标 2 将使用我们现有的管理协议 LAIV 疫苗作为流感病毒感染的模型，以确认介导增强的机制 吸烟者体内对流感感染的易感性。 LAIV诱导的病毒复制和抗病毒防御 将使用鼻活检组织中测量的终点来评估吸烟者和非吸烟者的反应 灌洗液。每个研究队列的结果将根据先天免疫防御的变化进行分组 特定目标 1 中发现的基因表达。特定目标 3 将使用体外和体内模型来 确定抗氧化基因表达、抗病毒途径和病毒诱导之间的关系 吸烟者和非吸烟者的炎症。我们将评估 HO-1 的上调是如何导致的 补充 SFN 可以改善抗病毒途径和炎症/免疫的关键异常 如 SA1+2 中所确定的，与吸烟者相关的反应变化。从这些研究中得出的数据将产生 深入了解吸烟者和流感病毒感染易感性增强的机制 使用转化研究设计探索潜在的治疗干预措施。