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.

以往的研究表明，呼吸道病毒感染的发病率和严重程度在