Cigarette Smoke and Susceptibility to Influenza Infection

香烟烟雾与流感感染的易感性

基本信息

批准号：
8307709
负责人：
ILONA JASPERS
金额：
$ 5.72万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-12 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307709
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 Health 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

项目摘要

DESCRIPTION (provided by applicant): 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 Specific Aims 1 and 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. PUBLIC HEALTH RELEVANCE: Susceptibility to and severity of influenza infections is enhanced in smokers, but the mechanisms mediating this effect are largely unknown. We have established human in vitro and in vivo experimental models of influenza infections, which will be applied to determine cellular and molecular mechanisms mediating enhanced susceptibility to influenza virus in smokers and to explore potential therapeutic interventions. Knowledge obtained from these studies can be exploited to develop new therapeutic strategies aimed at mitigating respiratory virus infections and their effects in individuals chronically exposed to tobacco smoke.

描述（由申请人提供）：先前的研究表明，吸烟者呼吸道病毒感染的发病率和严重程度高于非吸烟者，但目前尚不清楚介导这些反应的机制。我们的初步数据表明，培养的吸烟者鼻上皮细胞更容易受到流感病毒感染，排出更多病毒，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吸烟者对流感病毒易感性增强的细胞和分子基础。此外，我们的初步数据表明，减毒活流感病毒（LAIV）的鼻腔给药提供了在人体内安全研究流感病毒感染的可能性。该提案旨在利用紧密相连的人体体外和体内方法来检验以下假设：长期接触香烟烟雾会通过两种潜在相关机制改变上皮抗病毒和炎症反应，以应对流感病毒感染：II相（抗氧化）酶表达减少以及抑制 1 型干扰素（抗病毒）途径。我们进一步假设，通过补充 SFN 来上调 II 相酶是减轻这些影响的潜在治疗策略。具体目标 1 将使用分化的人鼻上皮细胞的体外模型来确定改变吸烟者流感诱导的抗病毒防御反应的机制，最初侧重于 I 型 IFN 抗病毒防御反应的作用以及香烟烟雾诱导的潜在作用基因沉默。具体目标 2 将使用我们现有的 LAIV 疫苗管理方案作为流感病毒感染的模型，以确认介导吸烟者体内流感感染易感性增强的机制。将使用鼻活检组织和灌洗液中测量的终点来评估吸烟者和非吸烟者中 LAIV 诱导的病毒复制和抗病毒防御反应。每个研究队列的结果将根据特定目标 1 中发现的先天免疫防御基因表达的变化进行分组。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、抗病毒途径和病毒之间的关系-引起吸烟者和非吸烟者的炎症。我们将评估补充 SFN 导致的 HO-1 上调如何改善与吸烟者相关的抗病毒途径的关键异常以及与吸烟者相关的炎症/免疫反应变化，如具体目标 1 和 2 中所确定的。从这些研究中获得的数据将产生见解研究增强吸烟者对流感病毒感染易感性的机制，并利用转化研究设计探索潜在的治疗干预措施。公共卫生相关性：吸烟者对流感感染的易感性和严重程度有所增加，但介导这种影响的机制在很大程度上尚不清楚。我们建立了人类流感感染的体外和体内实验模型，该模型将用于确定介导吸烟者对流感病毒易感性增强的细胞和分子机制，并探索潜在的治疗干预措施。从这些研究中获得的知识可用于开发新的治疗策略，旨在减轻呼吸道病毒感染及其对长期暴露于烟草烟雾的个体的影响。