Cigarette Smoke and Susceptibility to Influenza Infection

先前的研究表明，呼吸道病毒感染的发病率和严重程度在 吸烟者的反应比不吸烟者的反应要好，但目前调节这些反应的机制还不完善 明白我们的初步数据表明，培养的吸烟者鼻上皮细胞比吸烟者的鼻上皮细胞多。 易受流感病毒感染，脱落更多病毒，并且1型干扰素的表达降低。 因此，这种体外模型提供了一个重要的工具，以研究细胞和分子基础，增强 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）的施用提供了研究流感病毒的可能性 在人体内安全感染。使用紧密连接的人体外和体内方法，该提议是 旨在检验长期暴露于香烟烟雾会改变上皮抗病毒和 通过两种可能相关的机制对流感病毒感染的炎症反应： 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的营养，II相酶的上调是一种 潜在的治疗策略，以减轻这些影响。具体目标1将使用分化的体外模型， 人鼻上皮细胞用于确定修饰流感诱导的抗病毒防御的机制 吸烟者的反应，最初侧重于I型干扰素抗病毒防御反应的作用和潜在的 香烟烟雾诱导的基因沉默。具体目标2将使用我们现有的给药方案 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评估吸烟者和非吸烟者的缓解情况， 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 在特定目标1中发现的基因表达。具体目标3将使用体外和体内模型， 确定抗氧化基因表达，抗病毒途径和病毒诱导的 吸烟者和非吸烟者的炎症。我们将评估HO-1的上调是如何作为一个结果， 补充SFN可以改善抗病毒途径和炎症/免疫系统中的关键异常， 与吸烟者相关的反应变化，如在SA 1 +2中确定的。从这些研究中获得的数据将产生 深入了解增强吸烟者对流感病毒感染易感性的机制， 使用转化研究设计探索潜在的治疗干预措施。

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.