Cigarette Smoke and Susceptibility to Influenza Infection

以前的研究表明，呼吸道病毒感染的发生率和严重性在 吸烟者多于不吸烟者，但调节这些反应的机制目前还不是很好 明白了。我们的初步数据显示，吸烟者培养的鼻黏膜上皮细胞 易受流感病毒感染，排出更多病毒，1型干扰素表达减少。 因此，这种体外模型为研究增强型糖尿病的细胞和分子基础提供了重要的工具。 吸烟者对流感病毒的易感性。此外，我们的初步数据表明，鼻腔 接种减毒活流感病毒(LAIV)为研究流感病毒提供了可能性 在活体内安全地感染人类。使用紧密相连的人类体外和体内方法，这一建议是 旨在测试长期暴露在香烟烟雾中会改变上皮细胞抗病毒和 通过两种可能相关的机制对流感病毒感染的炎症反应：减少 第二阶段(抗氧化剂)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营养上调II相酶是一种 减轻这些影响的潜在治疗策略。特定目标1将使用分化的体外模型 人鼻上皮细胞确定改变流感诱导的抗病毒防御的机制 吸烟者的反应，最初集中在I型干扰素抗病毒防御反应的作用和潜在的 吸烟诱导基因沉默的作用。特定目标2将使用我们现有的管理方案 LAIV疫苗作为流感病毒感染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诱导的病毒复制与抗病毒防御 吸烟者和非吸烟者的反应将使用鼻活检组织和 灌洗液。每个研究队列中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可改善抗病毒途径和炎症/免疫的关键异常 SA1+2中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 对提高吸烟者和吸烟者对流感病毒感染易感性的机制的见解 使用转化性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.