IFN-lambda polymorphisms and host response to respiratory viral infections in hum

摘要 2009年H1N1大流行性流感病毒靶向远端肺细胞，并导致弥漫性肺泡损伤， 严重和致命的病例。最近的研究和我们的初步数据表明，在宿主中存在变异 人类对这种病毒的易感性。尽管动物研究提供了关于 宿主遗传因素对流感易感性的影响，这一信息并不容易转化为人类 情况和临床医学。我们仍然不知道病毒是如何逃避宿主防御造成肺损伤的 在某些个体中，主要是因为很难直接研究流感患者。为了解决这个问题，我们 已经开发了一种人肺泡上皮细胞的原代培养系统， 和禽流感。这将使我们能够研究宿主对流感病毒感染的反应， 捐助者。我们以前的研究表明，干扰素（IFN）-1是这些细胞产生的主要干扰素 在流感感染期间。此外，IFN-1基因中的功能多态性已被证明是 与人类病毒清除和对丙型肝炎病毒反应性的结果相关。但无论 这种IFN-1多态性影响宿主对呼吸道病毒感染的应答是未知的。拟议 研究中，我们将确定IFN-13基因中的关键单核苷酸多态性（SNP）rs 12979860 在人原代肺泡上皮细胞中影响宿主对H1N1 pdm病毒的应答。此外，我们将 研究IFN-1在这些细胞中流感诱导的上皮损伤中的作用。我们假设SNP rs 12979860 TT与流感感染易感性增加和对IFN-γ无反应性相关。 l治疗。我们的方法有三个主要的新特点。首先，研究宿主对大流行的反应 流感在我们独特的人类原代培养系统中，使我们能够直接研究流感最相关的目标 病毒其次，我们将研究IFN-13中的功能性SNP对肺泡上皮细胞对IFN-13的易感性的影响。 流感和流感感染期间流感诱导的上皮损伤。第三，我们将研究 IFN-1限制病毒诱导的上皮损伤。IFN-1因其在上皮细胞中的抗病毒活性而众所周知，但 它是否保护上皮屏障还没有被研究。我们的研究将揭示新的信息 宿主遗传因子参与调节对流感感染的易感性和反应，因此提供了 改进流感预防策略和开发更好的流感治疗方法的新方法- 诱发病理学

Abstract The 2009 H1N1 pandemic influenza virus targets distal lung cells and causes diffuse alveolar damage in severe and fatal cases. Recent studies and our preliminary data indicate that there is variation in host susceptibility to this virus among humans. Although animal studies provide valuable information on the effect of host genetic factors on the susceptibility to influenza, this information does not translate readily into the human situation and clinical medicine. We still do not know how the virus evades the host defense to cause lung injury in certain individuals, largely because it is difficult to study influenza patients directly. To address this issue, we have developed a primary culture system for human lung alveolar epithelial cells, the key targets for pandemic and avian flu. This will allow us to study the host response to influenza infection in the cells from deidentified donors. Our previous study indicates that interferon (IFN)-l is the predominant IFN produced by these cells during influenza infection. Additionally, a functional polymorphism in the IFN-l gene has been shown to be related to the outcome of viral clearance and responsiveness to hepatitis C virus in humans. However, whether this IFN-l polymorphism affects host response to respiratory viral infections is not known. In the proposed study, we will determine how the critical single nucleotide polymorphism (SNP) rs12979860 in the IFN-l3 gene affects host response to H1N1 pdm virus in human primary lung alveolar epithelial cells. In addition, we will investigate the role of IFN-l in influenza-induced epithelial injury in these cells. We hypothesize that SNP rs12979860 TT is associated with increased susceptibility to influenza infection and nonresponsiveness to IFN- l treatment. Our approach has three major novel features. First, studying the host response to the pandemic flu in our unique human primary culture system allows us to directly study the most relevant targets for the flu virus. Second, we will study the effect of the functional SNP in IFN-l3 on alveolar epithelial cell susceptibility to influenza and influenza-induced epithelial injury during influenza infection. Third, we will study the function of IFN-l in limiting virus-induced epithelial injury. IFN-l is well known for its antiviral activity in epithelial cells, but whether it protects the epithelial barrier has not been studied. Our study will reveal novel information on the host genetic factors involved in regulating susceptibility and response to influenza infection, therefore providing novel approaches to improve influenza prevention strategies and develop better treatments for influenza- induced pathology.