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

摘要 2009年H1N1大流行性流感病毒以远端肺细胞为目标，并在 严重和致命的病例。最近的研究和我们的初步数据表明，寄主存在变异 人类对这种病毒的易感性。尽管动物研究提供了有价值的信息，说明了 宿主遗传因素对流感的易感性，这一信息不容易转化为人类 情况与临床医学。我们仍然不知道病毒是如何逃避宿主防御导致肺损伤的 在某些人中，很大程度上是因为很难直接研究流感患者。为了解决这个问题，我们 已经开发出人肺泡上皮细胞的原代培养系统，这是大流行的关键目标 还有禽流感。这将使我们能够研究宿主对流感感染的反应，从识别的细胞 捐赠者。我们先前的研究表明，干扰素-L是这些细胞产生的主要干扰素 在流感感染期间。此外，干扰素-L基因的一个功能多态性已被证明是 与病毒清除的结果和人类对丙型肝炎病毒的应答有关。然而，无论是 这种干扰素-L基因多态性影响宿主对呼吸道病毒感染的反应尚不清楚。在建议的 研究中，我们将确定关键单核苷酸多态(SNP)rs12979860在干扰素-L3基因中是如何 在人的原代肺泡上皮细胞中影响宿主对H1N1 pdm病毒的反应。此外，我们还将 探讨干扰素-L在流感诱导的细胞上皮损伤中的作用。我们假设SNP Rs12979860TT与流感感染易感性增加和对干扰素-1无反应性有关 L治疗。我们的方法有三个主要的新奇特征。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允许我们直接研究与流感最相关的目标 病毒。第二，我们将研究干扰素-L3中功能性SNP对肺泡上皮细胞易感性的影响。 流感及流感感染过程中引起的上皮损伤。第三，我们将研究它的功能 干扰素-L在限制病毒诱导的上皮损伤中的作用。干扰素-L因其在上皮细胞中的抗病毒活性而闻名，但 它是否保护上皮屏障还没有研究。我们的研究将揭示关于 宿主遗传因素参与调节对流感感染的易感性和反应，因此提供 改进流感预防策略和开发更好的流感治疗方法的新方法- 诱导病理学。

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.