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

描述（由申请方提供）：2009年H1N1大流行性流感病毒靶向远端肺细胞，并在严重和致命病例中引起弥漫性肺泡损伤。最近的研究和我们的初步数据表明，存在着不同的宿主对这种病毒在人类之间的易感性。虽然动物研究提供了关于宿主遗传因素对流感易感性的影响的有价值的信息，但这些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的防御而导致某些个体的肺损伤的，这主要是因为很难直接研究感染患者。为了解决这个问题，我们已经开发了一个原代培养系统的人肺泡上皮细胞，大流行和禽流感的关键目标。这将使我们能够研究宿主对来自去识别供体的细胞中的流感感染的反应。我们以前的研究表明，干扰素（IFN）-1是流感病毒感染期间这些细胞产生的主要IFN。此外，IFN-1基因中的功能多态性已显示与人类中病毒清除的结果和对丙型肝炎病毒的应答性相关。然而，该IFN-1多态性是否影响宿主对呼吸道病毒感染的应答尚不清楚。在本研究中，我们将确定IFN-13基因中的关键单核苷酸多态性（SNP）rs 12979860如何影响人原代肺泡上皮细胞对H1N1 pdm病毒的宿主反应。此外，我们将研究IFN-1在肿瘤细胞中的作用。 流感引起的上皮细胞损伤。我们假设SNP rs 12979860 TT与对流感感染的易感性增加和对IFN-1治疗的无反应性相关。我们的方法有三个主要的新特点。首先，在我们独特的人类原代培养系统中研究宿主对大流行性流感的反应，使我们能够直接研究流感病毒最相关的靶标。第二，我们将研究IFN-1中的功能性SNP对肺泡上皮细胞对流感的易感性和流感感染期间流感诱导的上皮损伤的影响。第三，我们将研究IFN-1在限制病毒诱导的上皮损伤中的功能。IFN-1在上皮细胞中的抗病毒活性是众所周知的，但它是否保护上皮屏障还没有研究。我们的研究将揭示参与调节流感感染易感性和应答的宿主遗传因素的新信息，从而为改进流感预防策略和开发更好的流感诱导病理学治疗方法提供新方法。

DESCRIPTION (provided by applicant): 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 amon 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 influnza 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-l on alveolar epithelial cell susceptibility to influenza and influenza-induced epithelial injury durng influenza infection. Third, we will study the function of IFN-l in limiting virus-induced epithelia injury. IFN-l is well known for its antiviral activity in epithelial cells, but whether it protectsthe 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, therefor providing novel approaches to improve influenza prevention strategies and develop better treatments for influenza- induced pathology.