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

描述(申请人提供)：2009年H1N1大流行流感病毒以远端肺细胞为目标，在严重和致命病例中造成弥漫性肺泡损伤。最近的研究和我们的初步数据表明，人类对这种病毒的宿主易感性存在差异。虽然动物研究提供了宿主遗传因素对流感易感性的影响的宝贵信息，但这些信息并不容易转化为人类状况和临床医学。我们仍然不知道病毒如何逃避宿主防御而导致某些人的肺损伤，主要是因为很难直接研究影响患者。为了解决这个问题，我们开发了人肺泡上皮细胞的原代培养系统，这是大流行和禽流感的关键靶标。这将使我们能够研究来自身份不明捐赠者的细胞中宿主对流感感染的反应。我们先前的研究表明，在流感感染过程中，干扰素-L是这些细胞产生的主要干扰素。此外，干扰素-L基因的功能多态性已被证明与人类丙型肝炎病毒清除和应答的结果有关。然而，这种干扰素-L基因多态性是否会影响宿主对呼吸道病毒感染的反应尚不清楚。在这项拟议的研究中，我们将确定干扰素-L3基因的关键单核苷酸多态(SNP)rs12979860如何影响人类原代肺泡上皮细胞对H1N1丙型肝炎病毒的宿主反应。此外，我们还将研究干扰素-L在 流感引起的这些细胞上皮损伤。我们假设SNP rs12979860TT与流感感染的易感性增加和对干扰素-L治疗无效有关。我们的方法有三个主要的新奇特征。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流感的反应，使我们能够直接研究与流感病毒最相关的目标。其次，我们将研究干扰素-L中的功能性单核苷酸多态对肺泡上皮细胞对流感的易感性以及流感感染时引起的上皮损伤的影响。第三，我们将研究干扰素-L在限制病毒诱导的上皮细胞损伤中的作用。干扰素-L因其在上皮细胞中的抗病毒活性而广为人知，但它是否能保护上皮屏障还没有研究。我们的研究将揭示涉及调节流感感染易感性和反应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治疗提供新的途径。 公共卫生相关性：流感是一种常见的公共卫生问题，每年造成超过3.5万人死亡、20万人住院和超过375亿美元的经济损失(www.cdc.gov)。根据世界卫生组织的数据，最近的2009年H1N1大流行流感病毒导致全球超过18,000人确诊死亡。这种病毒的目标是人类肺部深处负责气体交换的细胞。然而，临床疾病的程度是高度可变的，因此肯定有一些因素改变了宿主的易感性。这项拟议的研究旨在确定关键宿主抗病毒因子干扰素-lambda的变异是否会影响原代人类肺上皮细胞对流感感染和感染诱导的肺损伤的敏感性。这些研究的结果将揭示关于易受流感感染的人群中危险因素的有价值的信息，并为预防和治疗流感引起的疾病提供新的方法。

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. PUBLIC HEALTH RELEVANCE: Statement Influenza is a common public health problem responsible annually for more than 35,000 deaths, 200,000 hospitalizations, and more than $37.5 billion in economic loss (www.cdc.gov). According to the WHO, the recent 2009 H1N1 pandemic influenza virus led to over 18,000 verified deaths worldwide. This virus targets cells deep within the human lung that are responsible for gas exchange. However, the degree of clinical illness is highly variable, and therefore there must be some factors that alter host susceptibility. The proposed studies aim to determine whether variations in a key host antiviral factor, interferon-lambda, affect susceptibility of primary human lung epithelial cells to influenz infection and infection-induced lung injury. Results from these studies will reveal valuable information about risk factors within a population susceptible to influenza infection and provide novel approaches for the prevention and treatment of influenza-induced disease.