RSV Inhibition of Interferon-Dependent Airway Immunity

RSV 对干扰素依赖性气道免疫的抑制

• 批准号: 7085509
• 负责人: Dwight C Look
• 金额: $ 28.81万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085509
• 关键词: biological signal transduction; bronchoscopy; clinical research; gene expression; host organism interaction; human subject; immunity; microorganism immunology; patient oriented research; proteasome; respiratory epithelium; respiratory infections; respiratory syncytial virus; tissue /cell culture; transcription factor; virus infection mechanism; virus protein

DESCRIPTION (provided by applicant): Airway infection with respiratory syncytial virus (RSV) is associated with worsening airway function in healthy infants and young children as well as patients with lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Efficient clearance of RSV from the lung requires airway epithelial cell participation in type I interferon-dependent immunity. The specific aims of this proposal are based on four observations regarding expression of antiviral genes in human airway epithelial cells after RSV infection: 1) airway epithelial cells response to both type I and II interferons by expression of antiviral proteins; 2) RSV infection selectively inhibits type I interferon signal transduction inside airway epithelial cells; 3) RSV inhibits type I interferon-induced Stat1 phosphorylation; and 4) RSV rapidly downregulates Stat2 expression. Based on these observations, we hypothesize that RSV may possess multiple mechanisms that modulate interferon-dependent immunity, but a critical mechanism for this effect is through decreased expression of Stat2 in human airway epithelial cells. It is likely that RSV evolution has generated these mechanisms in order to allow viral subversion of the airway defense response. The overall goal of this proposal is to generate a better understanding of the biochemical basis for RSV effects on antiviral gene expression in human airway epithelial cells and uncover strategies for selectively modifying damaging viral effects but not beneficial immunity in airway epithelium. Accordingly, our specific aims are to: I. Identify RSV effects on type I interferon signaling in airway epithelial cells. This aim will take advantage of human airway epithelial cell models and their sensitivity to RSV infection and interferon-dependent gene activation. Systematic evaluation of viral effects will be accomplished by assessment of the type I interferon JAK-STAT signaling pathway from receptor ligation to STAT phosphorylation. Because RSV may affect more than one-step in type I interferon signaling, viral effects on type I interferon-induced antiviral gene expression that are independent of STAT activation will also be identified. II. Develop strategies to overcome RSV effects on type I interferon signaling. This aim will take advantage of the same airway epithelial cell model systems for RSV infection and interferon-dependent gene activation. Modulation of proteasome function and viral protein expression will be used to bypass RSV effects and restore type I interferon-dependent signal transduction, gene expression, and antiviral effects in airway epithelial cells.

描述（由申请人提供）：呼吸道合胞病毒（RSV）的气道感染与健康婴儿和幼儿的气道功能恶化以及肺部疾病患者（如哮喘，慢性阻塞性肺部疾病和囊性纤维化）有关。从肺中对RSV的有效清除需要气道上皮细胞参与I型干扰素依赖性免疫。该提案的具体目的是基于RSV感染后人类气道上皮细胞表达的四个观察结果：1）气道上皮细胞对I型和II型干扰素的反应通过抗病毒蛋白的表达； 2）RSV感染有选择地抑制气道上皮细胞内的I型干扰素信号转导； 3）RSV抑制I型干扰素诱导的STAT1磷酸化； 4）RSV迅速下调STAT2表达。基于这些观察结果，我们假设RSV可能具有调节干扰素依赖性免疫的多种机制，但是这种效果的关键机制是通过在人体气道上皮细胞中降低STAT2的表达。 RSV进化很可能已经产生了这些机制，以便使气道防御反应病毒颠覆。该提案的总体目标是更好地了解人类气道上皮细胞中RSV对抗病毒基因表达的影响的生化基础，并发现有选择地修饰损害病毒效应但在呼吸道上皮中没有有益的免疫力的策略。因此，我们的具体目的是： I.确定对气道上皮细胞中I型干扰素信号传导的影响。该目标将利用人类气道上皮细胞模型及其对RSV感染和干扰素依赖性基因激活的敏感性。通过评估从受体连接到STAT磷酸化的I型干扰素JAK-STAT信号通路来评估病毒效应的系统评估。由于RSV可能会影响I型干扰素信号传导一步，因此还将确定对I型干扰素诱导的抗病毒基因表达的病毒作用，这些抗病毒基因表达独立于Stat激活。 ii。制定克服RSV对I型干扰素信号的影响的策略。该目标将利用相同的气道上皮细胞模型系统，用于RSV感染和干扰素依赖性基因激活。蛋白酶体功能和病毒蛋白表达的调节将用于绕过RSV效应并恢复I型干扰素依赖性信号转导，基因表达和气道上皮细胞中的抗病毒作用。