RESPIRATORY SYNCYTIAL VIRUS ON ALLERGIC AIRWAY DISEASE

呼吸道合胞病毒（RSV）是最常见的病毒性病因， 儿童严重下呼吸道疾病。重度RSV诱导 疾病与儿童哮喘有关，哮喘的发病率 在工业化国家，因此了解 呼吸道合胞病毒和变应原诱导的气道相关分子和细胞 功能障碍对于设计预防性疫苗很重要， 影响儿童发病机制的免疫策略 哮喘 本提案的目的是定义病毒学和 诱导气道高反应性（AHR）的免疫决定因素 过敏原致敏环境中的RSV感染。特别是， RSV G糖蛋白诱导的气道功能障碍的机制将进一步阐明 定义了此外，选择的细胞因子和T细胞亚群的作用， 在卵清蛋白（ova）致敏的RSV感染小鼠中诱导AHR 将被定义。在正常条件下，RSV感染诱导Th 1- 类似的细胞因子表达模式。我们的初步数据支持 卵致敏产生免疫环境假说 促进RSV特异性CD 4 + Th 2对感染的应答， 增强卵特异性过敏性气道炎症和AHR。此外，本发明还 我们假设RSV感染可以永久性地改变免疫系统， 通过T细胞产生的因子，如 IFN-α或IL-15影响卵巢特异性 “旁观者”T淋巴细胞。为了验证这些假设，我们将使用 表征的RSV感染和卵致敏的鼠模型，和 测量乙酰甲胆碱诱导的AHR在麻醉，机械- 通过全身体积描记法测定通气小鼠。除了定义 RSV和OVA诱导细胞因子和T淋巴细胞亚群在 介导对AHR的保护或增强，候选疫苗和 将评估免疫方法的能力， 降低RSV攻击后卵致敏小鼠的AHR。

Respiratory syncytial virus (RSV) is the most common viral cause of severe lower respiratory tract disease in childhood. Severe RSV-induced disease is associated with childhood asthma, and the incidence of asthma in industrialized countries is increasing. Therefore, understanding the molecular and cellular correlates of RSV-and allergen-induced airway dysfunction is important for devising preventive vaccine and immunotherapeutic strategies to influence the pathogenesis of childhood asthma. The objective of this proposal is to define the virologic and immunologic determinants of airway hyperresponsiveness (AHR) induced by RSV infection in the setting of allergen sensitization. In particular, the mechanism of RSV G glycoprotein-induced airway dysfunction will e defined. In addition, the role of selected cytokines and T cell subsets on the induction of AHR in ovalbumin (ova)-sensitized, RSV-infected mice will be defined. Under normal conditions RSV infection induces a Th1- like pattern of cytokine expression. Our preliminary data supports the hypothesis that ova-sensitization produces an immunologic environment that promotes RSV-specific CD4+ Th2 responses to infection which further potentiate ova-specific allergic airway inflammation and AHR. Further, we hypothesize that RSV infection can permanently alter the immune response to aeroallergens through T cell production of factors such as IFN-alpha or IL-15 that influence memory induction in ova-specific "bystander" T lymphocytes. To test this hypotheses, we will use well characterized murine models of RSV infection and ova sensitization, and measure methacholine-induced AHR in anesthetized, mechanically- ventilated mice by whole body plethysmography. In addition to defining the role of RSV- and ova-induced cytokines and T lymphocytes subsets in mediating protection from or enhancement of AHR, candidate vaccines and immunotherapeutic approaches will be evaluated for their ability to reduce AHR in ova-sensitized mice following RSV challenge.