RESPIRATORY SYNCYTIAL VIRUS ON ALLERGIC AIRWAY DISEASE

呼吸道合胞病毒(RSV)是引起 儿童时期患有严重的下呼吸道疾病。严重呼吸道合胞病毒感染 疾病与儿童哮喘有关，哮喘的发病率 在工业化国家，这一比例正在增加。因此，理解 呼吸道合胞病毒和变应原诱导的呼吸道的分子和细胞相关性 功能障碍对于设计预防性疫苗和 影响儿童发病机制的免疫治疗策略 哮喘。这项提案的目标是定义病毒学和 急性呼吸道高反应性(AHR)的免疫学决定因素 呼吸道合胞病毒感染在变应原致敏的背景下。特别是， 呼吸道合胞病毒G糖蛋白诱导的呼吸道功能障碍的机制 已定义。此外，选定的细胞因子和T细胞亚群的作用 卵蛋白致敏、呼吸道合胞病毒感染小鼠AHR的诱导 将会被定义。在正常情况下，RSV感染会诱导Th1- 类似于细胞因子的表达模式。我们的初步数据支持 卵子致敏产生免疫环境的假说 这促进了RSV特异性的CD4+Th2对感染的反应，从而进一步 增强卵子特异性过敏性呼吸道炎症和AHR。此外， 我们假设呼吸道合胞病毒感染可以永久改变免疫系统 通过T细胞产生以下因子对空气变应原的反应 干扰素-α或白介素15对卵子特异性记忆诱导的影响 “旁观者”T淋巴细胞。为了检验这些假设，我们将使用Well 具有RSV感染和卵子致敏特征的小鼠模型，以及 在麻醉状态下，机械地测量乙酰甲胆碱诱导的AHR 采用全身体积描记法测定小鼠通气量。除了定义 呼吸道合胞病毒和卵子诱导的细胞因子和T淋巴细胞亚群在人类免疫缺陷病毒感染中的作用 调解保护或增强AHR、候选疫苗和 将评估免疫治疗方法的能力 降低RSV攻击后卵子致敏小鼠的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.