RSV ENHANCES SENSITIZATION AND AIRWAY RESPONSIVENESS

病毒性毛细支气管炎继发于呼吸道合胞病毒，通常与婴儿最初的喘息发作有关。在许多婴儿中，这些发作发生在哮喘发作之前。然而，这些病毒诱导的发作的发病机制以及与过敏性炎症和哮喘的关系都没有很好的确定。为了了解病毒呼吸道感染如何影响过敏性致敏、呼吸道炎症和气道功能改变的发展，已经建立了一个小鼠模型来确定这些相互作用。在这个模型中，暴露于活的(不是灭活的)RSV的小鼠对吸入的乙酰甲胆碱(MCH)产生呼吸道高反应性(AHR)，先前的RSV感染增强了对随后的过敏原暴露的反应。对RSV和变应原的反应以嗜酸性炎症为特征，已证实在AHR对病毒或变应原的发展过程中需要嗜酸性粒细胞。在目前的提案中，这些观察将被用来确定T细胞在急性RSV感染后肺部炎症和AHR的发展中的作用，以及在病毒感染后对变应原的呼吸道敏化中的作用。利用T细胞耗尽和特定T细胞群体的过继转移，将描述CD4和CD8T细胞在调节这些反应中的作用。Th-1和Th-2细胞因子在这些反应的发展中的重要性将通过免疫和基因缺陷动物靶向特定的细胞因子和趋化因子来检验。在这些实验中，将确定嗜酸性炎症在反应的不同阶段的调节和重要性。我们将确定IL-4和IgE在急性呼吸道合胞病毒或病毒后暴露于变应原中的作用，确定“特应性”是否影响这些反应的严重程度。这些研究为确定RSV改变呼吸道反应性的机制，检查呼吸道功能的神经控制，特别是针对胆碱能收缩反应提供了基础。改变呼吸道功能的机制也将作为发生呼吸道损伤(呼吸道合胞病毒感染+过敏原暴露)的年龄的函数来处理。为了实现这些目标，我们将利用免疫和遗传操纵的小鼠品系，以及通过全身体积描记术随着时间的推移监测吸入MCH的呼吸道功能的能力。这一建议提供了一种结合免疫学和生理学技术的新方法，以确定对RSV的炎症反应如何促进过敏原驱动的AHR的发展，并揭示预防RSV感染后果的策略。

Viral bronchiolitis, secondary to RSV, is often associated with initial wheezing episodes in infancy. In many infants, these episodes precede the onset of asthma. However, neither the pathogenesis of these virus-induced episodes nor a relationship to allergic inflammation and asthma have been well defined. To understand how viral respiratory tract infections influence allergic sensitization, airway inflammation and the development of altered airway function, a murine model to define such interactions has been developed. In this model, mice exposed to live (not inactivated) RSV develop airway hyperresponsiveness (AHR) to inhaled methacholine (MCh) and prior RSV infection enhances the response to subsequent allergen exposure. The responses to RSV and allergen are characterized by eosinophilic inflammation and a requirement for eosinophils in the development of AHR to virus or allergen has been demonstrated. In the current proposal, these observations will be used to define the role of T cells in the development of pulmonary inflammation and AHR following acute RSV infection and in post-viral airway sensitization to allergen. Utilizing T-cell depletion and adoptive transfer of specific T-cell populations, the role of CD4 and CD8 T cells in mediating these responses will be delineated. The importance of Th-1 and Th-2 cytokines in the development of these responses will be examined by targeting specific cytokines and chemokines immunologically and with gene-deficient animals. In these experiments, the regulation and importance of eosinophilic inflammation at different phases of the response will be identified. We will define the role of IL-4 and IgE in response to acute RSV or post-virus exposure to allergen, determining if "atopy" influences the severity of these responses. These studies provide the foundation for defining the mechanism by which RSV alters airway responsiveness, examining neural control of airway function, particularly targeting cholinergic contractile responsiveness. Mechanisms that alter airway function will also be addressed as a function of the age at which the airway insult (RSV infection + allergen exposure) occurs. To accomplish these goals, we will utilize immunologically- and genetically-manipulated strains of mice as well as the ability to monitor airway function to inhaled MCh over time by whole body plethysmography. This proposal provides a novel approach combining immunologic and physiologic techniques to define how the inflammatory response to RSV contributes to the development of allergen-driven AHR and reveal strategies to prevent the consequences of RSV infection.