Age-Dependent Increases in Airway Responsiveness by RSV

描述（由申请方提供）：呼吸道合胞病毒（RSV）是婴儿毛细支气管炎和下呼吸道感染的主要原因。急性RSV导致喘息，并且再感染（常见事件）导致甚至更严重的气道症状。RSV和反应性气道疾病以及随后哮喘发展之间的相关性的致病基础尚未明确阐明。尽管如此，婴儿期RSV细支气管炎似乎与以后发生哮喘的风险增加有关，这种风险可能持续数年。我们已经在小鼠模型中证明，先前的RSV感染增强了对随后的过敏原暴露的气道反应（气道炎症和高反应性）。我们的假设是，初始RSV感染时的年龄不仅在对急性感染的反应中起重要作用，而且还决定或塑造了对随后再感染RSV或过敏原暴露的反应。免疫/炎症反应和气道功能的神经原性控制都是年龄依赖性的。我们现在知道，初次接触RSV的年龄越小，急性和随后再次感染或过敏原暴露时的炎症反应和气道反应性越强烈。使用RSV感染/再感染/过敏原暴露的模型，我们将进一步表征< 1、3和8周龄小鼠中RSV感染后的免疫/炎症反应和气道功能。在这些反应中，我们将系统地定义RSV结构蛋白，细胞因子的产生，神经肽水平，RSV特异性抗体，特别是IgE的产生的作用，并确定，在T细胞水平，如何急性RSV在不同年龄的影响T辅助细胞的分化。根据这些信息，我们将确定这些因素如何指导随后对再次感染或过敏原的反应。所提出的方法得到了广泛的初步数据的支持，所有的分子和细胞技术，试剂和小鼠突变株的可用性，以及监测小于1周龄小鼠感染和肺功能的能力。这些研究产生的信息将描述对肺部免疫/炎症反应的重要年龄依赖性影响，并揭示预防婴儿期RSV感染长期后遗症的治疗干预的新选择。

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and lower respiratory tract infection in infants. Acute RSV leads to wheezing, and re-infection, a common event, results in even more severe airway symptoms. The pathogenic basis for the association between RSV and reactive airway disease and the subsequent development of asthma is not clearly elucidated. Nonetheless, RSV bronchiolitis in infancy appears associated with an increased risk for later development of asthma, a risk that may persist for several years. We have demonstrated in a murine model that prior RSV infection enhances the airway response (airway inflammation and hyperresponsiveness) to subsequent allergen exposure. Our hypothesis is that the age at initial RSV infection not only plays an important role in response to the acute infection, but also dictates or shapes the response to subsequent re-infection with RSV or allergen exposure. Both the immune/inflammatory responses and neurogenic control of airway function are age-dependent. We now know that the younger the age at initial encounter with RSV, the more vigorous the inflammatory response and airway responsiveness are, both acutely and subsequently on re-infection or allergen-exposure. Using a model of RSV infection/re-infection/allergen exposure, we will further characterize the immune/inflammatory responses and airway function following RSV infection in < 1, 3 and 8 week old mice. In these responses, we will systematically define the role of RSV structural proteins, cytokine production, neuropeptide levels, the production of RSV-specific antibody, especially IgE, and identify, at the T cell level, how acute RSV at the different ages influences the differentiation of T helper cells. Based on this information, we will then define how these factors direct the subsequent response to re-infection or allergen. The approach proposed is supported by extensive preliminary data, the availability of all of the molecular and cellular techniques, reagents and mutant strains of mice, as well as the ability to monitor infection and lung function in mice less than 1 week of age. The information generated from these studies will delineate the important age-dependent influences on the immune/inflammatory response in the lung and reveal new options for therapeutic intervention to prevent the long-term sequelae of RSV infection in infancy.