Age-Dependent Increases in Airway Responsiveness by RSV

描述(申请人提供)：呼吸道合胞病毒(RSV)是毛细支气管炎和婴儿下呼吸道感染的主要原因。急性呼吸道合胞病毒会导致喘息，而再次感染是一种常见事件，会导致更严重的呼吸道症状。呼吸道合胞病毒与反应性呼吸道疾病之间的联系以及随后的哮喘发展的致病基础尚不清楚。尽管如此，婴儿期呼吸道合胞病毒毛细支气管炎似乎与日后发展为哮喘的风险增加有关，这种风险可能会持续数年。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呼吸道反应(呼吸道炎症和高反应性)。我们的假设是，初次感染RSV时的年龄不仅在对急性感染的反应中发挥重要作用，而且还决定或塑造对随后再次感染RSV或接触变应原的反应。免疫/炎症反应和对呼吸道功能的神经源性控制都与年龄有关。我们现在知道，初次感染RSV的年龄越小，炎症反应和呼吸道反应就越强烈，无论是急性还是随后的再次感染或过敏原暴露。利用RSV感染/再感染/变应原暴露的模型，我们将进一步表征RSV感染后1、3和8周龄小鼠的免疫/炎症反应和呼吸道功能。在这些反应中，我们将系统地确定RSV结构蛋白的作用、细胞因子的产生、神经肽水平、RSV特异性抗体的产生，特别是IgE的产生，并在T细胞水平上识别不同年龄的急性RSV如何影响T辅助细胞的分化。基于这些信息，我们将确定这些因素如何指导后续对再次感染或过敏原的反应。提出的方法得到了广泛的初步数据的支持，所有分子和细胞技术、试剂和突变小鼠品系的可用性，以及监测出生不到一周的小鼠的感染和肺功能的能力。这些研究产生的信息将描绘出年龄对肺部免疫/炎症反应的重要影响，并揭示治疗干预的新选择，以防止婴儿时期RSV感染的长期后遗症。

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.