Defining the importance of IL-25 in rhinovirus-induced asthma exacerbations

哮喘是最常见的呼吸系统疾病，近几十年来有所增加，在许多欧洲国家，约30%的儿童在过去一年报告有喘息。鼻病毒(RV)感染是成人和儿童急性加重的主要个体原因。尽管存在巨大的相关疾病，但目前的治疗方法都是无效的，轮状病毒引起的哮喘恶化的机制也鲜为人知。哮喘患者的肺部会产生一种名为IL-25的分子，这种分子可能会导致病情恶化。我们的目标是了解IL-25在轮状病毒感染和哮喘恶化的免疫反应中的作用，并确定该分子是否适合开发更好的治疗方法。为了确定IL-25是否与调节哮喘加重程度的免疫反应有关，我们开发了一个人类实验性轮状病毒诱导的哮喘恶化模型。这项研究的临床样本将使我们能够调查IL-25表达和导致哮喘加重的宿主反应之间的联系。为了支持人类研究，我们最近开发了世界上第一个鼻病毒感染和哮喘恶化的小鼠模型，展示了许多与哮喘相关的结果，这些结果因小鼠感染而加剧。这些鼻病毒感染和哮喘加重的小鼠模型将使在哺乳动物呼吸道内的研究能够确定IL-25在疾病中的因果作用。因此，这项建议的目的是利用人和鼻病毒诱导的哮喘加重模型来确定IL-25在免疫反应和呼吸道疾病中的作用，这是开发更好的哮喘加重治疗方法的基础研究。

Asthma is the most common respiratory disease and has increased over recent decades, such that in many European countries ~30% of children now report wheeze in the last year. Rhinovirus (RV) infection is the dominant individual cause of acute exacerbations in both adults and children. Despite the enormous associated illness current therapies are ineffective and the mechanisms of RV induced asthma exacerbations are poorly understood. Asthmatics produce a molecule in their lungs, IL-25, that is potentially important in causing exacerbations. We aim to understand the role of IL-25 in immune responses to RV infections and asthma exacerbations and determine if this molecule is a suitable candidate for development of better treatments. To determine if IL-25 is associated with immune responses that regulate exacerbation severity we have developed a human experimental RV-induced asthma exacerbation model. Clinical samples from this study will enable us to investigate the association between IL-25 expression and host responses that cause asthma exacerbations. To support human studies we have recently developed the world?s first mouse models of rhinovirus infection and exacerbation of asthma demonstrating numerous asthma related outcomes exacerbated by infection in the mouse. These mouse models of rhinovirus infection and asthma exacerbation will enable investigation within the mammalian airway to establish a causal role in disease for IL-25. The objective of this proposal is therefore to utilize human and models of rhinovirus-induced asthma exacerbation to define a role for IL-25 in the immune response and airways disease, research fundamental to the development of better treatments for asthma exacerbations.