The Role of IL-17 in RSV-induced Mucus and Airway Responsiveness

描述（由申请方提供）：病毒感染与大多数儿童和成人哮喘急性发作相关。在这种情况下，病毒诱导的哮喘急性发作最常发生在潜在的肺部过敏性炎症的情况下。呼吸道合胞病毒（RSV）感染可导致儿童和成人大量哮喘急性发作;然而，RSV感染导致哮喘症状恶化和肺功能下降的机制尚未完全确定。我们的初步数据表明，白细胞介素（IL）-17 A是RSV诱导的气道反应性（AR）和粘液表达的关键调节因子。在小鼠模型中，我们发现，与过敏性炎症期间未用RSV激发的小鼠相比，过敏性肺病背景下的RSV激发导致AR增加和气道粘液表达增强。在存在过敏性炎症的情况下接受RSV攻击的小鼠中AR和粘液表达的增加与IL-13的肺表达无关，IL-13是一种细胞因子，被认为是AR和气道粘液表达的中枢调节因子，但相反与肺IL-17 A表达的显著增加相关。相比之下，在不存在过敏性肺部炎症的情况下，RSV激发不会导致AR、粘液表达或可检测的IL-17 A水平。在这个提议中，我们假设过敏性炎症和RSV攻击联合产生的IL-17 A介导RSV诱导的AR和气道粘液增强。该提案的长期目标是：1）充分定义IL-17 A在持续过敏性气道炎症期间发生RSV攻击时导致的AR和气道粘液表达升高中的作用，以及2）定义持续过敏性炎症产生的前列腺素E2（PGE 2）在RSV诱导的肺IL-23表达中的作用。IL-23是由树突状细胞产生的细胞因子，其对于产生IL-17 A的T细胞（现在称为Th 17细胞）的扩增和维持至关重要。确定IL-17 A在病毒介导的AR和粘液诱导的免疫生物学中的作用可能会导致药物开发的新靶点。

DESCRIPTION (provided by applicant): Viral infections are associated with a majority of asthma exacerbations in both children and adults. In such instances, virally-induced asthma exacerbations most often occur in the setting of underlying pulmonary allergic inflammation. Respiratory syncytial virus (RSV) infections cause a significant number of asthma exacerbations in both children and adults; however, the mechanisms by which RSV infection leads to worsening of asthma symptoms and decreased lung function are not fully defined. Our preliminary data suggests that interleukin (IL)-17A is a critical regulator of RSV-induced airway responsiveness (AR) and mucus expression. In a mouse model, we found that RSV challenge in the setting of allergic lung disease resulted in increased AR and augmented airway mucus expression, compared to mice that were not challenged with RSV during allergic inflammation. The heightened AR and mucus expression in the mice that were RSV-challenged in the presence of allergic inflammation did not correlate with the lung expression of IL-13, a cytokine that is proposed to be central regulator of AR and airway mucus expression, but instead was associated with significantly increased lung IL-17A expression. In contrast, RSV challenge in the absence of allergic lung inflammation did not result in AR, mucus expression, or detectable IL-17A levels. In this proposal, we hypothesize that IL-17A produced by the combination of allergic inflammation and RSV challenge mediates RSV-induced augmented AR and airway mucus. The long-term goals of this proposal are to: 1) fully define the role of IL-17A in the heightened AR and airway mucus expression that results when RSV challenge occurs during ongoing allergic airway inflammation, and 2) define the role of prostaglandin E2 (PGE2) produced by ongoing allergic inflammation in RSV-induced lung IL-23 expression. IL-23 is a cytokine made by dendritic cells which is critical to the expansion and maintenance of IL-17A producing T cells, now known as Th17 cells. Defining the role of IL-17A in the immunobiology of virally-mediated AR and mucus induction may result in novel targets for drug development.