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

描述(申请人提供)：病毒感染与大多数儿童和成人的哮喘恶化有关。在这种情况下，病毒引起的哮喘恶化最常发生在潜在的肺部过敏性炎症的环境中。呼吸道合胞病毒(RSV)感染导致大量儿童和成人哮喘加重；然而，RSV感染导致哮喘症状恶化和肺功能下降的机制尚不完全清楚。我们的初步数据表明，白介素17A是呼吸道合胞病毒诱导的呼吸道反应性(AR)和粘液表达的关键调节因子。在一个小鼠模型中，我们发现在过敏性肺部疾病的背景下，与在过敏性炎症期间没有受到RSV攻击的小鼠相比，RSV攻击导致AR增加和呼吸道粘液表达增加。在存在过敏性炎症的情况下，RSV攻击小鼠的AR和粘液表达增加与肺IL-13的表达无关，IL-13是一种被认为是AR和呼吸道粘液表达的中枢调节因子，相反，它与肺IL-17A的表达显著增加有关。相反，在没有过敏性肺部炎症的情况下，RSV攻击不会导致AR、粘液表达或可检测到的IL-17A水平。在这项建议中，我们假设由过敏性炎症和RSV攻击相结合产生的IL-17A介导了RSV诱导的AR和呼吸道粘液的增加。这项建议的长期目标是：1)充分确定IL-17A在RSV攻击持续过敏性呼吸道炎症期间引起的AR和呼吸道粘液表达增加中的作用，以及2)确定持续变态反应性炎症产生的前列腺素E2(PGE2)在RSV诱导的肺IL-23表达中的作用。IL-23是一种由树突状细胞产生的细胞因子，对产生IL-17A的T细胞(现在称为Th17细胞)的扩增和维持至关重要。明确IL-17A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.