Regulation of Il-17A Expression with RSV Infection During Allergic Inflammation

描述(申请人提供)：这项提案的长期目标是确定呼吸道合胞病毒(RSV)感染导致持续过敏性肺部炎症的小鼠肺IL-17A表达的相关机制。病毒感染引发了大多数急性哮喘症状，呼吸道合胞病毒是哮喘恶化的重要原因，特别是在儿童和老年人中。这些由病毒引起的哮喘恶化大多发生在有呼吸道过敏性炎症的患者中，但病毒感染导致哮喘症状和肺功能下降的确切机制在很大程度上仍不清楚。与仅用卵蛋白(OVA)致敏和激发的BALB/c小鼠或仅感染RSV(RSV)的小鼠相比，在卵蛋白诱导的变态反应性炎症(OVA/RSV)期间感染RSV的小鼠具有显著的气道高反应性(AHR)和气道粘液表达增加。OVA/RSV小鼠AHR和呼吸道粘液的协同增加与肺IL-17A蛋白表达的增加密切相关，而OVA小鼠和RSV小鼠中IL-17A的表达可以忽略不计。在特定的目标1中，我们将确定在RSV感染和卵蛋白诱导的肺部变应性炎症的背景下，负责的T细胞群和增加肺IL-17A产生所必需的细胞因子背景。我们将在特定的目标1中测试这一点，方法是确定负责肺IL-17A表达的T细胞的抗原特异性性质，以及OVA/RSV诱导的肺IL-17A产生所必需的Th2炎症成分。在特定的目标2中，我们将确定特定的树突状细胞亚群及其在肺部IL-17A表达中的作用，在呼吸道合胞病毒感染的持续过敏性呼吸道炎症过程中。具体地说，我们将确定血浆细胞样树突状细胞的耗尽是否会导致OVA/RSV诱导的肺内IL-17A产生增加。此外，我们还将确定血浆细胞样树突状细胞或髓系树突状细胞的过敏性抗原提呈以及随后的抗原攻击对RSV诱导的肺IL-17A表达的影响。明确过敏背景下RSV感染诱导肺IL-17A产生的机制可能为减少RSV诱导的哮喘恶化提供潜在的治疗靶点。

DESCRIPTION (provided by applicant): The long term objective of this proposal is to define the mechanisms involved in lung IL-17A expression that result from respiratory syncytial virus (RSV) infection of mice that have ongoing allergic lung inflammation. Viral infections trigger the majority of acute asthma symptoms and RSV is an important cause of asthma exacerbations, particularly in children and the elderly. Most of these virus-induced asthma exacerbations occur in patients with airway allergic inflammation, but the exact mechanisms by which viral infection results in asthma symptoms and decline in lung function remain largely unknown. Compared to BALB/c mice that are allergically-sensitized and challenged with ovalbumin alone (OVA), or mice that are infected with RSV alone (RSV), mice that are RSV-infected during ongoing ovalbumin-induced allergic inflammation (OVA/RSV) have significant airway hyperresponsiveness (AHR) and augmented airway mucus expression. This synergistic increase in AHR and airway mucus present in OVA/RSV mice is strongly associated with increased expression of lung IL-17A protein, whereas there is negligible IL-17A in OVA mice and none in RSV mice. In Specific Aim 1, we will determine the responsible T cell population and the cytokine background necessary for increased lung IL-17A production in the setting of RSV infection and ovalbumin-induced pulmonary allergic inflammation. We will test this in Specific Aim 1 by determining the antigen-specific nature of the T cells responsible for lung IL-17A expression and the component of Th2 inflammation necessary for the OVA/RSV-induced lung IL-17A production. In Specific Aim 2, we will determine the role of specific dendritic cell subsets and their function in lung IL-17A expression in the setting of RSV infection during ongoing allergic airway inflammation. Specifically, we will determine if depletion of plasmacytoid dendritic cells results in an increase in OVA/RSV-induced IL-17A production in the lung. In addition, we will determine the effect of allergic antigen presentation by either plasmacytoid or myeloid dendritic cells and subsequent antigen challenge on RSV-induced lung IL-17A expression. Defining the mechanisms by which RSV-infection on an allergic background induces lung IL-17A production may provide potential therapeutic targets for reducing RSV-induced asthma exacerbations.