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

描述（由申请方提供）：本提案的长期目标是确定肺部IL-17 A表达所涉及的机制，该机制由呼吸道合胞病毒（RSV）感染持续过敏性肺部炎症的小鼠引起。病毒感染引发大多数急性哮喘症状，RSV是哮喘恶化的重要原因，特别是在儿童和老年人中。这些病毒诱导的哮喘急性发作大多发生在气道过敏性炎症患者中，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然未知。与过敏性致敏并单独用卵清蛋白（OVA）攻击的BALB/c小鼠或单独用RSV（RSV）感染的小鼠相比，在进行中的卵清蛋白诱导的过敏性炎症（OVA/RSV）期间被RSV感染的小鼠具有显著的气道高反应性（AHR）和增强的气道粘液表达。存在于OVA/RSV小鼠中的AHR和气道粘液的这种协同增加与肺IL-17 A蛋白表达的增加强烈相关，而在OVA小鼠中存在可忽略的IL-17 A，而在RSV小鼠中没有。在特定目标1中，我们将确定在RSV感染和卵清蛋白诱导的肺过敏性炎症的情况下增加肺IL-17 A产生所需的负责T细胞群和细胞因子背景。我们将通过确定负责肺IL-17 A表达的T细胞的抗原特异性性质和OVA/RSV诱导的肺IL-17 A产生所需的Th 2炎症组分来在特异性目标1中对此进行测试。在特定目标2中，我们将确定特定树突状细胞亚群的作用及其在持续过敏性气道炎症期间RSV感染背景下肺IL-17 A表达中的功能。具体来说，我们将确定是否耗尽浆细胞样树突状细胞的结果在OVA/RSV诱导的IL-17 A的生产在肺中的增加。此外，我们将确定过敏性抗原呈递的影响，无论是浆细胞或髓样树突状细胞和随后的抗原攻击RSV诱导的肺IL-17 A的表达。明确过敏背景下RSV感染诱导肺IL-17 A产生的机制可能为减少RSV诱导的哮喘急性发作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.