Targeting innate lymphoid cells during influenza virus-induced asthma

该项目的长期目标是开发更好的治疗急性流感病毒引起的呼吸道疾病的方法。 疾病和哮喘。流感病毒(NIAID C类病原体)引起的感染是主要的公共 健康问题，导致美国每年约40,000人死亡，20多万人住院， 总成本超过100亿美元/年。2009年的猪流感大流行表明，患有 哮喘与住院相关的严重流感感染的风险特别高。 和死亡。正如数字所反映的那样，目前治疗急性流感引起的呼吸道疾病的方法并不是 完全有效，部分原因是宿主与流感的相互作用导致，以及 流感感染的原因、急性呼吸道疾病和哮喘还没有完全了解。 在特定目标1中，我们将检查针对一种新的先天淋巴样细胞类型的特定干预。 肺，称为天然辅助细胞或有核细胞。我们最近发现，天然的辅助细胞是 特别是在流感感染期间被激活，是流感引起的小鼠哮喘所必需的。我们 将使用一种独特的流感引起的呼吸道炎症和气道高反应性的实验模型 (AHR)(哮喘的一个主要特征)，独立于Th2细胞和适应性免疫发展，以及 这可能反映了人类流感引起的呼吸道疾病和哮喘。响应在以下情况下启动 流感感染肺泡巨噬细胞，导致下垂和IL-33的释放，然后被激活 天然辅助细胞产生IL-13，进而介导急性AHR。我们将通过以下方式来证明这一点 C-Kit激酶抑制剂(伊马替尼或马西替尼)靶向天然辅助细胞，流感诱导的呼吸道 病理学是可以废除的。这种疗法可能比大剂量皮质类固醇有效得多， 常用于流感引起的哮喘患者。 在具体目标2中，我们将进一步细化流感期间针对自然辅助细胞的方法 感染，并检测流感与宿主细胞的相互作用导致IL-33，IL-25， 和TSLP。这三种细胞因子都能有效地激活天然辅助细胞，诱导它们产生IL-13。 这些研究将确定宿主与流感的相互作用以及这个复合体中天然辅助细胞的生物学。 一年前才描述的先天路径。了解这一途径的许多组成部分是 对c-Kit激酶抑制剂如何适应减少天然辅助细胞的这一途径提供关键见解 活跃性和流感诱发的哮喘。这些研究将集中于开发一种治疗急性、 流行性感冒引起的呼吸道疾病和哮喘是严重的、常见的临床问题。这个 拟议的治疗方法将针对一种由流感激活的宿主细胞类型，这是其发病机制所必需的。 此外，对这种疗法的研究将扩大我们对粘膜免疫反应的基本了解。

The long-term goal of this project is to develop better therapies for acute influenza virus-induced respiratory disease and asthma. Influenza virus (an NIAID Category C pathogen) causes infection that is major public health problem, resulting in about 40,000 deaths and more than 200,000 hospitalizations annually in the US, with a total cost of over $10 billion/year. The 2009 swine flu pandemic demonstrated that patients with asthma are at particularly high risk for developing severe influenza infection, associated with hospitalization and death. As the numbers reflect, current therapies for acute influenza-induced respiratory disease are not fully effective, in part because the host-influenza interactions resulting in, and mechanisms by which influenza infection causes, acute respiratory disease and asthma are not fully understood. In Specific Aim 1 we will examine a specific intervention that targets a novel innate lymphoid cell type in the lungs, called natural helper cells or nuocytes. We recently showed that natural helper cells are specifically activated during influenza infection and are required for influenza-induced asthma in mice. We will use a unique experimental model of influenza-induced airway inflammation and airway hyperreactivity (AHR) (a cardinal feature of asthma) that develops independently of Th2 cells and adaptive immunity, and which may reflect human influenza-induced respiratory disease and asthma. The response is initiated when influenza infects alveolar macrophages, leading to pyroptosis and release of IL-33, which then activates natural helper cells to produce IL-13, which in turn mediates acute AHR. We will demonstrate that by targeting natural helper cells with c-Kit kinase inhibitors (imatinib or masitinib), influenza-induced airway pathology can be abolished. Such therapy may be much more effective than high dose corticosteroids, commonly used in patients with influenza-induced asthma. In Specific Aim 2 we will further refine the approach of targeting natural helper cells during influenza infection, and examine the interaction of influenza with host cells resulting in the production of IL-33, IL-25, and TSLP. All three of these cytokines potently activate natural helper cells, inducing them to produce IL-13. These studies will define host-influenza interactions and the biology of natural helper cells in this complex innate pathway, described only one year ago. Understanding the many components of this pathway is critical to provide key insights into how c-Kit kinase inhibitors fit into this pathway to reduce natural helper cell activity and influenza-induced asthma. These studies will focus on developing a novel therapeutic for acute, influenza-induced respiratory disease and asthma, which are serious, common clinical problems. The proposed therapeutic will target a host cell type activated by influenza and required for its pathogenesis. Moreover, study of this therapy will extend our fundamental understanding of mucosal immune responses.