Fungal Asthma and Lung Innate Immunity

摘要： 长期以来，环境霉菌（真菌）暴露被认为是哮喘和哮喘的关键危险因素 加重真菌致敏的患病率在哮喘患者中可高达48%， 常常管理不善，经常恶化和住院。努力减少室内真菌 在最近的HEAL研究中，已经证明通过清洁进行暴露是不可能的。然而，一个普通人 每天暴露在大量的真菌孢子中，在 真菌季节，没有可检测到的呼吸系统异常，并不是所有的人与真菌致敏 患上哮喘因此，了解这种弹性的机制基础以维持气道 尽管真菌产生的大量致喘物质的影响，有趣的是，IFN 在使用活链格孢属孢子的真菌哮喘模型中发现了这些特征。发现上皮细胞 通过触发IFN-I/III的产生以及它们的下游信号级联来感知真菌孢子。IFN-I 受体阻断或缺乏可增强哮喘表型，提示IFN-Ⅰ对哮喘的保护作用。 哮喘因此，我们的总体假设是真菌孢子感应激活了保护性IFN-Ⅰ/Ⅲ途径， 这种保护的损害导致哮喘。为了验证这一假设，我们将阐明 使用一组基因敲除小鼠在真菌哮喘模型中IFN-Ⅰ/Ⅲ的表达。然后，我们将确定 真菌检测和先天防御的基础。最后，重要的是，我们将在临床上检查IFN信号。 通过利用NIH的数据集和样本， 支持哮喘研究计划。这份提案的完成将增进我们对 真菌哮喘的发病机制，并为进一步开发治疗方法奠定基础 哮喘的类型

Abstract: Environmental mold (fungal) exposure has long been recognized as a critical risk factor for asthma and asthma exacerbation. The prevalence of fungal sensitization can be up to 48% in asthmatics and fungal asthma is oftentimes poorly managed with frequent exacerbations and hospitalizations. Efforts to reduce indoor fungal exposure by cleaning have been proven impossible in the recent HEAL study. However, an average person exposing to a large number of fungal spores each day, up to 50,000 spores per cubic meter of air during the fungal season, has no detectable respiratory abnormality and not all individuals with fungal sensitization develop asthma. Thus, it is significant to understand the mechanistic basis of this resilience to maintain airway homeostasis despite the impact of abundant asthmagenic substances produced by fungi. Interestingly, IFN signatures were discovered in the fungal asthma model using live Alternaria spores. Epithelial cells were found to sense fungal spores by triggering IFN-I/III production as well as their downstream signaling cascades. IFN-I receptor blockade or deficiency augmented asthmatic phenotypes, suggesting a protective role of IFN-I against asthma. Thus, our overall hypothesis is that fungal spore sensing activates protective IFN-I/III pathway and the impairment of this protection leads to asthma. To test this hypothesis, we will elucidate the protective function of IFN-I/III in the fungal asthma model using a set of knockout mice. Then, we will determine the mechanistic basis of fungal detection and innate defense. Finally yet importantly, we will examine IFN signatures in clinical samples from human asthma with or without fungal sensitization by utilizing datasets and samples from a NIH- supported Asthma Research Program. The completion of this proposal will advance our knowledge about the pathogenesis of fungal asthma, and establish a foundation for the further therapeutic development to treat this type of asthma.