Fungal Asthma and Lung Innate Immunity

摘要： 长期以来，环境霉菌(真菌)暴露一直被认为是哮喘和哮喘的关键危险因素 病情恶化。在哮喘患者中，真菌致敏的患病率可高达48%，而真菌哮喘 往往管理不善，病情恶化和住院治疗频繁。努力减少室内真菌 在最近的Hear研究中，通过清洁暴露已被证明是不可能的。然而，一个普通人 每天暴露在大量真菌孢子中，每立方米空气中高达5万个孢子 真菌季节，没有可检测到的呼吸异常，也不是所有有真菌过敏的人 患上哮喘。因此，了解这种弹性维持呼吸道的机制基础具有重要意义。 尽管受到真菌产生的大量致哮喘物质的影响，但体内仍保持稳定。有趣的是，干扰素 在使用链格孢菌活孢子的真菌哮喘模型中发现了特征。发现了上皮细胞。 通过触发干扰素-I/III的产生及其下游信号级联来感应真菌孢子。干扰素-I 受体阻断或缺乏增加哮喘表型，提示干扰素-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的干扰素-I/III途径，而 这种保护功能的受损会导致哮喘。为了验证这一假设，我们将阐明保护功能 使用一组基因敲除小鼠在真菌性哮喘模型中检测干扰素-I/III。然后，我们将确定机械的 真菌检测和天然防御的基础。最后，同样重要的是，我们将检查临床上的干扰素信号。 利用来自美国国立卫生研究院的数据集和样本，对有或没有真菌致敏的人类哮喘样本进行研究- 支持哮喘研究计划。这项建议的完成将促进我们对 探讨真菌性哮喘的发病机制，为进一步开发治疗该病的药物奠定了基础 哮喘类型。

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.