Aspergillus fumigatus infection and fibrosis

烟曲霉菌是一种环境霉菌，可导致一种危及生命的肺炎。 称为侵袭性曲霉病。感染从吸入分生孢子(孢子)进入肺部开始。在一个 健康的个体，孢子被免疫系统清除。然而，在免疫抑制的情况下 人群或ICU中的患者，如果不能根除真菌，就会使孢子萌发。烟曲霉菌 随着它的生长，会释放一种降解酶，导致对肺的严重损害 薄壁组织。成纤维细胞是对组织损伤做出反应的主要细胞类型之一。作为对受伤的回应， 这些细胞分化为激活状态，这是稳定组织和促进修复所必需的。 然而，成纤维细胞的活性并不局限于基质分泌；新的证据表明，它们也 具有检测微生物病原体并通过分泌具有潜在能力的介体作出反应的能力 有助于清除病原体。在这笔赠款中，我们建议利用独特的遗传小鼠模型 我们开发的目的是确定肺成纤维细胞对烟曲霉转归的贡献 曝光。我们假设成纤维细胞激活对烟曲霉菌引起的肺损伤的反应放大。 一种保护性炎症反应。拟议的AIMS将通过确定 免疫活性和成纤维细胞对烟曲霉菌的激活和失活 免疫抑制小鼠，成纤维细胞对烟曲霉菌暴露的转录反应，以及 成纤维细胞在小鼠成纤维细胞消融模型致病结局中的作用。这项研究的发现 研究将提供关于寄主对烟曲霉菌和其他潜在寄主的防御机制的新信息。 破坏人类肺部的病原体。 1

Aspergillus fumigatus is an environmental mold that is responsible for a life-threatening pneumonia known as invasive aspergillosis. The infection begins with the inhalation of conidia (spores) into the lung. In a healthy individual, the spores are cleared by the immune system. However, in the immunosuppressed population, or patients in the ICU, failure to eradicate the fungus allows the spores to germinate. A. fumigatus releases an armamentarium of degradative enzymes as it grows, resulting in severe damage to the lung parenchyma. Fibroblasts are one of the major cell types that respond to tissue damage. In response to injury, these cells differentiate into an activated state, which is required to stabilize the tissue and promote repair. However, fibroblast activity is not restricted to matrix secretion; emerging evidence suggests that they also possess the ability to detect microbial pathogens and to respond by secreting mediators with the potential to contribute to pathogen clearance. In this grant, we propose to take advantage of unique genetic mouse models that we have developed to determine the contribution of pulmonary fibroblasts to the outcome of A. fumigatus exposure. We hypothesize that fibroblast activation in response to A. fumigatus-induced lung damage amplifies a protective inflammatory response. The proposed aims will test this hypothesis by determining the dynamics of fibroblast activation and deactivation in response to A. fumigatus in both immunocompetent and immunosuppressed mice, the transcriptional response of fibroblasts to A. fumigatus exposure, and the contribution of fibroblasts to pathogenic outcome in a mouse model of fibroblast ablation. The findings of this study will provide new information on mechanisms of host defense against A. fumigatus and potentially other pathogens that damage the human lung. 1