Aspergillus fumigatus infection and fibrosis

烟曲霉感染和纤维化

基本信息

批准号：
10685373
负责人：
DAVID S ASKEW
金额：
$ 40.5万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685373
关键词：
Ablation Acute Acute Respiratory Distress Syndrome Affect Allergic Bronchopulmonary Aspergillosis Aspergillosis Aspergillus Aspergillus fumigatus Atmosphere Behavior Biological Models Blood capillaries COVID-19 Cell Differentiation process Chronic Complication Connective Tissue Data Dendritic Cells Development Disease Effectiveness Environment Enzymes Epithelium Exposure to Extracellular Matrix Failure Fibroblasts Fibrosis Foundations Fright Gene Expression Profile Genetic Genetic Models Genetic Transcription Geographic Locations Germination Goals Grant Growth Factor Hematogenous Hematopoietic stem cells Host Defense Host Defense Mechanism Human Hyphae Immune Immune system Immunocompetent Immunosuppression Incidence Individual Infection Inflammatory Inflammatory Response Inhalation Innate Immune System Knowledge Life Light Lung Lung infections Macrophage Mediator Molds Mus Myelogenous Myeloid Cells Opportunistic Infections Organ Transplantation Outcome Outcome Study Pathogenesis Pathogenicity Pathology Patients Pneumonia Population Process Production Pulmonary Fibrosis Pulmonary vessels Reaction Reproduction spores Severities Solid Structural defect Structure of parenchyma of lung Testing Tissues Transplantation cell type cytokine fungus immunological status immunoregulation immunosuppressed improved outcome in vivo interstitial long-term sequelae lung injury lung pathogen mouse genetics mouse model novel novel therapeutic intervention pathogen pathogenic fungus pathogenic microbe repaired respiratory response response to injury treatment strategy

项目摘要

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

烟曲霉是一种环境霉菌，可导致危及生命的肺炎称为侵袭性曲霉菌病。感染始于分生孢子（孢子）吸入肺部。在一个健康个体，孢子会被免疫系统清除。然而，在免疫抑制的情况下人群或 ICU 患者中，如果未能根除真菌，孢子就会发芽。烟曲霉随着其生长，会释放出大量的降解酶，对肺部造成严重损害薄壁组织。成纤维细胞是对组织损伤做出反应的主要细胞类型之一。为了应对受伤的情况，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；新出现的证据表明，他们还具有检测微生物病原体并通过分泌介质做出反应的能力，这些介质具有潜在的有助于病原体清除。在这笔赠款中，我们建议利用独特的基因小鼠模型我们开发的目的是确定肺成纤维细胞对烟曲霉结果的贡献接触。我们假设成纤维细胞活化响应烟曲霉引起的肺损伤，从而放大保护性炎症反应。拟议的目标将通过确定动态来检验这一假设成纤维细胞的激活和失活对免疫活性和烟曲霉的反应免疫抑制小鼠，成纤维细胞对烟曲霉暴露的转录反应，以及成纤维细胞对成纤维细胞消融小鼠模型中致病结果的贡献。本次调查结果研究将提供有关宿主针对烟曲霉和其他潜在的防御机制的新信息损害人类肺部的病原体。 1