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

曲霉富马图斯是一种环境模具，负责威胁生命的肺炎被称为侵入性曲霉菌病。感染始于将分生孢子（孢子）吸入到肺中。在健康的个体，孢子被免疫系统清除。但是，在免疫抑制人口或ICU中的患者未能消除真菌使孢子发芽。 A.富马图斯随着降解酶的生长，会释放出降解酶的武器库，从而严重损害实质。成纤维细胞是应对组织损伤的主要细胞类型之一。响应伤害，这些细胞分化为活化状态，这是稳定组织并促进修复所必需的。但是，成纤维细胞活性不仅限于基质分泌。新兴证据表明他们也具有检测微生物病原体的能力，并通过分泌介体的作用有助于病原体清除。在这笔赠款中，我们建议利用独特的遗传小鼠模型我们已经开发出来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激活对烟曲霉诱导的肺损伤有所扩增保护性炎症反应。提出的目标将通过确定的动态来检验这一假设在免疫能力和免疫抑制的小鼠，成纤维细胞对烟曲霉的转录反应，以及成纤维细胞消融小鼠模型中成纤维细胞对致病结果的贡献。这个发现研究将提供有关宿主防御机制针对烟曲霉的机制以及其他潜在的其他信息损害人肺的病原体。 1