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Identification of Pathways and Targets in Post-influenza Invasive Pulmonary Aspergillosis

流感后侵袭性肺曲霉病的途径和靶标的确定

基本信息

批准号：
10224339
负责人：
Keven Mara Robinson
金额：
$ 6.81万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224339
关键词：
Affect Allergic Bronchopulmonary Aspergillosis Antiviral Agents Architecture Aspergillosis Aspergillus Aspergillus fumigatus Bacterial Pneumonia Cell physiology Cells Cellular Assay Cessation of life Clinical Critical Illness DNA Sequencing Facility Data Development Disease Future Genes Genomics Goals Health Hematopoietic Stem Cell Transplantation Heterogeneity Host Defense Human Immune Immune Targeting Immune response Immune system Immunocompromised Host Individual Infection Inflammation Influenza Influenza A virus Inhalation Inherited Interferons Invaded Investigation Knowledge Laboratories Learning Leukocytes Life Lung Lung Transplantation Lung infections Maps Methods Modeling Molecular Morbidity - disease rate Mus Mycoses Neutropenia PTPRC gene Pathway interactions Patients Play Population Predisposition Preparation Regulator Genes Reproduction spores Research Research Project Grants Research Support Resolution Respiratory System Respiratory Tract Infections Risk Risk Factors Sampling Secondary to Signal Pathway Signal Transduction Structure of parenchyma of lung Therapeutic Intervention Universities acquired immunodeficiency base cell type experience experimental study fungus inflammatory milieu influenza epidemic influenza infection mortality mouse model novel therapeutic intervention pathogenic fungus prevent respiratory response single cell sequencing single-cell RNA sequencing superinfection transcriptome transcriptomics

项目摘要

PROJECT SUMMARY Fungal pathogens are a serious threat to human health. Invasive pulmonary aspergillosis (IPA) is a severe, life- threatening disease that occurs when Aspergillus fumigatus (AF) spores are inhaled into the respiratory tract and invade airway or lung tissue. More than 200,000 cases of invasive aspergillosis occur each year. A newly identified risk factor for IPA in critically ill patients is influenza infection. Influenza is a common respiratory illness that affects 5-20% of the population each year. Our long-term goal is to develop novel therapeutic interventions for use in clinical settings to prevent morbidity and mortality from IPA. The focus of this application is to identify cell signaling pathways that increase susceptibility to invasive fungal disease following influenza infection. We hypothesize that preceding influenza A infection inhibits leukocyte responses against secondary Aspergillus fumigatus infection through the induction of IFN, leading to invasive pulmonary aspergillosis. Our research aims include 1) To characterize the gene regulatory architecture of leukocytes at a single cell resolution during post- influenza invasive pulmonary aspergillosis. We will perform single cell RNA sequencing on CD45+ immune cells collected from lung tissue from (1) wild-type and (2) IFN -/- mice infected with aspergillus, influenza, and super- infected with influenza followed by aspergillus.

项目概要真菌病原体严重威胁人类健康。侵袭性肺曲霉病（IPA）是一种严重的、危及生命的疾病。当烟曲霉 (AF) 孢子被吸入呼吸道时发生的威胁性疾病并侵入气道或肺组织。每年发生超过 20 万例侵袭性曲霉菌病。一个新的已确定重症患者发生 IPA 的危险因素是流感感染。流感是一种常见的呼吸道疾病每年影响 5-20% 的人口。我们的长期目标是开发新的治疗干预措施用于临床环境中预防 IPA 的发病率和死亡率。该应用程序的重点是识别流感感染后增加对侵袭性真菌病易感性的细胞信号传导途径。我们假设先前的甲型流感感染抑制白细胞针对继发曲霉的反应烟曲菌感染通过诱导 IFNα 产生，导致侵袭性肺曲霉病。我们的研究目标包括 1) 以单细胞分辨率表征白细胞的基因调控结构。流感侵袭性肺曲霉菌病。我们将对CD45+免疫细胞进行单细胞RNA测序从 (1) 野生型和 (2) IFN-/- 感染曲霉、流感和超级小鼠的肺组织中收集感染流感，随后感染曲霉菌。