Influenza Attenuates Innate Pulmonary Host Defense against Invasive Pulmonary Aspergillosis

流感削弱肺宿主对侵袭性肺曲霉病的先天防御

基本信息

批准号：
10651832
负责人：
Keven Mara Robinson
金额：
$ 51.24万
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：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651832
关键词：
Adhesions Affect Allergic Bronchopulmonary Aspergillosis Alveolar Macrophages Aspergillosis Aspergillus Aspergillus fumigatus Attenuated Bacterial Pneumonia Blood C Type Lectin Receptors CXCL1 gene Cell Adhesion Cells Clinical Critical Illness Data Dendritic Cells Development Disease Effector Cell Endothelium Exposure to Future Germination Goals Health Hematopoietic Stem Cell Transplantation Host Defense Human Hyphae IL17 gene ITGAX gene Immune Immune response Immune system Immunity Immunocompromised Host Immunology Infection Inflammation Mediators Influenza Influenza A virus Inhalation Inherited Innate Immune System Integration Host Factors Interferons Invaded Knowledge Life Lung Lung Transplantation Lung infections Macrophage Measures Modeling Molecular Morbidity - disease rate Mus Mycoses Natural Immunity Neutropenia Neutrophil Infiltration Organ Pathogenesis Patients Phagocytosis Phenotype Population Predisposition Production Reproduction spores Research Research Project Grants Respiratory Burst Respiratory System Respiratory Tract Infections Risk Risk Factors Role STAT1 gene Scientific Advances and Accomplishments Secondary to Signal Pathway Signal Transduction Structure of parenchyma of lung T-Lymphocyte Therapeutic Intervention Tissue-Specific Gene Expression Work acquired immunodeficiency attenuation chemokine cytokine fungus in vivo influenza infection insight intravital microscopy migration mortality neutrophil novel therapeutic intervention pathogen pathogenic fungus patient population prevent receptor recruit respiratory response superinfection trafficking

Adhesions Affect Allergic Bronchopulmonary Aspergillosis Alveolar Macrophages Aspergillosis Aspergillus Aspergillus fumigatus Attenuated Bacterial Pneumonia Blood C Type Lectin Receptors CXCL1 gene Cell Adhesion Cells Clinical Critical Illness Data Dendritic Cells Development Disease Effector Cell Endothelium Exposure to Future Germination Goals Health Hematopoietic Stem Cell Transplantation Host Defense Human Hyphae IL17 gene ITGAX gene Immune Immune response Immune system Immunity Immunocompromised Host Immunology Infection Inflammation Mediators Influenza Influenza A virus Inhalation Inherited Innate Immune System Integration Host Factors Interferons Invaded Knowledge Life Lung Lung Transplantation Lung infections Macrophage Measures Modeling Molecular Morbidity - disease rate Mus Mycoses Natural Immunity Neutropenia Neutrophil Infiltration Organ Pathogenesis Patients Phagocytosis Phenotype Population Predisposition Production Reproduction spores Research Research Project Grants Respiratory Burst Respiratory System Respiratory Tract Infections Risk Risk Factors Role STAT1 gene Scientific Advances and Accomplishments Secondary to Signal Pathway Signal Transduction Structure of parenchyma of lung T-Lymphocyte Therapeutic Intervention Tissue-Specific Gene Expression Work acquired immunodeficiency attenuation chemokine cytokine fungus in vivo influenza infection insight intravital microscopy migration mortality neutrophil novel therapeutic intervention pathogen pathogenic fungus patient population prevent receptor recruit respiratory response superinfection trafficking

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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. Our preliminary data support that preceding influenza inhibits neutrophil recruitment to the lung, in contrast to post- bacterial pneumonia, and neutropenia is a key risk factor for the development of IPA. Additionally, preceding influenza inhibits neutrophil function against secondary AF infection. Furthermore, our preliminary data demonstrate that the pathogen recognition receptor, CD209a, is decreased in post-influenza IPA, suggesting that preceding influenza may inhibit fungal-sensing. Based on our preliminary data, we hypothesize that preceding influenza A infection limits innate immunity and increases susceptibility to invasive pulmonary aspergillosis by inhibiting CD209a and reducing the host response to secondary Aspergillus fumigatus infection in the lung, including neutrophil recruitment and function. Our research aims include 1) Determine whether neutrophil recruitment and effector functions are inhibited in post-influenza IPA, and 2) Determine whether suppression of CD209a-dependent AF sensing promotes post-influenza IPA. The proposed studies will increase our understanding of how influenza inhibits neutrophil migration to and function within the lung in response to subsequent AF infection (Aim1) and how the immune response to AF is initiated in the lung (Aim 2).

项目摘要真菌病原体是对人类健康的严重威胁。侵入性肺曲霉菌病（IPA）是一种严重的生活 - 当曲霉（AF）孢子被吸入呼吸道时，发生威胁性疾病并入侵气道或肺组织。每年发生超过200,000例侵入性曲霉病。一个新的危重患者中IPA的鉴定危险因素是流感感染。流感是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颖的治疗干预措施用于在临床环境中使用以防止IPA发病和死亡率。该应用程序的重点是确定流感感染后增加对浸润性真菌疾病的敏感性的细胞信号通路。我们的在流感之前的初步数据支持抑制肺中性粒细胞的募集，与后细菌性肺炎和中性粒细胞减少是IPA发展的关键危险因素。另外，在之前流感抑制嗜中性粒细胞功能对继发AF感染。此外，我们的初步数据证明病原体识别受体CD209A在IMFLUENZA IPA中降低，表明先前的流感可能会抑制真菌感应。根据我们的初步数据，我们假设先前的流感A感染限制了先天免疫力，并增加了侵入性肺的敏感性曲霉病通过抑制CD209A并减少对辅助曲霉感染的宿主反应在肺中，包括中性粒细胞的募集和功能。我们的研究目的包括1）确定是否中性粒细胞募集和效应子功能受到IMFLUENZA IPA的抑制，2）确定是否确定是否是否 CD209A依赖性AF感应的抑制会促进INFLUENZA IPA。拟议的研究将增加我们对流感如何抑制嗜中性粒细胞迁移到肺部内部并起作用的理解随后的AF感染（AIM1）以及如何在肺中启动对AF的免疫反应（AIM 2）。