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

• 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
• 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

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。我们的 初步数据支持，流感之前会抑制中性粒细胞向肺部的募集，而流感之后则相反。 细菌性肺炎和中性粒细胞减少症是发生 IPA 的关键危险因素。另外，前面的 流感抑制中性粒细胞抵抗继发性房颤感染的功能。此外，我们的初步数据 证明病原体识别受体 CD209a 在流感后 IPA 中减少，表明 之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 甲型流感之前的感染限制了先天免疫并增加了对侵袭性肺部感染的易感性 通过抑制 CD209a 并减少宿主对继发烟曲霉感染的反应来抑制曲霉菌病 在肺部，包括中性粒细胞的募集和功能。我们的研究目标包括 1) 确定是否 中性粒细胞募集和效应子功能在流感后 IPA 中受到抑制，2) 确定是否 抑制 CD209a 依赖性 AF 感应可促进流感后 IPA。拟议的研究将增加 我们对流感如何抑制中性粒细胞迁移至肺并在肺内发挥作用的理解 随后的 AF 感染（目标 1）以及肺部如何启动对 AF 的免疫反应（目标 2）。