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).

项目摘要 真菌病原体严重威胁人类健康。侵袭性肺曲霉菌病（IPA）是一种严重的、终身的- 当烟曲霉（AF）孢子被吸入呼吸道时发生的一种威胁性疾病 侵入气道或肺组织。每年有超过20万例侵袭性曲霉病发生。一个新 在危重患者中，IPA的确定风险因素是流感感染。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，以预防IPA的发病率和死亡率。该应用程序的重点是识别 细胞信号通路，增加流感感染后对侵袭性真菌疾病的易感性。我们 初步数据支持，与流感后相比，流感前抑制中性粒细胞向肺的募集。 细菌性肺炎和中性粒细胞减少症是IPA发展的关键风险因素。此外，此前 流感抑制中性粒细胞对继发性AF感染的功能。此外，我们的初步数据显示， 证明病原体识别受体CD 209 a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， 先前的甲型流感感染限制了先天免疫，增加了对侵袭性肺疾病的易感性。 通过抑制CD 209 a和降低宿主对继发性烟曲霉感染的反应来治疗曲霉病 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，以及2）确定是否 抑制CD 209 a依赖性AF感知促进流感后IPA。建议的研究将增加 我们对流感如何抑制中性粒细胞迁移到肺内并在肺内发挥功能的理解， 随后的AF感染（Aim 1）以及对AF的免疫应答如何在肺中启动（Aim 2）。