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

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 假设先前的甲型流感感染抑制白细胞对继发曲霉菌的应答 烟曲霉感染通过IFN γ的诱导，导致侵袭性肺曲霉病。我们的研究旨在 包括：1）在后处理期间，以单细胞分辨率表征白细胞的基因调控结构。 流行性感冒侵袭性肺曲霉病。我们将对CD 45+免疫细胞进行单细胞RNA测序 从（1）野生型和（2）IFN γ-/-小鼠的肺组织中收集，所述小鼠感染曲霉菌、流感病毒和超级 感染了流感接着是曲霉菌病

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.