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

项目总结 真菌病原体是对人类健康的严重威胁。侵袭性肺曲霉病(IPA)是一种严重的生命- 当烟曲霉(AF)孢子吸入呼吸道时发生的一种危险的疾病 并侵入呼吸道或肺组织。每年发生的侵袭性曲霉病病例超过20万例。一个新的 已确定的危重患者IPA的危险因素是流感感染。流感是一种常见的呼吸道疾病。 这每年影响5%-20%的人口。我们的长期目标是开发新的治疗干预措施 在临床环境中使用，以防止IPA的发病率和死亡率。这个应用程序的重点是识别 增加流感感染后侵袭性真菌疾病易感性的细胞信号通路。我们 假设之前的甲型流感感染抑制了白细胞对继发性曲霉的反应 烟曲霉菌通过诱导干扰素感染，导致侵袭性肺曲霉菌病。我们的研究目的是 包括1)描述在单个细胞分辨率下的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 收集自(1)野生型和(2)干扰素-/-小鼠的肺组织，这些小鼠感染曲霉、流感和超级 感染了流感，随后又感染了曲霉。

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.