Clinical Phenotyping and Human Core

项目概要核心B 在美国，下呼吸道感染导致近80%的传染病死亡， 病毒，如流感和SARS-CoV-2，越来越多地被认为是严重的常见原因， 社区获得性肺炎（CAP）由于严重CAP的死亡率持续存在， 抗菌治疗和致病病原体的清除，项目研究人员假设 严重病毒性CAP的死亡率和持续性器官衰竭代表持续性炎症损伤， 肺修复机制的失效。持续的炎症和未修复的器官损伤导致长期不良的 严重CAP后的结果，生物标志物表明，严重CAP患者的结果较差， 尽管清除了假定的病原体，但仍具有持续的促炎状态。核心B将允许项目 研究者将验证流感患者中流感肺炎的因果性鼠模型和细胞模型的结果， 病毒性病原体引起的严重CAP。核心B的主要目标是提供连续的支气管肺泡 从具有严重流感和SARS-CoV-2的良好表型的患者获得的灌洗（BAL）样品 根据以下特定目的的定义，向项目研究者提供肺炎：1）提供BAL液 来自流感和SARS-CoV-2肺炎插管患者，用于a）流式细胞术分选的BAL肺泡 用于转录组学和表观基因组学分析免疫细胞亚群，和B）用于 代谢组学和生物标志物/蛋白质分析。2)定义每个BAL采样时间的微生物环境 关于a）存在病毒病原体（病毒PCR），B）存在细菌共感染（培养 和PCR），以及c）微生物组改变。3)应用稳健的临床表型和相关临床终点。 核心B将利用肺炎治疗中成功临床应答的现有基础设施 （CBT）系统生物学中心在西北大学和其严格的出版协议流 肺泡免疫细胞群的细胞计数分选、微生物分析和临床表型。 最终，该PPG的目标是定义免疫系统途径和失败解决机制， 流感和SARS-CoV-2肺炎后的修复，适用于治疗干预。核心B 通过证明与拟议的研究结果的强烈临床相关性， 鼠模型。

PROJECT SUMMARY CORE B Lower respiratory tract infections cause nearly 80% of deaths from infectious diseases in the US, and respiratory viruses, such as influenza and SARS-CoV-2, are increasingly recognized as common causes of severe community-acquired pneumonia (CAP). As mortality from severe CAP persists despite appropriate antimicrobial treatment and clearance of the causative pathogen, Program Project Investigators hypothesize that mortality and persistent organ failure in severe viral CAP represent persistent inflammatory injury and a failure of lung repair mechanisms. Persistent inflammation and unrepaired organ damage drive poor long-term outcomes following severe CAP, and biomarkers suggest that patients with poor outcomes from severe CAP have a persistent pro-inflammatory state despite clearance of the presumed pathogen. Core B will allow Project Investigators to validate findings from causal murine and cell models of influenza pneumonia in patients with severe CAP induced by viral pathogens. The major goal of Core B is to provide serial bronchoalveolar lavage (BAL) samples obtained from well-phenotyped patients with severe influenza and SARS-CoV-2 pneumonia to the Project Investigators, as defined in the following Specific Aims: 1) Provide BAL fluid from intubated patients with influenza and SARS-CoV-2 pneumonia for a) flow cytometry-sorted BAL alveolar immune cell subsets for transcriptomic and epigenomic analysis and b) cell-free supernatant fluid for metabolomic and biomarker/protein analyses. 2) Define the microbiologic milieu at each BAL sampling time point regarding a) the presence of viral pathogens (viral PCR), b) the presence of bacterial co-infection (culture and PCR), and c) microbiome alterations. 3) Apply robust clinical phenotypes and relevant clinical endpoints. Core B will leverage the existing infrastructure of the Successful Clinical Response In Pneumonia Therapy (SCRIPT) Systems Biology Center at Northwestern University and its rigorous published protocols for flow cytometry sorting of alveolar immune cell populations, microbiologic analysis, and clinical phenotyping. Ultimately, the goal of this PPG is to define immune system pathways and mechanisms of failed resolution and repair following influenza and SARS-CoV-2 pneumonia that are amenable to therapeutic interventions. Core B is integral to supporting this goal by demonstrating strong clinical correlations to findings from the proposed murine models.