Clinical Phenotyping and Human Core

项目摘要核心B 在美国，近80%的传染病死亡是由下呼吸道感染造成的，而呼吸道感染 流感和SARS-CoV-2等病毒越来越多地被认为是严重肺炎的常见原因 社区获得性肺炎(CAP)。尽管适当，但严重CAP的死亡率仍在持续 抗菌治疗和病原体清除，计划项目调查人员假设 重症病毒性肺炎的死亡率和持续性器官衰竭是持续性炎症性损伤和 肺修复机制失效。持续的炎症和未修复的器官损伤导致长期不良 严重CAP后的结果，以及生物标志物表明严重CAP预后较差的患者 有持续的促炎状态，尽管推定的病原体已被清除。核心B将允许项目 研究人员验证流感肺炎患者因果小鼠和细胞模型的研究结果 由病毒病原体引起的严重CAP。核心B的主要目标是提供连续的支气管肺泡 严重流感和SARS-CoV-2表型良好的患者的灌洗液(BAL)样本 肺炎对项目调查人员的影响，具体目标如下：1)提供BAL液 来自插管的流感和SARS-CoV-2肺炎患者的a)流式细胞术-BAL肺泡分选 用于转录和表观基因组分析的免疫细胞亚群和b)无细胞上清液 代谢组学和生物标志物/蛋白质分析。2)确定每个BAL采样时间的微生物环境 关于a)存在病毒病原体(病毒聚合酶链式反应)，b)存在细菌混合感染(培养 和聚合酶链式反应)，以及c)微生物组改变。3)应用健壮的临床表型和相关的临床终点。 核心B将利用肺炎治疗中成功的临床反应的现有基础设施 (脚本)西北大学系统生物学中心及其严格发布的FLOW协议 肺泡免疫细胞群的细胞术分类、微生物学分析和临床表型。 最终，这种PPG的目标是定义免疫系统失败的途径和机制，以及 在流感和SARS-CoV-2肺炎后进行修复，这是可以采取治疗措施的。核心B 是支持这一目标不可或缺的一部分，因为它证明了与建议的 小鼠模型。

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.