Clinical Phenotyping and Human Core

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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.