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Low Density Neutrophils Link Inflammation and Coagulopathy in COVID-19

低密度中性粒细胞与 COVID-19 中的炎症和凝血病有关

基本信息

批准号：
10708740
负责人：
Jiapeng Huang
金额：
$ 76.14万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708740
关键词：
2019-nCoV Acute Lung Injury Acute Respiratory Distress Syndrome Alpha Granule Antibodies Apoptosis Bilateral Blood Coagulation Disorders Blood capillaries Blood specimen Bronchoalveolar Lavage Fluid COVID-19 COVID-19 patient COVID-19 severity COVID-19/ARDS Cells Chemotaxis Chimeric Proteins Circulation Clinical Coagulation Process Cytoplasmic Granules Data Diffuse Disease Disease Outcome Disease Progression Economics Endothelial Cells Exocytosis Exocytosis Inhibition FCGR3B gene Fibrin fragment D Fibrinogen Functional disorder Gene Expression Hemorrhage Histologic Hypoxia Immune Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-6 Life Link Lower respiratory tract structure Lung Lymphocyte Measures Mediating Modeling Neutrophil Infiltration Outcome Patients Pattern Perfusion Phagocytosis Plasma Platelet Activation Platelet Count measurement Play Pneumonia Population Predisposing Factor Proteome Proteomics Pulmonary Inflammation Reactive Oxygen Species Respiratory Burst Role SARS-CoV-2 negative Sampling Severity of illness Structure of parenchyma of lung Surface T-Lymphocyte TNF gene Therapeutic Therapeutic Intervention Thrombus Time Venous Viral antimicrobial cell injury cytokine cytokine release syndrome cytotoxic density design exhaustion experience extracellular immune activation immunoregulation immunothrombosis in vivo inhibitor insight lung injury mouse model neutrophil novel novel marker novel therapeutic intervention pandemic disease pathogen pathogenic virus peripheral blood prevent response therapeutic target therapeutically effective transcriptome sequencing transcriptomics treatment effect ventilation

项目摘要

Project Summary Coronavirus disease 2019 (COVID-19) is a potentially life threatening disease caused by the novel viral pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Approximately 20% of COVID-19 patients experience severe disease, typically presenting with bilateral pneumonia, and about 5% progress to acute respiratory distress syndrome (ARDS). ARDS results from a combination of virally induced lung injury and the rapid influx of immune cells that release inflammatory mediators leading to a hyper-activated state known as cytokine storm. COVID-19 ARDS is further exacerbated by a unique diffuse coagulopathy leading to thrombus formation in the venous and arterial circulations and microthrombi in capillaries of the lungs. Predisposing factors for this coagulopathy include increased fibrinogen, activated coagulation cascade, platelet activation, hyper- inflammation, neutrophil extracellular trap (NET) formation, and endothelial cell damage. Understanding the pathophysiology of COVID-19 coagulopathy and ARDS is critical to finding effective therapeutic interventions. Accumulating evidence indicates critical roles of neutrophils in both ARDS and immunothrombosis in COVID-19. Our preliminary studies identified a novel population of low-density neutrophils (LDN) which expresses intermediate levels of CD16 (CD16Int LDN) in COVID-19 patients. The number of CD16Int LDN correlated with disease severity, levels of inflammatory cytokines IL-6/TNF-a, D-dimer levels, and clinical outcomes. In addition, CD16Int LDN showed spontaneous NET formation and evidence of in vivo platelet activation and granule exocytosis. Based on these findings, we postulate that CD16Int LDN play a critical role in the induction of coagulopathy and pulmonary inflammation in severe and critical COVID-19 patients. Three specific Aims are proposed to further dissect the underlying mechanisms. Aim 1 will comprehensively characterize LDN subsets using proteomics and transcriptomics approaches. The information gained from those studies will be used to refine our CyTOF antibody panel. We will use this panel to track differential neutrophil clusters in longitudinal patient samples. Aim 2 will determine LDN subsets functional changes during disease progression and their contributions to dysregulated inflammatory response and coagulopathy in severe and critical COVID- 19 patients. Neutrophil degranulation, NET formation, phagocytosis, chemotaxis, apoptosis, and cytokine release will be examined. We will also determine if LDN promote coagulopathy in COVID-19 patients. Aim 3 will determine whether inhibition of neutrophil granule exocytosis using our novel TAT-fusion protein inhibitors prevents activated neutrophil-mediated functional changes and hypercoagulation. We will also use a hACE2 Tg mouse model to determine the in vivo efficacy of TAT-fusion proteins on lung inflammation and impaired function. Successful completion of this proposal will provide novel insights into COVID-19 pathophysiology by defining the role of a unique subset of neutrophils and by establishing neutrophil degranulation as a therapeutic target for inhibiting inflammatory lung injury and immunothrombosis in COVID-19.

项目总结