权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms and pathogenicity of SARS-CoV-2-induced neutrophil extracellular traps

SARS-CoV-2诱导中性粒细胞胞外陷阱的机制和致病性

基本信息

批准号：
10365868
负责人：
MARK ROBERTS LOONEY
金额：
$ 62.33万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365868
关键词：
2019-nCoV ACE2 Acute Lung Injury Adult Respiratory Distress Syndrome Alveolar Aspirate substance Attention Biological Biology Blood COVID-19 COVID-19 pandemic COVID-19 patient COVID-19/ARDS Cause of Death Cessation of life Chromatin Cleaved cell Coagulation Process Complement Complement Activation Containment Deoxyribonucleases Development Disease Excess Mortality Extracellular Space Feedback Host Defense Human Infection Infection Control Influenza Influenza A virus Knowledge Literature Lung Lung infections Mass Spectrum Analysis Measures Modeling Molecular Mouse Strains Mus Neutrophil Activation Neutrophilia Pathogenesis Pathogenicity Pathway interactions Patients Peptide Hydrolases Plasma Platelet Activation Pneumonia Positioning Attribute Process Production Proteins Proteomics Reporting Role SARS-CoV-2 infection SARS-CoV-2 spike protein Sepsis Severities Sterility Testing Therapeutic Transgenic Organisms Viral Pathogenesis Viral Pneumonia Virus Virus Diseases base cohort coronavirus disease effective therapy experimental study extracellular grasp in vivo evaluation loss of function loss of function mutation lung injury microbial mortality mouse model neutrophil novel novel strategies novel therapeutic intervention pandemic disease pathogen peripheral blood prevent respiratory pathogen response severe COVID-19 therapeutic evaluation therapeutic target tissue injury

项目摘要

Project Summary/Abstract The acute respiratory distress syndrome (ARDS) was first formally described in 1967, but it has likely been the predominant cause of death in pandemic viral infections for centuries. Now, the world is at grips with a new pandemic from SARS-CoV-2, or COVID-19, which has infected over 100 million people worldwide resulting in >2 million deaths. Central to the immunopathogenesis of ARDS is the role of neutrophils and neutrophil activation, including the release of neutrophil chromatin into the extracellular space in a process termed neutrophil extracellular traps, or NETs. Originally described as a form of host defense to inactivate pathogens, NETs have emerged as a potentially maladaptive response to infections, producing substantial bystander injury to tissues and serving as a nidus for coagulation. We have shown that NETs are produced in response to both sterile and pathogen-induced acute lung injury (including Influenza A), and when neutralized, lung injury is reduced without compromising microbial containment. We have also shown that NETs are increased in the plasma of patients with ARDS and associate with more severe ARDS and ARDS mortality. Emerging reports indicate that NETs are also present in the blood and lungs of COVID-19 patients. We are now positioned to rapidly test the role of NETs in response to SARS-CoV-2 in this application, and to develop novel approaches to neutralize NETs for therapeutic purposes. In Aim 1, we will challenge neutrophils with SARS-CoV-2 virus or spike protein to determine the production of NETs and NET-induction molecular pathways. We hypothesize that secreted neutrophil proteases and NETs themselves will cleave spike protein to prime for enhanced viral pathogenesis. We will also embark on unbiased studies of neutrophil proteins using mass spectrometry to determine novel pathways of neutrophil activation resulting from SARS-CoV-2, including from neutrophils isolated from COVID-19 patients. In Aim 2, we will turn our attention to a mouse model of COVID-19 in which mouse strains expressing human ACE2 will be challenged with SARS-CoV-2 and lung injury, NETs, and systemic effects measured. We hypothesize that NETs will be produced and predominantly localize to the alveolar spaces. We will use mice with gain and loss of function mutations in NET pathways (PAD4-/-, DNase1- /-, DNase1L3-/-) to test for their pathogenicity in this model. In these studies, we will also test a novel DNase to neutralize NETs into non-toxic mononucleosomes, which could be rapidly deployed to COVID-19 patients. Finally, we will test for the role of NET-associated platelet activation, complement activation, and coagulation responses, and therapeutic strategies to mitigate these systemic effects. In summary, these studies will establish new knowledge on neutrophil activation and the definitive role of NETs in COVID-19 and identify therapeutic approaches to target NETs in SARS-CoV-2-induced ARDS.

项目总结/文摘