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Regulation of Cell Death and Inflammation by ISG15 during SARS-CoV2 Infection

SARS-CoV2 感染期间 ISG15 对细胞死亡和炎症的调节

基本信息

批准号：
10424558
负责人：
Deborah J Lenschow
金额：
$ 23.63万
依托单位：
WASHINGTON UNIVERSITY
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：
2021-06-08 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424558
关键词：
2019-nCoV Acute Respiratory Distress Syndrome Affect Age Animal Model Apoptosis Avian Influenza COVID-19 COVID-19 patient CRISPR screen Caspase Cell Death Cells Cessation of life Clinical Research Cohort Analysis Complex Coronavirus Data Development Disease Elderly Epithelial Cells Evaluation Functional disorder Future Goals HMGB1 Protein Histologic Histopathology Human ISG15 gene Immune response In Vitro Infection Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Interferons Knockout Mice Lung Machine Learning Maps Molecular Morbidity - disease rate Mus Pathogenesis Pathology Pathway interactions Pattern Persons Play Population Production Proteins Pulmonary Inflammation RIPK3 gene Regulation Respiratory Failure Role SARS coronavirus SARS-CoV-2 infection SARS-CoV-2 pathogenesis Source Symptoms Testing Tracheal Epithelium Tropism Ubiquitin Like Proteins Viral Viral Load result Viral Proteins Viral Respiratory Tract Infection Virus Virus Diseases Virus Replication Work aged airway epithelium base biomarker identification cell type chemokine cytokine cytokine release syndrome diagnostic biomarker genome-wide high risk population human coronavirus in vivo insight mortality novel older patient pandemic disease severe COVID-19 systemic inflammatory response therapeutic development therapeutically effective

项目摘要

SARS-CoV2 is a highly contagious, novel human coronavirus that causes coronavirus disease 2019 (COVID-19). Currently over 7.4 million people in the US have confirmed infection with SARS-CoV2 and over 215,000 have died. Severe COVID-19 is characterized by pulmonary and systemic inflammation and multi-organ dysfunction, which disproportionally affects elderly patients. The mechanism by which SARS-CoV2 triggers such severe pathogenesis is poorly understood. Recent clinical studies have suggested that cell death, especially the induction of necroptosis, may be predictor of severe COVID-19 disease. The mechanism by which the host restricts necroptosis is unclear. In the preliminary data we have shown that the interferon induced protein, ISG15, acts as a negative regulator of necroptosis and its downstream inflammatory responses during viral infection. In this proposal we will test the hypothesis that SARS-CoV2 induces necroptosis and that ISG15 functions as a negative regulator of necroptosis in respiratory epithelial cells. We will use in vitro primary tracheal epithelial cultures (hTECs) and an in vivo mouse adapted SARS-CoV2 animal model to ask several questions including: 1) Does SARS- CoV2 induce necroptosis in respiratory epithelial cells; 2) Does ISG15 modulate necroptotic cell death as well as proinflammatory cytokine/chemokine production in respiratory epithelial cells during SARS-CoV2 infection?; 3) Does necroptosis and its regulation by ISG15 contribute to SARS-CoV2 pathogenesis? Overall, our studies will provide important insight into the pathogenesis of SARS-CoV2 infection and provide potential insight into mechanisms underlying severe disease, which may direct efforts toward the development of diagnostic markers and future countermeasures.

SARS-CoV2是一种高度传染性的新型人类冠状病毒，可引起冠状病毒病