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冠状病毒，引起冠状病毒病 2019（Covid-19）。目前，美国已有740万人确认感染 SARS-COV2和超过215,000人死亡。严重的Covid-19的特征是肺和系统性炎症和多器官功能障碍，对老年人的影响不成比例患者。 SARS-COV2触发如此严重的发病机理的机制很差理解。最近的临床研究表明，细胞死亡，尤其是诱导坏死性，可能是严重Covid-19疾病的预测指标。主机的机制限制坏死性尚不清楚。在初步数据中，我们表明干扰素诱导蛋白质（ISG15）充当坏死剂及其下游炎症的负调节剂病毒感染期间的反应。在此提案中，我们将测试SARS-COV2的假设诱导坏死性，ISG15在呼吸道中起坏死性的负调节剂上皮细胞。我们将使用体外原发性气管上皮培养（HTEC）和体内小鼠改编的SARS-COV2动物模型提出了几个问题，包括：1）SARS- COV2在呼吸性上皮细胞中诱导坏死； 2）iSG15调节坏死细胞呼吸性上皮细胞中的死亡以及促炎性细胞因子/趋化因子的产生在SARS-COV2感染期间？ 3）死坏死及其对ISG15的调节有助于 SARS-COV2发病机理？总体而言，我们的研究将为您提供重要的见解 SARS-COV2感染的发病机理，并提供对机制的潜在洞察力严重的疾病，这可能会导致诊断标记和未来发展的努力对策。