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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：
10287787
负责人：
Deborah J Lenschow
金额：
$ 19.69万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287787
关键词：
2019-nCoV Adult 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 Patients Pattern Play Population Production Proteins Pulmonary Inflammation RIPK3 gene Regulation Respiratory Failure Role SARS-CoV-2 infection Severe Acute Respiratory Syndrome Source Structure of respiratory epithelium 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 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-CoV 2是一种高度传染性的新型人类冠状病毒，可导致冠状病毒疾病 2019年（COVID-19）。目前，美国已有超过740万人确认感染了 SARS-CoV 2和超过215，000人死亡。严重的COVID-19的特征是肺部和全身性炎症和多器官功能障碍，严重影响老年人患者SARS-CoV 2引发这种严重发病机制的机制尚不清楚，明白最近的临床研究表明，细胞死亡，特别是诱导坏死性凋亡可能是严重COVID-19疾病的预测因子。宿主通过这种机制是否限制了坏死性凋亡尚不清楚。在初步的数据中，我们已经表明干扰素诱导的 ISG 15蛋白是坏死性凋亡及其下游炎症反应的负调节因子，病毒感染时的反应。在本提案中，我们将测试SARS-CoV 2的假设诱导坏死性凋亡，ISG 15在呼吸系统中作为坏死性凋亡的负调节剂发挥作用，上皮细胞我们将使用体外原代气管上皮细胞培养物（hTEC）和体内培养物。小鼠适应SARS-CoV 2动物模型提出了几个问题，包括：1）SARS- CoV 2诱导呼吸道上皮细胞坏死性凋亡; 2）ISG 15是否调节坏死性细胞凋亡呼吸道上皮细胞中的死亡以及促炎细胞因子/趋化因子产生在SARS-CoV 2感染期间？3)坏死性凋亡和ISG 15对其的调节是否有助于 SARS-CoV 2发病机制？总的来说，我们的研究将提供重要的见解， SARS-CoV 2感染的发病机制，并提供潜在的洞察机制，严重的疾病，这可能会直接努力发展诊断标志物和未来对策