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-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 2019 年（新冠肺炎 (COVID-19)）。目前美国已有超过740万人确诊感染 SARS-CoV2 和超过 215,000 人死亡。严重的 COVID-19 的特点是肺部和全身炎症和多器官功能障碍，对老年人的影响尤为严重患者。 SARS-CoV2 引发如此严重的发病机制的机制尚不清楚明白了。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。主机所采用的机制限制坏死性凋亡尚不清楚。在初步数据中，我们已经表明干扰素诱导蛋白质 ISG15 充当坏死性凋亡及其下游炎症的负调节因子病毒感染期间的反应。在本提案中，我们将测试 SARS-CoV2 的假设诱导坏死性凋亡，ISG15 作为呼吸系统坏死性凋亡的负调节因子上皮细胞。我们将使用体外原代气管上皮培养物 (hTEC) 和体内小鼠适应了 SARS-CoV2 动物模型，提出了几个问题，包括：1) SARS- CoV2诱导呼吸道上皮细胞坏死性凋亡； 2) ISG15是否调节坏死性细胞死亡以及呼吸道上皮细胞中促炎细胞因子/趋化因子的产生 SARS-CoV2 感染期间？ 3) 坏死性凋亡及其 ISG15 的调节是否有助于 SARS-CoV2 发病机制？总的来说，我们的研究将为我们提供重要的见解 SARS-CoV2 感染的发病机制，并提供对潜在机制的潜在见解严重疾病，这可能会引导人们努力开发诊断标记物和未来对策。