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Mechanistic characterization of SARS-CoV2 associated kidney injury

SARS-CoV2相关肾损伤的机制特征

基本信息

批准号：
10427448
负责人：
Deborah J Lenschow
金额：
$ 39.38万
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：
2021-06-11 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10427448
关键词：
2019-nCoV Acute Acute Renal Failure with Renal Papillary Necrosis Acute Respiratory Distress Syndrome Age Apoptosis COVID-19 COVID-19 complications COVID-19 patient CRISPR screen Caspase Cell Death Cells Cessation of life Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Cohort Analysis Complex Coronavirus Data Disease Etiology Functional disorder Genes Goals HMGB1 gene Histopathology Human ISG15 gene In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Injury Injury to Kidney Integration Host Factors Interferons K-18 conjugate Kidney Knockout Mice Lung Maps Mediating Modeling Molecular Mus Organ Organoids Pathogenesis Pathway interactions Patients Pattern Persons Play Predisposition Production Protein Kinase Proteins Pulmonary Inflammation RIPK1 gene Regulation Reperfusion Injury Reporting Risk Factors Role SARS coronavirus SARS-CoV-2 infection SARS-CoV-2 pathogenesis Serum Severity of illness Source System Testing Therapeutic Tracheal Epithelium Transgenic Mice Tropism Tubular formation Ubiquitin Like Proteins United States Viral Viral Load result Viral Proteins Virus Virus Diseases Work base cell injury chemokine cytokine cytokine release syndrome effective intervention genome-wide human coronavirus in vivo induced pluripotent stem cell insight kidney cell kidney epithelial cell mortality risk mouse model novel renal damage response severe COVID-19 systemic inflammatory response therapeutic development

项目摘要

SARS-CoV2 is a highly contagious, novel human coronavirus that causes coronavirus disease 2019 (COVID- 19). Currently over 16.5 million people in the US have confirmed infection with SARS-CoV2 and over 300,000 have died. Severe COVID-19 is characterized by pulmonary and systemic inflammation and multi-organ dysfunction, with a significant portion of severe COVID patients developing acute kidney injury. 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 a predictor of severe COVID-19 disease. The mechanism by which the host restricts necroptosis is unclear. In 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. We have also shown that ISG15 deficient mice rapidly succumb to ischemia-reperfusion injury of the kidney characterized by a massive release of proinflammatory cytokines. In this proposal we will test the hypothesis that ISG15 serves as a critical host restriction factor in regulating programmed necroptosis and downstream inflammatory responses within the kidney to limit acute kidney injury during SARS-CoV2 infection. We will utilize kidney organoids derived from induce pluripotent stem cells in which ISG15 has been deleted by CRISPR, a co-culture system with kidney organoids and primary tracheal epithelial cultures (hTECs), and in vivo mouse model of SARS-CoV-2 to ask several questions including: 1) Does SARS- CoV2 induce damage to kidney epithelial cells via direct viral transduction or in response to systemic inflammation?; 2) Does ISG15 modulate necroptotic cell death as well as proinflammatory cytokine/chemokine production in kidney epithelial cells during SARS-CoV2 infection?; 3) Does necroptosis and its regulation by ISG15 contribute to acute kidney injury during SARS-CoV2 infection? Overall, our studies will provide important insight into host factors that restrict necroptosis and could be an important contributor to severe COVID-19 induced kidney injury.

SARS-CoV2 是一种高度传染性的新型人类冠状病毒，可导致 2019 年冠状病毒病 (COVID-19) 19）。目前美国已有超过 1650 万人确诊感染 SARS-CoV2，超过 30 万人确诊感染已经死了。严重的 COVID-19 的特点是肺部和全身炎症以及多器官功能障碍，相当一部分重症新冠肺炎患者出现急性肾损伤。机制 SARS-CoV2 是如何引发如此严重的发病机制的，人们知之甚少。最近的临床研究已表明细胞死亡，尤其是坏死性凋亡的诱导，可能是严重 COVID-19 的预测因素疾病。宿主限制坏死性凋亡的机制尚不清楚。在初步数据中我们已经显示干扰素诱导蛋白 ISG15 充当坏死性凋亡及其下游的负调节因子病毒感染期间的炎症反应。我们还表明，ISG15 缺陷小鼠会迅速死亡以大量释放促炎细胞因子为特征的肾脏缺血再灌注损伤。在本提案中，我们将测试 ISG15 作为调节中关键宿主限制因素的假设肾脏内的程序性坏死性凋亡和下游炎症反应，以限制急性肾损伤 SARS-CoV2 感染期间。我们将利用源自诱导多能干细胞的肾脏类器官，其中 ISG15 已被 CRISPR 删除，这是一种与肾类器官和原代气管上皮共培养系统培养物（hTEC）和 SARS-CoV-2 体内小鼠模型，提出几个问题，包括：1）SARS- 冠状病毒2通过直接病毒转导或响应全身性损伤诱导肾上皮细胞损伤炎？; 2) ISG15是否调节坏死性细胞死亡以及促炎细胞因子/趋化因子 SARS-CoV2 感染期间肾上皮细胞的产生？ 3) 坏死性凋亡及其调控是否通过 ISG15 会导致 SARS-CoV2 感染期间的急性肾损伤吗？总的来说，我们的研究将提供重要的深入了解限制坏死性凋亡的宿主因素，并可能是导致严重 COVID-19 的重要因素诱发肾损伤。