Understanding the interplay between local viral infection and local inflammation in COVID-19 kidney injury

了解 COVID-19 肾损伤中局部病毒感染和局部炎症之间的相互作用

• 批准号: 10318839
• 负责人: Maria Blasi
• 金额: $ 40.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318839
• 关键词: 2019-nCoV; Acute Kidney Tubular Necrosis; Acute Renal Failure with Renal Papillary Necrosis; Affect; African Green Monkey; Antiviral Agents; Archives; Autopsy; Biological Assay; Biopsy; COVID-19 patient; COVID-19 treatment; Cell Death; Cell Line; Cells; Cessation of life; Coagulation Process; Complication; DNA Sequence Alteration; Data; Databases; Deletion Mutation; Deposition; Detection; Diagnosis; Disease; Epithelial Cells; Frequencies; Genes; Genome; Goals; Growth; HIV; Hospital Mortality; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Kidney; Kidney Diseases; Mechanical ventilation; Mitochondria; Morbidity - disease rate; Mutation; Nature; Pathogenesis; Patients; Pattern; Play; Prevalence; Quantitative Reverse Transcriptase PCR; Renal glomerular disease; Renal tubule structure; Reporting; Resources; Respiratory System; Role; SARS-CoV-2 genome; SARS-CoV-2 infection; SARS-CoV-2 variant; Sampling; Site; Source; Specimen; Tissues; Urine; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Virus Shedding; adverse outcome; body system; coronavirus disease; cytokine; design; genetic analysis; hemodynamics; improved; inflammatory marker; inflammatory milieu; insight; kidney cell; kidney infection; mutant; nasal swab; pandemic disease; particle; podocyte; prevent; prospective; renal epithelium; shared database; systemic inflammatory response; therapy design; viral RNA; viral fitness

PROJECT ABSTRACT Acute kidney injury (AKI) is a common complication of Coronavirus disease 19 (COVID-19), affecting more than a third of patients hospitalized with COVID-19 and up to 90% of those requiring mechanical ventilation. Possible contributors to AKI in patients with COVID-19 include systemic inflammation and cytokine release, hemodynamic compromise, and intravascular coagulation. Additionally, several reports have suggested the presence of SARS- CoV-2 viral particles or viral RNA in the kidney tissue of patients who died from COVID-19, suggesting a potential role for local viral infection in the kidney. SARS-CoV-2 is known to infect and replicate in kidney cell lines, and in preliminary data we show that viral RNA can be amplified from the urine of patients with severe COVID-19 and AKI, even after the virus has been cleared in the respiratory tract. Genetic analysis of those viral RNA in urine demonstrated a predominant pattern of deletions and mutations at the furin-cleavage site of SARS-CoV-2 that have not been observed in over 180,000 SARS-CoV-2 genome sequences from respiratory tract samples deposited in the publicly available database GISAID. However, those mutations have been reported to occur after virus passaging in the African green monkey kidney cell line Vero-E6, raising the possibility that those mutations might be positively selected following virus replication in kidney cells. The primary goal of this application is to understand the interplay between local viral infection and local inflammation in COVID-19-related kidney injury by leveraging our expertise in the study of HIV-related kidney disease. Our specific objectives are 1) to isolate and genetically characterize SARS-CoV-2 from urine samples of COVID-19 patients with mild, moderate or severe disease, 2) to explore the relationship between SARS-CoV- 2 infection of renal cells and urine inflammatory markers; and 3) to determine the impact of genetic mutations on viral fitness. Understanding the role of direct viral infection of renal epithelial cells is key to the design of interventions to prevent and treat AKI in COVID-19. Further characterization of the viral mutants isolated from urine may provide insight into viral pathogenesis and would inform the design of antiviral and adjunctive therapies for SARS-CoV-2 infection.

项目摘要 急性肾损伤 (AKI) 是冠状病毒病 19 (COVID-19) 的常见并发症，影响超过 三分之一的患者因 COVID-19 住院，其中高达 90% 的患者需要机械通气。可能的 COVID-19 患者 AKI 的影响因素包括全身炎症和细胞因子释放、血流动力学 损害和血管内凝血。此外，一些报告表明存在 SARS- 死于 COVID-19 的患者肾组织中的 CoV-2 病毒颗粒或病毒 RNA，表明潜在的 肾脏局部病毒感染的作用。 已知 SARS-CoV-2 会在肾细胞系中感染和复制，在初步数据中，我们表明病毒 RNA 即使病毒已被清除，也可以从患有严重 COVID-19 和 AKI 的患者的尿液中扩增 在呼吸道中。对尿液中病毒 RNA 的基因分析表明，主要模式是 SARS-CoV-2 弗林蛋白酶裂解位点的缺失和突变在超过 180,000 个样本中未观察到 存放在公开数据库中的呼吸道样本中的 SARS-CoV-2 基因组序列 GISAID。然而，据报道，这些突变是在病毒在非洲绿地传代后发生的。 猴肾细胞系 Vero-E6，提高了这些突变可能在以下情况下被积极选择的可能性 病毒在肾细胞中复制。 该应用程序的主要目标是了解局部病毒感染和局部病毒感染之间的相互作用。 利用我们在 HIV 相关肾脏研究方面的专业知识，治疗与 COVID-19 相关的肾损伤中的炎症 疾病。我们的具体目标是 1) 从尿液样本中分离 SARS-CoV-2 并进行基因表征 患有轻度、中度或重度疾病的 COVID-19 患者，2) 探讨 SARS-CoV- 2肾细胞感染和尿液炎症标志物； 3）确定基因突变对 病毒式健身。 了解肾上皮细胞直接病毒感染的作用是设计干预措施的关键 预防和治疗 COVID-19 中的 AKI。从尿液中分离的病毒突变体的进一步表征可能 提供对病毒发病机制的深入了解，并为抗病毒和辅助疗法的设计提供信息 SARS-CoV-2 感染。