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: 10671045
• 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/10671045
• 关键词: 2019-nCoV; Acute Kidney Tubular Necrosis; Acute Renal Failure with Renal Papillary Necrosis; Affect; African Green Monkey; Archives; Autopsy; Biological Assay; Biopsy; COVID-19; COVID-19 detection; COVID-19 mortality; COVID-19 patient; COVID-19 treatment; Cell Death; Cell Line; Cells; Cessation of life; Coagulation Process; Complication; DNA Sequence Alteration; Data; Deposition; Diagnosis; Disease; Epithelial Cells; Frequencies; Genes; Genome; Goals; Growth; HIV; Hospital Mortality; Hospitalization; 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; 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; cytokine; design; genetic analysis; hemodynamics; improved; inflammatory marker; inflammatory milieu; insight; kidney cell; kidney infection; mutant; nasal swab; pandemic disease; particle; podocyte; prevent; prospective; public database; renal epithelium; severe COVID-19; 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 急性肾脏损伤（AKI）是冠状病毒19（COVID-19）的常见并发症，影响超过 三分之一的患者患有COVID-19，最多需要机械通气的患者，其中90％。可能的 COVID-19患者的AKI的贡献者包括全身性炎症和细胞因子释放，血液动力学 妥协和血管内凝血。此外，有几份报告表明存在SARS- 死于Covid-19的患者的肾脏组织中的COV-2病毒颗粒或病毒RNA，表明潜力 肾脏中局部病毒感染的作用。 已知SARS-COV-2在肾细胞系中感染和复制，在初步数据中，我们表明病毒RNA 即使已清除病毒，也可以从严重的COVID-19和AKI患者的尿液中扩增 在呼吸道中。尿液中那些病毒RNA的遗传分析表明 SARS-COV-2的Furin裂解位点的缺失和突变，在180,000多个中尚未观察到 来自呼吸道样品中的SARS-COV-2基因组序列，这些序列沉积在公共可用数据库中 Gisaid。但是，据报道，这些突变在非洲绿色的病毒传播后发生 猴肾细胞系Vero-E6，提高了可能会积极选择这些突变的可能性 肾细胞中的病毒复制。 该应用的主要目标是了解局部病毒感染与局部的相互作用 通过利用我们在与HIV相关肾脏研究的专业知识中，COVID-19相关肾脏损伤的炎症 疾病。我们的特定目标是1）隔离和遗传表征SARS-COV-2从尿液样品中 在199例轻度，中度或重度疾病的患者中，2）探索SARS-COV- 2感染肾细胞和尿液炎症标志物； 3）确定基因突变对 病毒健康。 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AKI在Covid-19中。从尿液中分离出的病毒突变体的进一步表征 提供有关病毒发病机理的见解，并将为抗病毒和辅助疗法的设计提供信息 SARS-COV-2感染。

项目成果

SARS-CoV-2 Employ BSG/CD147 and ACE2 Receptors to Directly Infect Human Induced Pluripotent Stem Cell-Derived Kidney Podocytes.

• DOI: 10.3389/fcell.2022.855340
• 发表时间: 2022
• 期刊: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
• 影响因子: 5.5
• 作者: Kalejaiye, Titilola D.;Bhattacharya, Rohan;Burt, Morgan A.;Travieso, Tatianna;Okafor, Arinze E.;Mou, Xingrui;Blasi, Maria;Musah, Samira
• 通讯作者: Musah, Samira