Establishing Cellular Models of SARS-CoV2 Infection for COVID-19 Studies

为 COVID-19 研究建立 SARS-CoV2 感染的细胞模型

• 批准号: 9924569
• 负责人: Abraam M. Yakoub
• 金额: $ 22.62万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2021-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924569
• 关键词: 2019-nCoV; Acute; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Antigen-Antibody Complex; Antiviral Agents; Autophagocytosis; Bacteria; Basic Science; Biological Assay; C Type Lectin Receptors; COVID-19; Cell model; Cells; Cessation of life; Coronavirus; Country; Data; Development; Disease; Disease model; Equilibrium; Event; FDA approved; Future; Goals; Growth; Homeostasis; Hospitalization; Immune System Diseases; Immune response; Individual; Infection; Infection Control; Infiltration; Inflammation; Inflammatory Response; Innate Immune Response; Integration Host Factors; Interferon Type I; Invaded; Kinetics; Klebsiella pneumoniae; Knockout Mice; Knowledge; Lead; Leukocytes; Ligands; Lower Respiratory Tract Infection; Lung; Mediating; Modeling; Molecular; Monitor; Mus; Myeloid Cells; Pathogenesis; Pathologic; Patients; Pattern; Pattern recognition receptor; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Play; Pneumonia; Process; Public Health; Regulation; Reporting; Research; Resolution; Respiratory Failure; Respiratory Tract Infections; Role; Sepsis; Shapes; Signal Transduction; Symptoms; TMPRSS2 gene; Techniques; Testing; Therapeutic Intervention; Tissues; Tropism; Tumor-infiltrating immune cells; United States; Vaccines; Viral; Viral Load result; Virus; Virus Diseases; Writing; antimicrobial; cell type; cofactor; cytokine; effective therapy; immunoregulation; mortality; neutrophil; novel; pathogen; prevent; public health relevance; receptor; response; septic; therapeutic candidate; therapeutic evaluation; time use; tissue tropism; uptake; virus tropism

Project Summary Coronavirus Disease of 2019 (COVID-19) is a US and global public health crisis. It has led to the deaths of, at the point of writing this application, over 476,000 patients and 10 million infected individuals worldwide. The US was the most affected country, with over 123,000 deaths thus far and over 2.4 M infections. COVID-19 is caused by a novel beta-coronavirus (CoV) known as Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV2), which was reported to cause severe pneumonia and lethal respiratory failure. There is no vaccine or FDA-approved drugs for COVID-19, and there is very little knowledge about this new virus at the basic science level. Thus, animal and cellular models are urgently needed to start to investigate the disease mechanism or test therapeutic interventions. Here, we propose to explore essential aspects of understanding COVID-19 viral infection: tissue tropism of the virus and antiviral innate immune responses of the host. Firstly, we will test viral tropism in various tissues relevant to reported COVID-19 symptoms and establish cellular models of the disease, by determining the expression of COVID-19 suggested entry receptor/cofactors, ACE2 and TMPRSS2, in various cell types and monitor the progress of infection over time using virus-specific assays and viral load quantification techniques. Secondly, we will test host cellular responses to SARS-CoV2 infection by determining the expression levels during infection, of proinflammatory cytokines and type-I interferons involved in antiviral defenses. We will also assess autophagy flux during infection, given that viruses gain growth advantage in cells by hijacking autophagy.

项目摘要 2019冠状病毒病（COVID-19）是美国和全球的公共卫生危机。在撰写本申请时，它已导致全世界超过476，000名患者和1，000万感染者死亡。美国是受影响最严重的国家，迄今已有超过123，000人死亡，超过240万人感染。COVID-19是由一种称为严重急性呼吸综合征冠状病毒2（SARS-CoV 2）的新型β-冠状病毒（CoV）引起的，据报道，该病毒可导致严重肺炎和致命的呼吸衰竭。目前还没有针对COVID-19的疫苗或FDA批准的药物，在基础科学层面对这种新病毒的了解也非常少。因此，迫切需要动物和细胞模型来开始研究疾病机制或测试治疗干预措施。在这里，我们建议探索理解COVID-19病毒感染的基本方面：病毒的组织嗜性和宿主的抗病毒先天免疫反应。首先，我们将测试与报告的COVID-19症状相关的各种组织中的病毒嗜性，并通过确定COVID-19建议的进入受体/辅因子ACE 2和TMPRSS 2在各种细胞类型中的表达来建立疾病的细胞模型，并使用病毒特异性测定和病毒载量定量技术监测感染随时间的进展。其次，我们将通过确定感染过程中参与抗病毒防御的促炎细胞因子和I型干扰素的表达水平来测试宿主细胞对SARS-CoV 2感染的反应。我们还将评估感染过程中的自噬通量，因为病毒通过劫持自噬在细胞中获得生长优势。