Administrative Supplements for Coronavirus Disease 2019 (COVID-19) Research

2019 年冠状病毒病 (COVID-19) 研究行政补充

• 批准号: 10177193
• 负责人: Cuong Q Nguyen
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-23 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177193
• 关键词: 2019-nCoV; Administrative Supplement; Adult; Aerosols; Affinity; Age; Alleles; Antigen Presentation; Antigens; Binding; Biological Assay; Biological Markers; Breathing; COVID-19; Cell physiology; Cessation of life; Child; Chills; China; Clinical; Congestive; Coronavirus; Coughing; Country; Data; Databases; Dengue; Disease; Epitopes; Fatigue; Fever; Foundations; Gene Frequency; General Population; Genetic; Genetic Predisposition to Disease; Genomic DNA; Genotype; HIV-1; HLA Antigens; Health Personnel; Human; Human Genetics; Immune; Immune response; Individual; Intervention; Laboratories; Measures; Medical; Membrane; Middle East Respiratory Syndrome; Mutation; Nucleocapsid; Oral health; Oxygen; Patients; Peptides; Peripheral Blood Mononuclear Cell; Persons; Play; Population; Predisposition; Production; Province; Reporting; Research; Risk; Role; SARS coronavirus; Safety; Saliva; Sampling; Science; Severe Acute Respiratory Syndrome; Severities; Severity of illness; Shortness of Breath; Sore Throat; Source; Surface; Symptoms; System; T cell response; T-Lymphocyte; Testing; Time; Travel; Vaccines; Ventilator; Viral; Viral Antibodies; Viral Antigens; Virus; Zoonoses; aged; antigen binding; base; cytokine; genetic association; high risk; hospitalization rates; human leukocyte antigen testing; human old age (65+); in silico; infection rate; novel coronavirus; pandemic disease; prevent; receptor; response; seroconversion; transmission process; viral detection; viral transmission; whole genome

COVID-19 is caused by a suspected zoonotic source of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). While coronaviruses (CoVs) are relatively common, mutations can cause severe symptoms in humans; the challenges of SARS-CoV-2 are: the long incubation period (2-14 days, median 5.1 days), high viral titer which can appear while a COVID-19+ patient is asymptomatic, and the long period of time in which it is viable outside of its host, both airborne and on surfaces. It is estimated as of May 28, 2020, that there are over 5.7 million cases in 212 countries. Symptoms can range from mild to severe and may include: fever, coughing, shortness of breath, sore throat, fatigue, congestion, and chills. Of those cases, 13.8% require medical interventions, with 6% of patients dying Tragically, there are no available vaccines against SARS-CoV-2. With a wide range of clinical symptoms and more importantly a large population of asymptomatic COVID-19+ patients, a crucial question regarding genetic susceptibility, i.e. whether human leukocyte antigens (HLA) play a role in the patient symptomology. Preliminary in-silico data have revealed binding affinity of specific HLAs to SARSCoV-2 antigens, indicating a genetic HLA association with COVID-19 clinical symptoms, which is the primary objective of this application. We hypothesize that “A certain HLA allele or combination of certain alleles can serve as biomarker for the severity of COVID-19”. To test this hypothesis, we propose to define HLA binding epitopes from dominant SARS-CoV-2 T cell antigens using in-silico analysis (Aim 1), determine the HLA alleles of symptomatic and asymptomatic of COVID-19 patients using whole genome genotyping (Aim 2), and examine the T cell function in correlation with HLA-associated disease protection and susceptibility (Aim 3). The results are expected to provide a broader understanding of the genetic HLA association pertaining to the severity of COVID-19. Additionally, results should provide critical measures in performing HLA typing and virus detection to identify high risk individuals. Utilizing this finding, we may be able to prevent transmission and mitigate the impact of this disease in our dental, health care personnel, and other front-line professionals who are particularly susceptible to aerosol or droplet virus transmission.

COVID-19 是由疑似人畜共患的严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 引起的。虽然冠状病毒 (CoV) 相对常见，但突变可能会导致人类出现严重症状； SARS-CoV-2 的挑战是：潜伏期长（2-14 天，中位数 5.1 天）、在 COVID-19+ 患者无症状时可能出现高病毒滴度，以及病毒在宿主体外（空气中和表面）的存活时间较长。截至2020年5月28日，估计212个国家的病例数超过570万例。症状从轻微到严重不等，可能包括：发烧、咳嗽、气短、喉咙痛、疲劳、充血和发冷。在这些病例中，13.8% 需要医疗干预，其中 6% 的患者死亡。悲惨的是，目前还没有针对 SARS-CoV-2 的可用疫苗。由于临床症状多种多样，更重要的是，有大量无症状的 COVID-19+ 患者，因此存在一个关于遗传易感性的关键问题，即人类白细胞抗原 (HLA) 是否在患者症状中发挥作用。初步的计算机数据显示了特定 HLA 与 SARSCoV-2 抗原的结合亲和力，表明 HLA 基因与 COVID-19 临床症状相关，这是本申请的主要目标。我们假设“某个 HLA 等位基因或某些等位基因的组合可以作为 COVID-19 严重程度的生物标志物”。为了检验这一假设，我们建议使用计算机分析来定义主要 SARS-CoV-2 T 细胞抗原的 HLA 结合表位（目标 1），使用全基因组基因分型确定有症状和无症状的 COVID-19 患者的 HLA 等位基因（目标 2），并检查与 HLA 相关疾病保护和易感性相关的 T 细胞功能（目标 3）。研究结果预计将有助于更广泛地了解与 COVID-19 严重程度相关的 HLA 基因关联。此外，结果应提供进行 HLA 分型和病毒检测以识别高风险个体的关键措施。利用这一发现，我们或许能够预防这种疾病的传播，并减轻这种疾病对牙科、医护人员和其他特别容易受到气溶胶或飞沫传播病毒传播的一线专业人员的影响。