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道综合征-冠状病毒2型（SARS-CoV-2）引起的。虽然冠状病毒（CoV）相对常见，但突变可导致人类出现严重症状; SARS-CoV-2的挑战是：潜伏期长（2-14天，中位数为5.1天），高病毒滴度可能在COVID-19+患者无症状时出现，以及它在宿主外（空气传播和表面）存活的时间长。据估计，截至2020年5月28日，在212个国家有超过570万例病例。症状从轻微到严重不等，可能包括：发烧、咳嗽、呼吸急促、喉咙痛、疲劳、充血和发冷。在这些病例中，13.8%需要医疗干预，6%的患者死亡。随着广泛的临床症状，更重要的是大量无症状COVID-19+患者，一个关于遗传易感性的关键问题，即人类白细胞抗原（HLA）是否在患者病理学中发挥作用。初步的计算机模拟数据揭示了特异性HLA与SARSCoV-2抗原的结合亲和力，表明HLA与COVID-19临床症状的遗传相关性，这是本申请的主要目的。我们假设“某种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”。为了验证这一假设，我们建议使用计算机模拟分析（Aim 1）来定义来自显性SARS-CoV-2 T细胞抗原的HLA结合表位，使用全基因组基因分型（Aim 2）来确定有症状和无症状COVID-19患者的HLA等位基因，并检查与HLA相关疾病保护和易感性相关的T细胞功能（Aim 3）。这些结果有望为与COVID-19严重程度相关的遗传HLA关联提供更广泛的理解。此外，结果应提供关键的措施，在执行HLA分型和病毒检测，以确定高风险的个人。利用这一发现，我们可能能够预防传播并减轻这种疾病在我们的牙科，卫生保健人员和其他一线专业人员中的影响，这些人特别容易受到气溶胶或飞沫病毒传播的影响。