Project 2

项目2

• 批准号: 10558424
• 负责人: Kristian Graugaard Andersen
• 金额: $ 64.26万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558424
• 关键词: 2019-nCoV; Acute; Africa; Animal Model; Arenavirus; Automobile Driving; Bioinformatics; Biological Markers; COVID-19; COVID-19 morbidity; COVID-19 pandemic; Case Fatality Rates; Case Study; Catalogs; Cells; Central Africa; Cessation of life; Clinical; Communicable Diseases; Complement; Complex; Coronavirus; Data; Data Set; Demographic Factors; Development; Disease; Disease Outbreaks; Disease Outcome; Ebola; Ebola virus; Environmental Risk Factor; Epidemiology; Evolution; Exposure to; Filovirus; Generations; Genetic; Genomics; Goals; Human; Immune; Immune response; Immunity; Individual; Infection; Investigation; Lassa virus; Modeling; Molecular; Molecular Epidemiology; Monoclonal Antibodies; Mutation; Nigeria; Outcome; Patients; Play; Process; Research; Role; SARS-CoV-2 infection; Seasons; Serology; Seroprevalences; Severities; Severity of illness; Sierra Leone; System; Systems Biology; Techniques; Technology; Testing; Vaccinated; Vaccination; Validation; Variant; Viral; Viral Genome; Viral Hemorrhagic Fevers; Virulence; Virus; Virus Diseases; Work; adaptive immunity; clinical predictive model; data integration; data management; human disease; long-term sequelae; multiple omics; open source; pathogen; predictive modeling; response; single cell sequencing; technological innovation; transcriptomics; variants of concern; virus genetics

Project Summary - Project 2 The objective of Project 2 is to investigate the complex interplay of virus genetics and host immunity in determining epidemiology and outcome of infection with Lassa virus, Ebola virus, and SARS-CoV-2. Our central hypothesis is that both host and virus factors play key roles in determining the severity of clinical outcomes including survival, disease severity and the development of long-term sequelae. To test this hypothesis, we will investigate viral genetics, development of host immunity, and how these processes interact as a result of viral infection or vaccination. In focusing on the host-pathogen interface, we will complement the host-focused studies from Project 1 to better understand the complex factors that determine the clinical outcome and epidemiology of Lassa, Ebola, and COVID-19. To accomplish this, we will complete the following: In Aim 1, we will refine viral sequencing techniques to generate large catalogs of Lassa virus and SARS-CoV-2 genomic diversity. We will then integrate these data with environmental and demographic data and apply phylodynamic models to identify virus mutations and variants most likely to have an effect on disease severity. In Aim 2, we will perform single cell sequencing and transcriptomics to deeply characterize the evolution of adaptive immunity in response to acute Lassa virus infection or vaccination. We will also isolate monoclonal antibodies from individuals previously infected with or vaccinated against Lassa virus, Ebola virus, or SARS-CoV-2 to understand the diversity of the human humoral response. In Aim 3, we will extend the multi-omics work proposed in Aim 2 to individuals infected with different viral variants, with the goal of developing a predictive model of immune response and clinical outcome. This model will integrate the systems serology data from Project 1 as part of a framework of repeated cycles of experimental data generation, integration, application, validation, and refinement to identify predictive biological markers of human disease and outbreak dynamics. Finally, in Aim 4, we will validate the findings from the previous aims in a BSL-4 setting (the biosafety level required for working with live Ebola or Lassa virus) and use the results of animal models to further refine our predictive models of clinical outcome.

项目摘要 - 项目 2 项目 2 的目标是研究病毒遗传学和宿主免疫之间的复杂相互作用。 确定拉沙病毒、埃博拉病毒和 SARS-CoV-2 感染的流行病学和结果。我们的 中心假设是宿主和病毒因素在决定临床疾病严重程度方面发挥着关键作用 结果包括生存、疾病严重程度和长期后遗症的发生。为了测试这个 假设，我们将研究病毒遗传学、宿主免疫的发展以及这些过程是如何进行的 由于病毒感染或疫苗接种而相互作用。在关注宿主-病原体界面时，我们将 补充项目 1 中以宿主为中心的研究，以更好地理解影响宿主的复杂因素 确定拉沙、埃博拉和 COVID-19 的临床结果和流行病学。 为了实现这一目标，我们将完成以下工作： 在目标 1 中，我们将改进病毒测序技术 生成拉沙病毒和 SARS-CoV-2 基因组多样性的大型目录。然后我们将整合这些 数据与环境和人口统计数据并应用系统动力学模型来识别病毒 最有可能影响疾病严重程度的突变和变异。在目标 2 中，我们将执行单人 细胞测序和转录组学以深入表征适应性免疫的进化 对急性拉沙病毒感染或疫苗接种的反应。我们还将从其中分离单克隆抗体 之前感染过拉沙病毒、埃博拉病毒或 SARS-CoV-2 或接种过疫苗的个体 了解人类体液反应的多样性。在目标 3 中，我们将扩展多组学工作 目标 2 中针对感染不同病毒变种的个体提出了建议，目标是开发一种 免疫反应和临床结果的预测模型。该模型将集成系统 来自项目 1 的血清学数据作为实验数据生成重复周期框架的一部分， 整合、应用、验证和完善，以识别人类的预测生物标记 疾病和爆发动态。最后，在目标 4 中，我们将验证之前目标的发现 BSL-4 设置（处理活埃博拉病毒或拉沙病毒所需的生物安全级别）并使用以下结果 动物模型进一步完善我们的临床结果预测模型。