Project 2

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。 确定感染拉萨病毒、埃博拉病毒和SARS-CoV-2的流行病学和结局。我们的 中心假设是宿主和病毒因素在决定临床严重程度方面起着关键作用。 结果包括生存、疾病严重程度和长期后遗症的发展。为了测试这一点 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 由于病毒感染或接种疫苗而相互作用。在关注宿主-病原体界面的过程中，我们将 补充项目1中以宿主为重点的研究，以更好地了解 确定拉萨、埃博拉和新冠肺炎的临床结果和流行病学。 为此，我们将完成以下工作：在目标1中，我们将重新fiNe病毒测序技术以 生成拉萨病毒和SARS-CoV-2基因组多样性的大型目录。然后，我们将整合这些内容 使用环境和人口统计数据，并应用系统动力学模型来识别病毒 突变和变异最有可能对疾病的严重程度有影响(eff)等。在目标2中，我们将表演单人 细胞测序和转录学深入研究获得性免疫的进化 对急性拉萨病毒感染或接种疫苗的反应。我们还将从 以前感染过拉萨病毒、埃博拉病毒或SARS-CoV-2或接种过疫苗的个人 理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 在目标2中向感染不同ff病毒变种的个人提出，目的是开发一种 免疫反应和临床结果的预测模型。该模型将系统集成在一起 来自项目1的血清学数据作为实验数据生成的重复循环框架的一部分， 识别人类预测性生物标志物的集成、应用、验证和重排 疾病和暴发动态。最后，在目标4中，我们将在一个 BSL-4设置(处理活的埃博拉或拉萨病毒所需的生物安全级别)，并使用 动物模型，以进一步重新fi我们的临床结果的预测模型。

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.