Core B: System Biological Analyses of Innate and Adpative Responses to Vaccination

最近出现的新型致病性SARS冠状病毒2（SARS-CoV-2）大流行 对全球健康构成重大挑战。冠状病毒病（COVID-19）是由SARS引起的- CoV-2是一种潜在致命疾病的病原体。科学已经非常 快速分离、测序和克隆病毒，并开发诊断试剂盒， 几周的事。然而，在以下方面仍然存在重大知识差距： 人类免疫系统和SARS-CoV-2。特别是，几个基本问题 关于其发病机制，以及需要诱导的保护性免疫机制， 接种疫苗，仍然没有答案。了解免疫系统如何感知SARS-CoV-2 感染和协调保护性免疫对于设计有效的疫苗至关重要， 治疗学我们以前的工作采用系统生物学、多组学的方法来分析 人类对疫苗接种的免疫应答已经描绘了先天免疫缺陷的分子特征， 免疫接种和感染，并提供了丰富的机制的见解，免疫 反应在本提案中，我们提出了一个特定地点的研究，以分析样本从 IMPACC子研究在Emory进行。我们将使用集成的多组学方法（单个 细胞转录组学、代谢组学、单细胞表观基因组学）来研究对COVID的先天免疫- 19人感染。我们将从IMPACC获得PBMC和气管抽吸物样本 将在埃默里进行的子研究。我们将讨论以下问题： 血液中对COVID-19感染的免疫反应的分子和细胞特征， 感染者的气管吸出物COVID-19感染是否会产生 先天免疫力？什么是髓系细胞亚群和气道的分子景观和功能 健康肺中的上皮细胞，以及COVID-19感染后？这些问题将 具体目标如下：1）确定单细胞转录和 血液和气管中对COVID-19感染的免疫反应的表观遗传景观 抽吸物，和2）确定骨髓细胞亚群的分子身份和功能， 人肺上皮细胞及其对COVID-19感染的反应。这些研究将提供 对人类对COVID-19感染的免疫反应的重要见解， 用于设计疫苗和治疗方法来预防或治疗感染。

The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) pandemic poses a major global health challenge. Coronavirus disease (COVID-19) is caused by SARS- CoV-2 and represents the causative agent of a potentially fatal disease. Science has moved very rapidly in isolating, sequencing, and cloning the virus, and developing diagnostic kits, within a matter of weeks. However, major knowledge gaps remain about the dynamic interaction between the human immune system and the SARS-CoV-2. In particular, several fundamental questions regarding its pathogenesis, and the mechanisms of protective immunity that need to be induced by vaccination, remain unanswered. Learning how the immune system senses SARS-CoV-2 infection and orchestrates protective immunity is critical for designing effective vaccines and therapeutics. Our previous work using systems biology, multi-omics approaches to analyze immune responses to vaccination in humans has delineated molecular signatures of innate immunity to vaccination and infection and have provided rich mechanistic insights into the immune response. In this proposal, we propose a site-specific study to analyze samples from the IMPACC sub-study performed at Emory. We will use an integrated multi-omics approach (single cell transcriptomics, metabolomics, single cell epigenomics) to study innate immunity to COVID- 19 infection in humans. We will obtain PBMCs and tracheal aspirate samples from the IMPACC sub-study that will be conducted at Emory. We will address the following questions: What are the molecular and cellular signatures of the immune response to COVID-19 infection in the blood and tracheal aspirates of infected subjects? Does COVID-19 infection exert an epigenetic imprint of innate immunity? What is the molecular landscape and function of myeloid cell subsets and airway epithelial cells in the healthy lung, and following COVID-19 infection? These questions will be addressed in the following specific aims: 1) Determine the single cell transcriptional and epigenetic landscape of the immune response to COVID-19 infection in blood and tracheal aspirates, and 2) Determine the molecular identity and functions of myeloid cell subsets and epithelial cells in human lung and their response to COVID-19 infection. These studies will provide significant insight into the human immune response to COVID-19 infection that can be leveraged for designing vaccines and therapeutics to prevent or treat the infection.