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

最近出现了新的致病性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(新冠肺炎)是由非典引起的- CoV-2，代表一种潜在致命疾病的病原体。科学已经取得了很大进展 快速分离、测序和克隆病毒，并开发诊断试剂盒 几个星期的事。然而，关于两国之间的动态相互作用的主要知识差距仍然存在 人类免疫系统和SARS-CoV-2。特别是，几个基本问题 关于其发病机制和需要诱导的保护性免疫机制 通过接种疫苗，保持无应答。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和 治疗学。我们以前的工作是使用系统生物学、多组学的方法来分析 人类对疫苗接种的免疫反应描绘了先天的分子特征 对疫苗接种和感染的免疫力，并提供了对免疫的丰富机械洞察力 回应。在这项建议中，我们建议进行一项特定地点的研究，以分析来自 IMPAC子研究在埃默里进行。我们将使用集成的多组学方法(单一 细胞转录学、代谢组学、单细胞表观基因组学)研究对柯萨奇病毒的天然免疫 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。我们将解决以下问题：什么是 血液和血液中新冠肺炎感染免疫应答的分子和细胞特征 感染者的气管抽吸物？新冠肺炎感染是否具有表观遗传学印记 先天免疫力？髓系细胞亚群和呼吸道的分子格局和功能是什么？ 健康肺中的上皮细胞，以及新冠肺炎感染后？这些问题将是 解决的具体目标如下：1)确定单细胞转录和 新冠肺炎感染后血液和气管免疫应答的表观遗传格局 以及2)确定髓系细胞亚群的分子特性和功能，以及 人肺上皮细胞及其对新冠肺炎感染的反应。这些研究将提供 对人类对新冠肺炎感染的免疫反应的重大洞察可以被利用 用于设计预防或治疗感染的疫苗和疗法。

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.