System Biological Analyses of Adaptive Responses to vaccination

疫苗接种适应性反应的系统生物学分析

基本信息

批准号：
10201503
负责人：
Rafi Ahmed
金额：
$ 230.01万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-13 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201503
关键词：
2019-nCoV ATAC-seq Address Aspirate substance Award Blood COVID-19 Cell Culture Techniques Cells Cloning Competence Diagnostic Disease Donor person Epigenetic Process Epithelial Cells Epitopes Genetic Transcription Grant Heterogeneity Hospitals Human Immune Immune response Immune system Immunity Infection Innate Immune Response Knowledge Learning Lung Lung Transplantation Metabolic Molecular Molecular Profiling Myelogenous Myeloid Cells Natural Immunity Parents Pathogenesis Pathogenicity Peripheral Blood Mononuclear Cell Sampling Science Site Stimulus Structure of parenchyma of lung Systems Biology Therapeutic Vaccination Vaccine Design Vaccines Virus Work airway epithelium biological systems coronavirus disease design epigenomics global health imprint indexing insight macrophage metabolomics monocyte multiple omics novel pandemic disease prevent programs response single-cell RNA sequencing transcriptome transcriptomics transplant centers

项目摘要

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 SARSCoV-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 response1-7 . 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 COVID19 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.

最近出现的新型致病性 SARS 冠状病毒 2 (SARS-CoV-2) 大流行构成了重大的全球健康挑战。冠状病毒病 (COVID-19) 由 SARSCoV-2 引起，是一种潜在致命疾病的病原体。科学已经发生了很大的变化在短时间内快速分离、测序和克隆病毒，并开发诊断试剂盒几周的事。然而，关于两者之间的动态相互作用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通过疫苗接种，仍然没有答案。了解免疫系统如何感知 SARS-CoV-2 感染并协调保护性免疫对于设计有效的疫苗和疗法。我们之前的工作使用系统生物学、多组学方法进行分析人类对疫苗接种的免疫反应描绘了先天性的分子特征对疫苗接种和感染的免疫力，并为免疫提供了丰富的机制见解回应1-7 。在本提案中，我们提出了一项特定地点的研究来分析来自 IMPACC 子研究在埃默里大学进行。我们将使用集成的多组学方法（单一细胞转录组学、代谢组学、单细胞表观基因组学）来研究人类对 COVID19 感染的先天免疫。我们将从 IMPACC 获取 PBMC 和气管抽吸样本将在埃默里大学进行的子研究。我们将解决以下问题：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抽吸物？ COVID-19 感染是否会产生表观遗传印记先天免疫？骨髓细胞亚群和气道的分子景观和功能是什么健康肺部的上皮细胞以及感染了 COVID-19 后的情况如何？这些问题将会解决以下具体目标：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，2) 确定骨髓细胞亚群的分子特性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 感染的免疫反应有重要的了解，可以利用用于设计预防或治疗感染的疫苗和疗法。