Project 2

项目2

• 批准号: 10599216
• 负责人: Maria Virginia Pascual
• 金额: $ 69.95万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599216
• 关键词: 2019-nCoV; ATAC-seq; Adult; Affect; Antibody Response; Antibody titer measurement; B-Lymphocytes; Bacterial Infections; Biological Assay; Blood; Blood Cells; CD8-Positive T-Lymphocytes; COVID-19 vaccine; Cell Count; Cell Nucleus; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Child; Childhood; Chromatin; Custom; Data; Data Set; Development; Disease; Enrollment; Epigenetic Process; Exposure to; Gene Expression Profile; Genetic Transcription; Health; Human; Immune; Immune response; Immune system; Immunity; Immunologic Monitoring; Immunophenotyping; Infant; Infection; Influenza; Influenza vaccination; Knowledge; Learning; Life; Longevity; Longitudinal Studies; Molecular; Monitor; Outcome; Participant; Pathway interactions; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Phenotype; Population; Production; Property; Risk; SARS-CoV-2 infection; Sample Size; Sampling; Shapes; Systems Biology; Technology; Vaccination; Vaccines; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; age group; age related; analysis pipeline; commensal microbes; cytokine; epigenome; experience; flexibility; genome-wide; high risk; human old age (65+); immune function; imprint; influenza infection; innovative technologies; multidimensional data; pathogenic microbe; postnatal; respiratory virus; response; seasonal influenza; severe COVID-19; tool; transcriptome; transcriptome sequencing; trend

ABSTRACT Infants and young children are at higher risk for severe manifestations of certain respiratory viruses, such as influenza and RSV, compared to older children or adults. Interestingly, SARS-CoV-2 infection has shown the opposite trend, with infants being at lower risk of serious outcomes. The molecular and cellular mechanisms underpinning vulnerability to some infections and protection from others are poorly understood, but intrinsic properties of the post-natal immune system might be at their core. Systems biology tools can resolve these knowledge gaps through detailed analysis of the transcriptome, epigenome and function of immune cell populations across the life span. This project capitalizes on our experience in studying the human immune system through childhood in health and disease, and the availability of immune monitoring assays for use with small-volume samples. Recently, we have leveraged innovative technologies, i.e., ATAC-seq for assessing chromatin accessibility, RNA-seq, high-definition cellular immunophenotyping at the bulk and single cell levels as well as custom-built integrative analysis pipelines. Our preliminary data confirm that we can maximally leverage infant samples to capture transcriptional and regulatory genome-wide signatures associated with the developing immune system in response to viral infections and vaccination with unprecedented granularity. We propose to assess the immune responses to infection with two viruses, influenza and SARS-CoV-2, occurring in the first six months of life by leveraging our immune profiling platform. We will track age-related changes in immune cell composition, transcriptome and epigenome during this first encounter with the virus and will subsequently monitor these parameters upon vaccination against these viruses yearly for a period of three years. Aim 1 will define the phenotype/cell composition, transcriptome and epigenome of infant PBMCs upon their first encounter with either Influenza or SARS-CoV-2 viruses. Aim 2 will Characterize the PBMC phenotype/cell composition, transcriptome and epigenome in response to vaccination against influenza and SARS-CoV-2.

摘要 婴儿和幼儿患某些呼吸道病毒的严重表现的风险较高，例如 流感和RSV，与年龄较大的儿童或成人相比。有趣的是，SARS-CoV-2感染显示， 相反的趋势，婴儿的严重后果风险较低。的分子机制 对某些感染的脆弱性和对其他感染的保护的基础了解甚少，但内在的 出生后免疫系统的特性可能是其核心。系统生物学工具可以解决这些问题 通过详细分析免疫细胞的转录组、表观基因组和功能， 整个生命周期的人口。这个项目利用了我们在研究人类免疫系统方面的经验。 系统通过儿童的健康和疾病，以及免疫监测测定的可用性， 小体积样品。最近，我们利用创新技术，即，用于评估的ATAC-seq 染色质可及性、RNA-seq、批量和单细胞水平的高清细胞免疫表型分析 以及定制的综合分析管道。我们的初步数据证实，我们可以最大限度地 利用婴儿样本来捕获转录和调节基因组范围内的签名， 发展免疫系统以应对病毒感染和前所未有的粒度接种疫苗。 我们建议评估对流感和SARS-CoV-2两种病毒感染的免疫反应， 发生在生命的前六个月，通过利用我们的免疫分析平台。我们将跟踪与年龄相关的 在第一次与病毒接触期间，免疫细胞组成、转录组和表观基因组的变化 并将随后在每年接种这些病毒疫苗后监测这些参数， 三年目的1：明确婴儿PBMC的表型/细胞组成、转录组和表观基因组 在他们第一次接触流感或SARS-CoV-2病毒时。目标2将表征PBMC 表型/细胞组成、转录组和表观基因组对流感疫苗接种的应答， SARS-CoV-2.