Early life respiratory viral infections shape immune development trajectories

生命早期呼吸道病毒感染塑造免疫发育轨迹

• 批准号: 10435211
• 负责人: Maria Virginia Pascual
• 金额: $ 169万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 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 2022-12-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435211
• 关键词: 2019-nCoV; ATAC-seq; Acute; Address; Affect; Antibodies; Antibody Response; Antibody titer measurement; Antigens; B-Lymphocytes; Blood; Blood Cells; CD8-Positive T-Lymphocytes; COVID-19 vaccination; COVID-19 vaccine; Cell Nucleus; Cell surface; Cells; Cellular Assay; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Child; Development; Disease; Epigenetic Process; Epitopes; Evaluation; Evolution; Exposure to; Genes; Genetic Transcription; Hospitalization; Immune; Immune response; Immune system; Immunity; Immunophenotyping; Individual; Infant; Infection; Influenza; Influenza vaccination; Lead; Learning; Life; Longitudinal cohort; Morbidity - disease rate; Multivariate Analysis; Participant; Pattern; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Phenotype; Production; Research Project Grants; SARS-CoV-2 infection; Shapes; Specificity; Vaccination; Vaccines; Viral Respiratory Tract Infection; Virus; Virus Diseases; acute infection; cytokine; design; droplet sequencing; epigenome; high risk population; imprint; improved; infant infection; influenza infection; influenzavirus; mortality; multidimensional data; respiratory virus; response; seasonal influenza; transcriptome

Abstract Viral respiratory infections are responsible for major morbidity and mortality in early life. Infants account for a significant proportion of influenza hospitalizations and are considered a top high-risk group. In addition to the acute morbidity, initial immune responses to influenza shape/imprint the immune system and affect subsequent responses to influenza infections and vaccinations, which tend to induce humoral responses skewed towards epitopes present in the first influenza antigen encountered. In contrast, SARS-CoV-2 infection in infants is generally mild and less severe than in older individuals. This is remarkable and suggests that there are unique features on how the infant immune system responds to SARS-CoV-2, compared to its responses against other respiratory viruses, that can be leveraged to improve our understanding of early life immunity. On the basis of these observations, we hypothesize that early life viral respiratory infections elicit virus-specific immune responses that lead to distinct immune developmental trajectories. To address this hypothesis, we will compare three longitudinal cohorts: i) infants infected with SARS-CoV-2; ii) infants infected with influenza virus; and as reference iii) healthy infants with none of those two infections. After acute infection children will be followed longitudinally for three years and immune responses assessed in the context of influenza and COVID- 19 vaccinations. We designed two integrated research projects, supported by three cores. Project 1 will define: 1) the differences of blood transcriptional immune signatures in infants with SARS-CoV-2 versus infants with influenza infection; 2) the magnitude, immunodominance pattern and breath of the antibody responses to influenza virus and evolution of antibody responses to SARS-CoV-2; and 3) perform high-throughput longitudinal evaluation of B cell responses to influenza and SARS-CoV-2. Project 2 will: 1) Assess the blood cell composition, transcriptome and epigenome in response to influenza and SARS-CoV-2 infection occurring in the first six months of life at the single cell level; and 2) Characterize the PBMC phenotype/cell composition, transcriptome and epigenome in response to vaccination against influenza and SARS-CoV-2.

抽象的 病毒呼吸道感染负责早期的主要发病率和死亡率。婴儿解释 流感住院的很大比例，被认为是高风险群体。除了 急性发病率，对流感形状/烙印免疫系统的初始免疫反应，并影响随后的 对流感感染和疫苗接种的反应，这些感染和疫苗接种倾向于引起体液反应 遇到的第一个流感抗原中存在的表位。相反，婴儿的SARS-COV-2感染是 通常比老年人轻度且不那么严重。这很了不起，表明有独特的 与其他针对其他的反应相比，婴儿免疫系统如何对SARS-COV-2响应 可以利用的呼吸道病毒来提高我们对早期免疫力的理解。 根据这些观察，我们假设早期生命病毒呼吸道感染引起了病毒特异性 免疫反应会导致不同的免疫发育轨迹。为了解决这一假设，我们将 比较三个纵向队列：i）感染SARS-COV-2的婴儿； ii）感染流感病毒的婴儿； 作为参考III）这两种感染的健康婴儿。急性感染后的孩子将 紧随其后的三年，并在流感和互联的背景下评估了免疫反应 19次疫苗接种。 我们设计了两个综合研究项目，并得到了三个核心的支持。项目1将定义：1）差异 患有SARS-COV-2的婴儿与流感感染的婴儿的血液转录免疫信号； 2）对流感病毒和 对SARS-COV-2的抗体反应的演变； 3）对B进行高通量纵向评估 细胞对流感和SARS-COV-2的反应。项目2将：1）评估血细胞组成，转录组 和表观基因组对流感和SARS-COV-2感染的反应在生命的前六个月发生 单细胞水平； 2）表征PBMC表型/细胞组成，转录组和表观基因组 对疫苗接种疫苗和SARS-COV-2的反应。