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: 10599202
• 负责人: Maria Virginia Pascual
• 金额: $ 176.76万
• 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/10599202
• 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; 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 病毒性呼吸道感染是生命早期发病和死亡的主要原因。婴儿占 significant proportion of influenza hospitalizations and are considered a top high-risk group.除了 急性发病、对流感的初始免疫反应塑造/印记免疫系统并影响后续 responses to influenza infections and vaccinations, which tend to induce humoral responses skewed towards epitopes present in the first influenza antigen encountered.相比之下，婴儿中的 SARS-CoV-2 感染是 与老年人相比，通常较轻且较轻。这是值得注意的，表明存在独特的 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. 根据这些观察结果，我们假设生命早期的病毒性呼吸道感染会引发病毒特异性 immune responses that lead to distinct immune developmental trajectories.为了解决这个假设，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； and as reference iii) healthy infants with none of those two infections.急性感染后，孩子会 followed longitudinally for three years and immune responses assessed in the context of influenza and COVID- 19 次疫苗接种。 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 针对 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) 评估血细胞成分、转录组 and epigenome in response to influenza and SARS-CoV-2 infection occurring in the first six months of life at the single cell level; 2) 表征 PBMC 表型/细胞组成、转录组和表观基因组 response to vaccination against influenza and SARS-CoV-2.