Early life respiratory viral infections shape immune development trajectories

摘要 病毒性呼吸道感染是生命早期主要发病率和死亡率的原因。婴儿占 流感住院的比例很大，被认为是最高的高危人群。除了有 急性发病率，对流感的初始免疫反应形成/印记免疫系统，并影响随后的 对流感感染和疫苗接种的反应，这往往会引起体液反应， 在遇到的第一个流感抗原中存在的表位。相比之下，婴儿的SARS-CoV-2感染 一般较轻，不像老年人那么严重。这是值得注意的，并表明有独特的 婴儿免疫系统对SARS-CoV-2的反应与对其他病毒的反应相比， 呼吸道病毒，这可以用来提高我们对早期生命免疫力的理解。 基于这些观察结果，我们假设早期病毒性呼吸道感染引起病毒特异性 导致不同免疫发育轨迹的免疫反应。为了解决这个问题，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; 和作为参照的iii）没有这两种感染的健康婴儿。儿童急性感染后， 纵向随访三年，并在流感和COVID-1背景下评估免疫反应。 19种疫苗 我们设计了两个综合研究项目，由三个核心支持。项目1将定义：1）差异 SARS-CoV-2感染婴儿与流感感染婴儿的血液转录免疫特征; 2)流感病毒抗体应答的幅度、免疫优势模式和呼吸， 对SARS-CoV-2的抗体应答的演变;和3）进行B的高通量纵向评价 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，发生在生命的前六个月， 单细胞水平;和2）表征PBMC表型/细胞组成、转录组和表观基因组， 对流感和SARS-CoV-2疫苗接种的反应。

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.