Early life respiratory viral infections shape immune development trajectories

摘要 病毒性呼吸道感染是导致早期生命的主要发病率和死亡率的原因。婴儿占到了 流感住院患者中有相当大的比例，被认为是最高风险群体。除 急性发病率，对流感的初始免疫反应塑造/影响免疫系统并影响后续 对流感感染和疫苗接种的反应，这往往会引起偏向于 目前出现的第一个流感抗原表位遇到。相比之下，婴儿感染SARS-CoV-2是 与老年人相比，一般情况下病情较轻，病情较轻。这是值得注意的，并表明有独特的 婴儿免疫系统对SARS-CoV-2的反应特点，与对其他病毒的反应比较 呼吸道病毒，这可以被用来提高我们对早期生命免疫的理解。 在这些观察的基础上，我们假设早期的病毒性呼吸道感染会引起病毒特异性。 免疫反应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)没有这两种感染的健康婴儿。在急性感染后，儿童将会 纵向跟踪了三年，并在流感和新冠肺炎的背景下评估了免疫反应- 接种了19次疫苗。 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 感染SARS-CoV-2的婴儿与感染流感的婴儿的血液转录免疫特征比较； 2)对流感病毒的抗体反应的大小、免疫优势模式和呼吸 SARS-CoV-2抗体反应的进化；以及3)高通量纵向评估B 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 和表观基因组对发生在生命的头六个月的流感和SARS-CoV-2感染的反应 单细胞水平；和2)表征PBMC的表型/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.