The postnatal maturation of human innate immunity against influenza infections and the associated risk for severe influenza diseases in dependence on the developing gut microbiome

与年龄较大的儿童和成人相比，5岁以下儿童与流感相关的死亡发生率较低。合并症并不能完全解释这种特殊性。随着年龄的增长，是什么重新编程的免疫系统加重了流感疾病的严重程度，这在很大程度上仍不清楚。对于甲型流感病毒（IAV），我们发现新生儿和成人在人初级气道上皮细胞（AECs）、巨噬细胞和单核细胞中的传染性和复制方面没有差异。然而，我们的数据表明，新生儿免受严重流感病程的保护与以细胞类型独立的方式特异性减弱炎症反应有关。人类新生儿和成人单核细胞的全球转录组分析显示，对IAV的差异反应主要可追溯到基线时的特定差异编程。我们确定了候选基因，其在环境适应过程中的个体重编程明显改变了单核细胞在以后的生活中抗iav反应的特征。来自新生儿的人类aec是否在转录和表观遗传上与成人不同尚不清楚。在小鼠中，已经反复表明，出生后定植的微生物群对常驻和非常驻免疫细胞具有很强的印记作用。在人类中，这种关系的明确证据仍未得到证实，特别是在抗禽流感病毒免疫方面。在这里，我们建议探索出生后呼吸道和先天免疫反应对流感感染的可塑性以及与发育中的肠道微生物群的联系。我们将首次分析新生儿与成人原发性AECs的转录和表观遗传程序，以及它们对IAV感染的反应模式。将在健康足月婴儿的前瞻性单中心出生队列中研究出生后抗iav免疫重编程，这些婴儿在出生后第一年的特定时间点进行检查和抽样。aec和单核细胞会在体外被IAV感染。在这个项目中，我们将首先关注单核细胞，跟踪年龄依赖性iav相关的转录和表观遗传变化。同时，从队列中收集鼻拭子和粪便样本。在这里，我们仅限于使用16S rRNA测序和从粪便样本中提取的DNA宏基因组学分析肠道微生物组。最后，关于免疫编程和微生物群组成的总体进展的数据将使用现代最先进的管道进行整合。目的是确定哪些微生物群在多大程度上很可能影响非常驻单核细胞对IAV的后期反应。了解个体对流感病毒的免疫在生命早期如何形成的分子机制，将为在生命中最早可能的时刻应对日益增加的严重流感感染易感性开辟新的途径。

Compared to older children and adults the incidence of influenza-associated deaths among children below 5 years of age is low. Comorbidities do not fully explain this particularity. It largely remains unclear what reprogramming of immunity aggravates the severity of influenza diseases with increasing age. For the influenza A virus (IAV) we found no differences between neonates and adults with respect to infectibility and replication in human primary airway epithelial cells (AECs), macrophages and monocytes. However, our data suggest that the protection of newborn infants from severe courses of influenza is linked to a specifically blunted inflammatory response in a cell-type-independent manner. Global transcriptome analyses in human neonatal and adult monocytes revealed that the differential response to IAV mainly traces back to a specific differential programming at baseline. We identified candidate genes whose individual reprogramming during environmental adaptation obviously changes the character of the anti-IAV response of monocytes later in life. Whether human AECs from newborn infants differ transcriptionally and epigenetically from adults is not known. In mice, it has been repeatedly shown that the postnatally colonizing microbiota has strong imprinting effects on resident and non-resident immune cells. In humans, clear evidences for such relationships are still pending, specifically with respect to anti-IAV immunity.Here we propose to explore the postnatal plasticity of respiratory and innate immune responses toward influenza infections and linkages with the developing gut microbiome. We will profile for the first time the transcriptional and epigenetic programming of neonatal compared to adult primary AECs and their response patterns to IAV infection. Postnatal reprogramming of anti-IAV immunity will be investigated within a prospective single-center birth cohort of healthy term babies that are examined and sampled at defined time points during the first year of life. AECs and monocytes will be infected ex vivo with IAV. In this project we will first focus on the monocytes in terms of tracking age-dependent IAV-relevant transcriptional and epigenetic changes. In parallel, nasal swabs and stool samples are collected from the cohort. Here, we restrict to the analysis of gut microbiomes using 16S rRNA sequencing and metagenomics of DNA extracted from the stool samples. Finally, data on the overall progression of immune programming and microbiota composition will be integrated using modern state-of-the art pipelines. Aim is to identify what microbiota at what extent very likely impacts on the later responsivity of non-resident monocytes toward IAV. Understanding the molecular mechanisms how individual immunity towards the influenza virus is shaped during early life will open new avenues to counter an increased susceptibility to severe influenza infections at the earliest conceivable moment in life.