Perinatal programming and postnatal reprogramming of innate immunity in preterm infants and its implications for diseases complicating the outcome after preterm birth

早产是全世界新生儿发病率和死亡率的主要原因。主要威胁是导致致命败血症的感染。此外，早产与各种不良的长期结果有关，这些结果都有一种共同的慢性炎症形式。新生儿免疫系统传统上被认为是缺陷的，而早产儿败血症的标志是炎症反应迅速。我们最近挑战了这种实验和临床研究结果的不一致性，并证明了先前涉及的新生儿微生物无反应性实际上是出生后的保护性报警蛋白介导的状态。在健康足月新生儿中，S100-alarmins大量释放并介导先天信号传导途径的预激活和连续耐受化。在早产儿中，我们发现血清和母乳中S100-alarmin水平的高度显著降低，这与脓毒症的风险密切相关。在人类单核细胞的初步全球转录组学研究中，单样本富集分析显示，NF-kB依赖性S100反应性促炎基因模块仅在足月儿中预激活，而在早产儿中未激活。这些发现支持了我们的假设，即早产儿缺乏S100-alarmins的免疫编程，使他们容易感染脓毒性疾病。流行病学数据也提示早产儿存在长期免疫偏差。在健康的足月新生儿中，我们发现单核细胞的出生后重编程主要发生在生命的第一年，将免疫调节转换为成人样表型。目前尚不清楚，早产如何改变出生后的免疫重编程序列，导致对感染性和慢性炎症性疾病的持续易感性。在此，我们建议在≤31+6孕周出生的早产新生儿的前瞻性出生队列中探索S100-alarmins在i）转录和表观遗传编程和ii）早产单核细胞的出生后重编程，包括它们对脂多糖的反应。此外，临床元数据的全面收集将用于iii）鉴定早产后伴随免疫介导的继发性疾病的人单核细胞的编程和重编程模式。对于数据整合，我们将使用最先进的生物信息学工具和分析管道，包括机器学习算法。申请人结合联合收割机的临床和实验专业知识，以深入了解人类早产单核细胞的炎症反应性编程如何参与作为主要终点的脓毒症和作为次要终点的慢性炎症性疾病的发病机制。了解这些过程中涉及的分子机制将为新的诊断工具和新概念铺平道路，以促进免疫成熟，并预防这一弱势患者群体的严重并发症。

Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. The key threat are infections that result in fatal sepsis. Moreover, preterm birth is associated with a variety of adverse long-term outcomes that all have a form of chronic inflammation in common. The neonatal immune system is traditionally regarded as deficient while the hallmark of sepsis in preterm infants is a rapid course with hyperinflammation. We recently challenged this inconsistency of experimental and clinical findings and demonstrated that the previously implicated microbial unresponsiveness of neonates actually is a protective alarmin-mediated state after birth. In healthy term newborns, S100-alarmins are massively released and mediate preactivation and consecutive tolerization of innate signaling pathways. In preterm infants, we find the height of S100-alarmin levels in serum and breast milk significantly reduced which correlates strongly with the risk of sepsis. In preliminary global transcriptomic studies in human monocytes single sample enrichment analyses revealed that NF-kB-dependent S100-responsive pro-inflammatory gene modules are only pre-activated in term but not in preterm infants. These findings support our hypothesis that the programming of immunity by S100-alarmins is lacking in preterm infants rendering them vulnerable to septic diseases. Epidemiologic data also suggest long-term immune deviations in preterm infants. In healthy term neonates we found that postnatal reprogramming of monocytes primarily takes place during the first year of life switching immune regulation to an adult-like phenotype. It is currently unknown, how premature birth alters the postnatal sequence of immune reprogramming leading to a sustained susceptibility to infectious and chronic inflammatory diseases.Here we propose to explore in a prospective birth cohort of preterm neonates born ≤31+6 gestational weeks the role of S100-alarmins for i) the transcriptional and epigenetic programming and ii) postnatal reprogramming of premature monocytes including their response to lipopolysaccharide. Moreover, the thorough collection of clinical metadata will be used iii) to identify the patterns of programming and reprogramming of human monocytes that are accompanied by immune-mediated secondary diseases after preterm birth. For data integration we will use state-of-the-art bioinformatics tools and analysis pipelines including machine learning algorithms.The applicants combine clinical and experimental expertise to provide insights into how the programming of the inflammatory responsivity of human preterm monocytes is involved in the pathogenesis of sepsis as primary endpoint and chronic inflammatory diseases as secondary endpoints. Understanding the molecular mechanisms involved in these processes will pave the way for novel diagnostic tools and new concepts to promote immune maturation and to prevent serious complicating diseases in this vulnerable patient group.