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

早产儿先天免疫的围产期规划和产后重编程及其对早产后结局复杂化的疾病的影响

• 批准号: 284126398
• 负责人: Dr. Sabine Pirr
• 金额: --
• 依托单位: Klinik für Pädiatrische Pneumologie, Allergologie und Neonatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/284126398?language=en
• 关键词: Perinatal; programming; postnatal; reprogramming; innate

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.

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后果有关，所有这些结果都有一种共同的慢性炎症形式。新生儿的免疫系统传统上被认为是有缺陷的，而早产儿败血症的特征是伴随着高度炎症的快速病程。我们最近对实验和临床结果的这种不一致提出了质疑，并证明了以前涉及的新生儿微生物无反应实际上是出生后由警蛋白介导的保护性状态。在健康足月新生儿中，S100-alarmin被大量释放，并介导先天信号通路的预激活和连续耐受。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。在对人类单核细胞的初步全球转录研究中，单样本浓缩分析表明，依赖于核因子-kB的S100反应的促炎基因模块只在足月时预激活，而在早产儿中不预激活。这些发现支持我们的假设，即早产儿缺乏S100-ararmins的免疫程序，使他们容易感染败血症疾病。流行病学数据还表明，早产儿存在长期免疫偏差。在健康足月新生儿中，我们发现，出生后单核细胞的重新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免疫重编程的序列，从而导致对感染性和慢性炎症性疾病的持续易感性。在此，我们提议在出生于≤31+6周的早产儿的预期出生队列中探索S100-ararmins在i)转录和表观遗传编程以及ii)早产单核细胞生后重编程包括其对脂多糖的反应中的作用。此外，临床元数据的全面收集将用于确定早产后伴随免疫介导性继发性疾病的人类单核细胞的编程和重新编程的模式。对于数据集成，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。申请者结合临床和实验专业知识，提供关于人类早产单核细胞炎症响应性的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的见解。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，以促进免疫成熟和预防这一脆弱患者群体中的严重复杂疾病。