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

• Applicants: Dr. Sabine Pirr; Professorin Dr. Dorothee Viemann
• Subject Area: Pediatric and Adolescent Medicine
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 284126398

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.

• DFG Programme: Research Grants