Systems biology approaches to unravelling neonatal sepsis and potential for precision diagnostics and therapeutics

Sepsis is a major cause of global neonatal mortality, affecting 1.3 to 1.9 million neonates worldwide. Accurate diagnoses and effective treatment of sepsis during the onset is essential to improve outcomes. Current efforts to develop sensitive molecular biomarkers, however, are limited by the lack of accurate diagnostic tests, particularly the lack of sensitive viral testing or blood culture methods with low blood inoculums from small neonates. Consequently, antibiotic treatments are often misused, contributing to antimicrobial resistance among neonates exposed to unnecessary antibiotics. To improve the management of neonatal sepsis, a thorough understanding of early neonatal immune development and the pathophysiology of the disease is required. In this review, we summarize the current understanding of the newborn's immune system based on different gestational ages and describe its influence on molecular mechanisms characterizing neonatal sepsis. We also focus on current endeavors for neonatal sepsis diagnosis and new approaches using omics-based biomarkers, highlighting their limitations and future directions for clinical applications. Lastly, we will discuss how utilizing systems immunology provides mechanistic insights and potential avenues towards therapeutics.