Paired Airway and Blood Multiomics Defines Coordinated Immune Adaptation Across the Airway-Blood Axis in Preterm Infants

Immune adaptation after birth requires coordinated remodeling across the airway-blood axis, yet how these compartments communicate during early postnatal life remains poorly understood. In preterms, dysregulation of this immune response determines mortality and morbidity. We performed paired single-cell RNA sequencing (scRNA-seq) and mass spectrometry-based proteomic profiling of airway samples (deep pharyngeal aspirates, DPA) and matched whole blood from 19 neonates spanning extreme preterm (<28 weeks) to term gestation, sampled at two postnatal timepoints (1-3 days and 4-10 days). This integrated multiomic atlas revealed coordinated and compartment-specific immune adaptation across the airway-blood axis during the first week of life. We observed gestational age-dependent shifts in cell composition in both compartments, including expansion of immature hematopoietic and myeloid populations in blood and distinct myeloid and epithelial programs in DPA, accompanied by compartment-specific inflammatory and innate immune gene expression that evolved during the first week of life. Unexpectedly, we identified a circulating respiratory epithelial-like cell population in neonatal blood whose abundance correlated with prematurity and lung disease and which we validated by flow cytometry as well as in independent datasets. Matched plasma proteomics revealed a gestational age axis and a disease-associated axis; an Organ-to-System Score derived from lung-restricted plasma proteins tracked lung injury severity and distinguished trajectories toward chronic lung disease as early as 72 hours after birth. Together, these multiomic data describe coordinated and divergent immune programs across mucosal and systemic compartments in early preterm life, identify circulating respiratory epithelial-like cells as a candidate blood-accessible signal of airway-blood interface perturbation, and prioritize ciliated-myeloid signaling (LAMA5-ITGB1) as a candidate axis underlying neonatal lung disease. This systems-level framework provides a platform for biomarker discovery and mechanistic studies in larger cohorts.