Neonatal Trained Immunity
The survival of non-vertebrate species that lack adaptive immunity has prompted discovery of memory mechanisms in innate immune cells, termed trained immunity. Because infants heavily depend on innate immunity to fight-off pathogens, leveraging these mechanisms in neonatal care may hold clinical significance. Yet, this is constrained by limited understanding of innate immune memory development during early life. By performing systems-level characterization of ß-glucan-trained monocyte-derived macrophages (MDMs) from adults, term infants, and preterm infants, we report maturation-dependent constraints in trained immunity. We corroborate these findings in a small cohort of premature infants with in-utero pathogen exposure. Alongside limited stimulus-induced reprogramming of innate immune responses in the clinical cohort, MDMs from premature infants exhibited metabolic alterations in glutaminolysis and tricarboxylic-acid cycle metabolism, pathways central to trained immunity. They also displayed a treatment-robust long-non-coding RNA landscape and transcriptional alterations in enzymes relevant to epigenetic induction of innate immune memory. Finally, network-based analyses implicated SMAD5 and ARNT as potential drivers of metabolic differences and provided evidence for altered chromatin organization across early-life development. Our results suggest that metabolic and transcriptomic immaturity constrains trained immunity in premature infants, highlighting a developmental mechanism that may affect host defense and guide future immunomodulatory strategies.
The survival of non-vertebrate species that lack adaptive immunity has prompted discovery of memory mechanisms in innate immune cells, termed trained immunity. Because infants heavily depend on innate immunity to fight-off pathogens, leveraging these mechanisms in neonatal care may hold clinical significance. Yet, this is constrained by limited understanding of innate immune memory development during early life. By performing systems-level characterization of ß-glucan-trained monocyte-derived macrophages (MDMs) from adults, term infants, and preterm infants, we report maturation-dependent constraints in trained immunity. We corroborate these findings in a small cohort of premature infants with in-utero pathogen exposure. Alongside limited stimulus-induced reprogramming of innate immune responses in the clinical cohort, MDMs from premature infants exhibited metabolic alterations in glutaminolysis and tricarboxylic-acid cycle metabolism, pathways central to trained immunity. They also displayed a treatment-robust long-non-coding RNA landscape and transcriptional alterations in enzymes relevant to epigenetic induction of innate immune memory. Finally, network-based analyses implicated SMAD5 and ARNT as potential drivers of metabolic differences and provided evidence for altered chromatin organization across early-life development. Our results suggest that metabolic and transcriptomic immaturity constrains trained immunity in premature infants, highlighting a developmental mechanism that may affect host defense and guide future immunomodulatory strategies.