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Because infants 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\u2010life. By performing systems\u2010level characterization of \u03b2\u2010glucan\u2010trained monocytes\u00a0from adults, term infants, and preterm infants, we report maturation\u2010dependent constraints in trained immunity. We corroborate these findings in a small cohort of premature infants with in utero pathogen exposure. Alongside limited stimulus\u2010induced reprogramming of innate immune responses in the clinical cohort, monocytes from premature infants exhibited metabolic alterations in glutaminolysis and tricarboxylic acid cycle metabolism, pathways central to trained immunity. They also displayed a treatment\u2010robust long noncoding RNA landscape and transcriptional alterations in enzymes relevant to epigenetic induction of innate immune memory. Finally, network\u2010based analyses implicated SMAD5 and ARNT as potential drivers of differences and provided evidence for altered transcriptional regulation of chromatin organization across early\u2010life 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.<\/jats:p>","DOI":"10.1002\/mco2.70939","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T08:09:56Z","timestamp":1791101396000},"source":"Crossref","is-referenced-by-count":0,"title":["Maturation\u2010Dependent Constraints in the Ability of Human Monocytes to Initiate Trained Immunity"],"prefix":"10.1002","volume":"7","author":[{"given":"Michael","family":"Eigenschink","sequence":"first","affiliation":[{"name":"Department of Pediatrics Division of Neonatology Pediatric Intensive Care and Neuropediatrics Medical University of Vienna  Vienna Austria"},{"name":"Comprehensive Center for Pediatrics Medical University of Vienna  Vienna 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