{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:36:26Z","timestamp":1791412586750,"version":"4.3.3"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Newborns exhibit distinct immune responses and are at high risk of infection. Neonatal immunization with BCG, the live attenuated vaccine against tuberculosis (TB), is associated with broad protection against a range of unrelated pathogens, possibly reflecting vaccine-induced training of innate immune cells (\u201cinnate memory\u201d). However, little is known regarding the impact of age on BCG-induced innate responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>Establish an age-specific human monocyte <jats:italic>in vitro<\/jats:italic> training platform to characterize and compare BCG-induced primary and memory cytokine responses and immunometabolic shifts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design\/Methods<\/jats:title><jats:p>Human neonatal and adult CD33-selected monocytes were stimulated for 24h with RPMI (control) or BCG (Danish strain) in 10% autologous serum, washed and cultured for 5 additional days, prior to re-stimulation with the TLR4 agonist LPS for another 24h. Supernatants were collected at Day 1 (D1) to measure <jats:italic>primary<\/jats:italic> innate responses and at Day 7 (D7) to assess <jats:italic>memory<\/jats:italic> innate responses by ELISA and multiplex cytokine and chemokine assays. Lactate, a signature metabolite increased during trained immunity, was measured by colorimetric assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cytokine production by human monocytes differed significantly by age at D1 (primary, BCG 1:750 and 1:100 vol\/vol, p&amp;lt;0.0001) and D7 (innate memory response, BCG 1:100 vol\/vol, p&amp;lt;0.05). Compared to RPMI control, newborn monocytes demonstrated greater TNF (1:100, 1:10 vol\/vol, p&amp;lt;0.01) and IL-12p40 (1:100 vol\/vol, p&amp;lt;0.05) production than adult monocytes (1:100, p&amp;lt;0.05). At D7, while BCG-trained adult monocytes, as previously reported, demonstrated enhanced LPS-induced TNF production, BCG-trained newborn monocytes demonstrated tolerization, as evidenced by significantly diminished subsequent LPS-induced TNF (RPMI vs. BCG 1:10, p &amp;lt;0.01), IL-10 and CCL5 production (p&amp;lt;0.05). With the exception of IL-1RA production by newborn monocytes, BCG-induced monocyte production of D1 cytokines\/chemokines was inversely correlated with D7 LPS-induced TNF in both age groups (p&amp;lt;0.0001). Compared to BCG-trained adult monocytes, newborn monocytes demonstrated markedly impaired BCG-induced production of lactate, a metabolite implicated in immune training in adults.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>BCG-induced human monocyte primary- and memory-innate cytokine responses were age-dependent and accompanied by distinct immunometabolic shifts that impact both glycolysis and training. Our results suggest that immune ontogeny may shape innate responses to live attenuated vaccines, suggesting age-specific approaches to leverage innate training for broad protection against infection.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.674334","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T13:42:45Z","timestamp":1626183765000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":30,"title":["Human Newborn Monocytes Demonstrate Distinct BCG-Induced Primary and Trained Innate Cytokine Production and Metabolic Activation In 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