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Adv."],"published-print":{"date-parts":[[2026,8,21]]},"abstract":"<jats:p>\n                    Trained immunity enhances innate host defense by endowing monocytes with memory-like properties, yet the underlying integrated metabolic and epigenetic mechanisms remain elusive. Here, we demonstrate that coimmunization with Bacille Calmette-Gu\u00e9rin (BCG) and bacterial lipoprotein (BLP) induces a durable form of trained immunity that provides robust, long-term protection against polymicrobial sepsis from early life into adulthood. Single-cell RNA sequencing revealed that this effect is mediated by an expansion of CCR5\n                    <jats:sup>hi<\/jats:sup>\n                    memory-like monocytes with enhanced antimicrobial capacity. Mechanistically, BCG\u00a0+\u00a0BLP vaccination activated the AKT\u2013mTOR\u2013HIF-1\u03b1 axis, driving glycolytic reprogramming and lactate accumulation. Elevated lactate enhanced KAT2B-dependent histone H3K18 lactylation, an epigenetic mark directly facilitating the transcription of phagocytic and inflammatory genes. In addition, BCG\u00a0+\u00a0BLP stimulation of human cord blood mononuclear cells induced CCR5\n                    <jats:sup>hi<\/jats:sup>\n                    monocytes that recapitulated trained immunity features. These findings identify a lactate-KAT2B-H3K18la epigenetic axis that orchestrates the long-term reprogramming of CCR5\n                    <jats:sup>hi<\/jats:sup>\n                    monocytes, highlighting CCR5\n                    <jats:sup>hi<\/jats:sup>\n                    monocytes as a promising therapeutic target for modulating innate immunity against lethal sepsis.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aee1634","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T17:58:41Z","timestamp":1787335121000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Metabolic-epigenetic rewiring of CCR5\n                    <sup>hi<\/sup>\n                    monocytes sustains long-term trained immunity against lethal sepsis"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4449-3711","authenticated-orcid":true,"given":"Lingqi","family":"Xu","sequence":"first","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University, Suzhou, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1316-7294","authenticated-orcid":true,"given":"Wenyan","family":"Hao","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University, Suzhou, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2864-7442","authenticated-orcid":true,"given":"Yingyi","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Research, Children\u2019s Hospital of Soochow University, Suzhou, Jiangsu, China."},{"name":"Department of Surgery, UT Southwestern 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