Authors
Lingqi Xu, Wenyan Hao, Yingyi Yang, Yu Wang, Yaoshuang Li, Yuan Gong, Yifang Ding, Jie Huang, Zhenjiang Bai, Qiang Shan, Rui Kang, Jiang Huai Wang, Haichao Wang, Timothy R Billiar, Jian Wang, Daolin Tang, Huiting Zhou
Published in
Science advances. Volume 12. Issue 34. Pages eaee1634. Aug 21, 2026. Epub Aug 21, 2026.
Abstract
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-Guérin (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 CCR5hi memory-like monocytes with enhanced antimicrobial capacity. Mechanistically, BCG + BLP vaccination activated the AKT-mTOR-HIF-1α 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 + BLP stimulation of human cord blood mononuclear cells induced CCR5hi monocytes that recapitulated trained immunity features. These findings identify a lactate-KAT2B-H3K18la epigenetic axis that orchestrates the long-term reprogramming of CCR5hi monocytes, highlighting CCR5hi monocytes as a promising therapeutic target for modulating innate immunity against lethal sepsis.
PMID:
42627899
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.
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