Trained immunity refers to a form of enhanced innate host defense in which innate immune cells—particularly monocytes—acquire memory-like properties after certain stimuli. The mechanisms that integrate metabolic shifts and epigenetic remodeling to produce durable trained immunity remain incompletely defined. The study summarized here examines how coimmunization with Bacille Calmette-Guérin (BCG) and bacterial lipoprotein (BLP) drives a long-lasting trained immunity state that protects against polymicrobial sepsis, and it delineates a linked metabolic and epigenetic pathway mediating this effect.
Coexposure to BCG + BLP produced a durable form of trained immunity that conferred robust, long-term protection against polymicrobial sepsis from early life into adulthood. The authors report that this vaccination strategy generated persistent functional changes in the monocyte compartment rather than a transient activation, indicating a form of long-term innate immune memory induced by the combined stimulus.
Using single-cell RNA sequencing, the investigators identified an expansion of a distinct subset of monocytes characterized by high expression of CCR5 (termed CCR5hi memory-like monocytes). These cells displayed enhanced antimicrobial capacity and transcriptional features consistent with a trained state. The expansion of CCR5hi monocytes was implicated as a cellular correlate of the protection observed after BCG + BLP vaccination.
Mechanistic interrogation revealed activation of the AKT‑mTOR‑HIF‑1α signaling axis following BCG + BLP stimulation. Activation of this pathway promoted glycolytic reprogramming in the responding monocytes, with resultant accumulation of lactate. The link between AKT‑mTOR‑HIF‑1α signaling and increased glycolysis supports a model in which metabolic state drives downstream functional and transcriptional changes in trained monocytes.
A key mechanistic insight from the study is that elevated intracellular lactate enhanced KAT2B-dependent histone H3 lysine 18 lactylation (H3K18la). This specific histone post-translational modification functioned as an epigenetic mark that directly facilitated transcription of genes involved in phagocytosis and inflammatory responses. The authors therefore describe a lactate‑KAT2B‑H3K18la epigenetic axis that couples metabolic reprogramming to durable changes in gene expression within CCR5hi monocytes.
The translational relevance of the pathway was supported by experiments using human cord blood mononuclear cells. Stimulation of these cells with BCG + BLP induced CCR5hi monocytes that recapitulated features of trained immunity described in the animal or model systems. This observation suggests that the identified metabolic and epigenetic mechanisms may be operative in human neonatal innate immune cells and could underlie enhanced antimicrobial function after similar stimuli.
Taken together, the reported data identify a mechanistic cascade—AKT‑mTOR‑HIF‑1α activation, glycolysis with lactate accumulation, and KAT2B‑mediated H3K18 lactylation—that sustains long-term reprogramming of CCR5hi monocytes after BCG + BLP coimmunization. Because the expanded CCR5hi monocyte population exhibits enhanced antimicrobial function and correlates with protection against polymicrobial sepsis, the authors highlight CCR5hi monocytes as a promising therapeutic target for modulating innate immunity in the context of lethal sepsis.
The abstract does not report detailed experimental parameters such as vaccination doses, timing, quantitative effect sizes, specific animal models used, or safety and tolerability data; those details would need to be consulted in the full text for clinical translation or experimental replication.
Overall, the study proposes a defined metabolic‑epigenetic pathway—the lactate‑KAT2B‑H3K18la axis—linking metabolic state to long-term transcriptional and functional reprogramming of CCR5hi monocytes in trained immunity against lethal sepsis.