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Metabolic–Epigenetic Rewiring of CCR5 hi Monocytes Sustains Long-Term Trained Immunity Against Lethal Sepsis [CUT&Tag]

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 co-immunization with Bacillus 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 subsequent lactate accumulation. We found that elevated lactate then promoted KAT2B-dependent histone H3K18 lactylation, an epigenetic mark directly facilitating the transcription of phagocytic and inflammatory genes. Critically, CCR5hi monocytes isolated from vaccinated human cord blood recapitulated these lactate-driven lactylation and trained immunity features. Together, our findings define a novel 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

ORGANISM(S): Mus musculus

PROVIDER: GSE331085 | GEO | 2026/05/20

REPOSITORIES: GEO

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Project description:Vaccination with Bacillus Calmette-Guérin (BCG) induces long-term innate immune memory, also called trained immunity, characterized by metabolic and epigenetic changes leading to enhanced responsiveness upon exposure to heterologous pathogens. BCG vaccination was also shown to reduce systemic inflammation. Thus, BCG counteracts two significant immunological changes associated with aging: impaired responsiveness and elevated systemic inflammation. However, if and how BCG impacts other aging-related processes in immune cells, such as telomere shortening, remains unexplored. In this study, we investigated the transcriptional impact of BCG training on telomere maintenance-related genes through RNA sequencing and determined average telomere length from whole blood via RT-qPCR before and three months after BCG vaccination in two independent human cohorts. Trained immunity response was measured by ex-vivo cytokine production induced by a heterologous stimulus three months after vaccination compared to baseline. In addition, we examined the effects of BCG on telomerase activation using an in vitro trained immunity model. In vitro BCG training upregulated processes related to telomere maintenance and telomerase localization. In vivo, we observed shorter telomeres three months after BCG vaccination in both studies. Interestingly, the induction of a trained immunity response by BCG was correlated to the change in telomere length: more telomere shortening was observed in trained immunity non-responder individuals, particularly in males. Higher testosterone concentrations before vaccination were linked to more telomere loss. In vitro, BCG training of human monocytes activated the telomerase enzyme, predominantly in females, an effect that was blocked by exogenous testosterone treatment. Overall, this study reports sex-specific long-term impacts of BCG vaccination on telomerase activity and telomere maintenance. These data add to the arguments that BCG vaccination impacts aging mechanisms, which warrants more investigation.

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Metabolic–Epigenetic Rewiring of CCR5 hi Monocytes Sustains Long-Term Trained Immunity Against Lethal Sepsis [CUT&Tag]

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