Although the Bacille-Calmette-Guérin (BCG) vaccine is used to prevent tuberculosis, it also offers protection against a diverse range of non-mycobacterial infections. However, the underlying protective mechanisms in humans are not yet fully understood. Here, we surveyed at single-cell resolution the gene expression and chromatin landscape of human bone marrow, aspirated before and 90 days after BCG vaccination or placebo. We showed that BCG alters both the gene expression and epigenetic profiles of human hematopoietic stem and progenitor cells (HSPCs). Changes in gene expression occurred primarily within uncommitted stem cells. By contrast, changes in chromatin accessibility were most prevalent within differentiated progenitor cells at sites influenced by Kruppel-like factor (KLF) and early growth response (EGR) transcription factors and were highly correlated (r > 0.8) with the interleukin (IL)-1β secretion capacity of paired peripheral blood mononuclear cells (PBMCs). Our findings shed light on BCG vaccination’s profound and lasting effects on HSPCs and its influence on innate immune responses and trained immunity.

虽然卡介苗 (BCG) 疫苗用于预防结核病，但它也可以预防多种非分枝杆菌感染。然而，人类潜在的保护机制尚未完全了解。在这里，我们以单细胞分辨率调查了接种 BCG 疫苗或安慰剂之前和之后 90 天抽取的人骨髓的基因表达和染色质景观。我们发现卡介苗可以改变人类造血干细胞和祖细胞 (HSPC) 的基因表达和表观遗传特征。基因表达的变化主要发生在未定型的干细胞内。相比之下，染色质可及性的变化在分化祖细胞中受 Kruppel 样因子 (KLF) 和早期生长反应 (EGR) 转录因子影响的位点最为普遍，并且与白细胞介素 (IL) 高度相关 (r > 0.8)配对外周血单核细胞（PBMC）的-1β分泌能力。我们的研究结果揭示了 BCG 疫苗接种对 HSPC 的深远而持久的影响及其对先天免疫反应和训练免疫力的影响。