A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or β-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or β-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.

需要更深入地了解造血干细胞 (HSC) 调节，以剖析针对结核分枝杆菌( Mtb ) 等引起慢性感染的病原体的保护性免疫和有害性免疫。我们已经证明，全身施用卡介苗 (BCG) 或 β-葡聚糖可分别通过 II 型干扰素 (IFN-II) 或白介素-1 (IL1) 反应重新编程骨髓 (BM) 中的 HSC，从而赋予针对Mtb 的保护性训练免疫力。在这里，我们证明，与 BCG 或 β-葡聚糖不同，Mtb通过 IFN-I 反应重新编程 HSC，从而抑制骨髓生成并损害针对Mtb 的保护性训练免疫力的发展。从机制上讲，IFN-I 信号传导失调铁代谢，使线粒体膜电位去极化，并特别诱导骨髓祖细胞死亡。此外，HSC 中 IFN-I/铁轴的激活会损害针对Mtb感染的训练有素的免疫力。这些结果确定了 BM 中Mtb的一种意想不到的免疫逃避策略，该策略控制着对感染的先天免疫的程度和内在抗微生物能力。