M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [Bulk_SERIES_1]

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 BCG or b-glucan reprograms HSCs in the BM via a type II interferon (IFN-II) or IL1 response, respectively, that confers protective trained immunity against Mtb. Yet, whether BCG/β-Glucan is unique in its ability to induce this protection remains unknown. Herein, we demonstrate that unlike BCG or b-glucan, Mtb reprograms HSCs via IFN-I response that suppresses myelopoiesis and impairs protective trained immunity to Mtb. Mechanistically, IFN-I response dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death in myeloid progenitors. Finally, activation of IFN-I/iron axis in myeloid progenitors generates a detrimental trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the bone marrow that controls the magnitude and anti-microbial capacity of innate immunity to infection Bulk RNA expression profiles of Multipotent progenitors (MPPs) and hematopoietic stem cells (HSCs) of mice injected -iv with either BCG, M.tuberculosis or PBS.

若要解析结核分枝杆菌（Mycobacterium tuberculosis, Mtb）等慢性感染病原体所诱导的保护性与致病性免疫反应，亟需深化对造血干细胞（hematopoietic stem cell, HSC）调控机制的认知。我们此前的研究证实，通过系统性给予卡介苗（BCG）或β-葡聚糖，可分别经由II型干扰素（IFN-II）或IL-1信号通路重编程骨髓（bone marrow, BM）中的造血干细胞，从而赋予机体针对结核分枝杆菌的保护性训练免疫。然而，BCG/β-葡聚糖是否是唯一可诱导此类保护效应的物质，目前仍未明确。本研究证实，与BCG或β-葡聚糖不同，结核分枝杆菌可通过I型干扰素（IFN-I）信号通路重编程造血干细胞，抑制髓系生成并削弱机体针对结核分枝杆菌的保护性训练免疫。从机制层面来看，I型干扰素信号通路会紊乱铁代谢、使线粒体膜电位去极化，并诱导髓系祖细胞发生细胞死亡。最终，髓系祖细胞中I型干扰素/铁信号轴的激活，会介导针对结核分枝杆菌感染的致病性训练免疫。上述研究结果揭示了结核分枝杆菌在骨髓中一种此前未被发现的免疫逃逸策略，该策略可调控固有免疫应对感染时的强度与抗菌能力。本数据集包含经静脉注射（iv）卡介苗、结核分枝杆菌或磷酸盐缓冲液（PBS）的小鼠多能祖细胞（Multipotent progenitors, MPPs）与造血干细胞（HSC）的批量RNA表达谱。