M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity.
M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity.
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DOI：
10.1016/j.cell.2020.09.062
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发表时间：
2020-10-29
期刊：
影响因子：
64.5
通讯作者：
Divangahi M
中科院分区：
文献类型：
--
作者：
Khan N;Downey J;Sanz J;Kaufmann E;Blankenhaus B;Pacis A;Pernet E;Ahmed E;Cardoso S;Nijnik A;Mazer B;Sassetti C;Behr MA;Soares MP;Barreiro LB;Divangahi M
对造血干细胞（HSC）调控有更深入的了解是剖析对引起慢性感染的病原体（如结核分枝杆菌（Mtb））的保护性免疫和有害免疫所必需的。我们已经证明，全身给药卡介苗（BCG）或β-葡聚糖分别通过II型干扰素（IFN-II）或白细胞介素-1 （IL1）反应重新编程骨髓（BM）中的hsc，从而赋予对结核杆菌的保护性训练免疫。在这里，我们证明，与卡介苗或β-葡聚糖不同，Mtb通过IFN-I反应重新编程hsc，抑制骨髓生成并损害对Mtb的保护性训练免疫的发展。在机制上，IFN-I信号失调铁代谢，线粒体膜电位去极化，并诱导髓系祖细胞特异性死亡。此外，造血干细胞中IFN-I/铁轴的激活会损害对结核杆菌感染的训练免疫。这些结果确定了BM中Mtb的一种意想不到的免疫逃避策略，该策略控制着感染先天免疫的大小和内在抗微生物能力。结核分枝杆菌通过I型IFN/铁轴对造血干细胞进行重编程，从而损害训练后的免疫。结核分枝杆菌通过I型IFN/铁信号轴对造血干细胞进行重编程，限制骨髓生成，同时通过I型IFN/铁信号轴损害训练后的免疫应答。
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. BCG and Mtb uniquely reprogram HSCs for at least 1 year Mtb suppresses myelopoiesis and impairs HSC engraftment Mtb hijacks a type I IFN/iron axis to induce necroptosis specifically in myeloid lineage Reprogramming of HSCs by a type I IFN/iron axis impairs trained immunity The pathogen Mycobacterium tuberculosis reprograms hematopoietic stem cells and limits myelopoiesis while impairing trained immunity responses via a type I IFN/iron signaling axis.
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影响因子：
5.3
作者：
Alter A;de Léséleuc L;Van Thuc N;Thai VH;Huong NT;Ba NN;Cardoso CC;Grant AV;Abel L;Moraes MO;Alcaïs A;Schurr E
通讯作者：
Schurr E
影响因子：
15.9
作者：
Antonelli, Lis R. V.;Rothfuchs, Antonio Gigliotti;Sher, Alan
通讯作者：
Sher, Alan
影响因子：
3.1
作者：
Chackerian, AA;Alt, JM;Behar, SM
通讯作者：
Behar, SM
影响因子：
168.9
作者：
GENEWEIN, A;TELENTI, A;BODMER, T
通讯作者：
BODMER, T
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J