Department of Microbiology and Physiological Systems
Bacteria | Bacterial Infections and Mycoses | Biological Phenomena, Cell Phenomena, and Immunity | Immunity | Immunology of Infectious Disease | Microbiology
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-Guerin (BCG) or beta-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 beta-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, Mycobacterium tuberculosis, hematopoietic stem cells, iron metabolism, macrophages, monocytes, myelopoiesis, necroptosis, trained immunity, type I IFN
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Copyright 2020. The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
DOI of Published Version
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. M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity. Cell. 2020 Oct 29;183(3):752-770.e22. doi: 10.1016/j.cell.2020.09.062. PMID: 33125891; PMCID: PMC7599081. Link to article on publisher's site
Khan N, Sassetti CM, Divangahi M. (2020). M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity. Open Access Publications by UMMS Authors. https://doi.org/10.1016/j.cell.2020.09.062. Retrieved from https://escholarship.umassmed.edu/oapubs/4395
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