M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity
UMass Chan AffiliationsDepartment of Microbiology and Physiological Systems
Document TypeJournal Article
hematopoietic stem cells
type I IFN
Bacterial Infections and Mycoses
Biological Phenomena, Cell Phenomena, and Immunity
Immunology of Infectious Disease
MetadataShow full item record
AbstractA 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.
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
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/41606
Full author list omitted for brevity. For the full list of authors, see article.