M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity

Khan, N. ; Downey, J. ; Sanz, J. (Universidad de Zaragoza) ; Kaufmann, E. ; Blankenhaus, B. ; Pacis, A. ; Pernet, E. ; Ahmed, E. ; Cardoso, S. ; Nijnik, A. ; Mazer, B. ; Sassetti, C. ; Behr, M.A. ; Soares, M.P. ; Barreiro, L.B. ; Divangahi, M.

Resumen: 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 ß-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 ß-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.

Idioma: Inglés

DOI: 10.1016/j.cell.2020.09.062

Año: 2020

Publicado en: CELL 183, 3 (2020), 752-770.e22
ISSN: 0092-8674

Factor impacto JCR: 41.582 (2020)

Categ. JCR: CELL BIOLOGY rank: 3 / 195 = 0.015 (2020) - Q1 - T1
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 2 / 297 = 0.007 (2020) - Q1 - T1

Factor impacto SCIMAGO: 26.303 - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA-FEDER/LMP117-18
Financiación: info:eu-repo/grantAgreement/EC/FP7/294709/EU/Tissue Damage Control Regulates The Pathogenesis of Immune Mediated Inflammatory Diseases/DAMAGECONTROL
Financiación: info:eu-repo/grantAgreement/EC/H2020/707998/EU/REGULATORY T CELLS AND TISSUE DAMAGE CONTROL/REGDAM
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2019-106859GA-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/RYC-2017-23560

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Física Teórica (Dpto. Física Teórica)