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dc.contributor.authorKhan, Nargis
dc.contributor.authorSassetti, Christopher M.
dc.contributor.authorDivangahi, Maziar
dc.date2022-08-11T08:09:57.000
dc.date.accessioned2022-08-23T16:50:09Z
dc.date.available2022-08-23T16:50:09Z
dc.date.issued2020-10-29
dc.date.submitted2020-11-30
dc.identifier.citation<p>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. <a href="https://doi.org/10.1016/j.cell.2020.09.062">Link to article on publisher's site</a></p>
dc.identifier.issn0092-8674 (Linking)
dc.identifier.doi10.1016/j.cell.2020.09.062
dc.identifier.pmid33125891
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41606
dc.description<p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=33125891&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright 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/).
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBCG
dc.subjectMycobacterium tuberculosis
dc.subjecthematopoietic stem cells
dc.subjectiron metabolism
dc.subjectmacrophages
dc.subjectmonocytes
dc.subjectmyelopoiesis
dc.subjectnecroptosis
dc.subjecttrained immunity
dc.subjecttype I IFN
dc.subjectBacteria
dc.subjectBacterial Infections and Mycoses
dc.subjectBiological Phenomena, Cell Phenomena, and Immunity
dc.subjectImmunity
dc.subjectImmunology of Infectious Disease
dc.subjectMicrobiology
dc.titleM. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity
dc.typeJournal Article
dc.source.journaltitleCell
dc.source.volume183
dc.source.issue3
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5424&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4395
dc.identifier.contextkey20344426
refterms.dateFOA2022-08-23T16:50:10Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathoapubs/4395
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.source.pages752-770.e22


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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/).
Except where otherwise noted, this item's license is described as 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/).