Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation
Open accessAbstract
Chronic infections affect a third of the world's population and can cause bone marrow suppression, a severe condition that increases mortality from infection. To uncover the basis for infection-associated bone marrow suppression, we conducted repeated infection of WT mice with Mycobacterium avium. After 4-6 months, mice became pancytopenic. Their hematopoietic stem and progenitor cells (HSPCs) were severely depleted and displayed interferon gamma (IFN-γ) signaling-dependent defects in self-renewal. There was no evidence of increased HSPC mobilization or apoptosis. However, consistent with known effects of IFN-γ, transcriptome analysis pointed toward increased myeloid differentiation of HSPCs and revealed the transcription factor Batf2 as a potential mediator of IFN-γ-induced HSPC differentiation. Gain- and loss-of-function studies uncovered a role for Batf2 in myeloid differentiation in both murine and human systems. We thus demonstrate that chronic infection can deplete HSPCs and identify BATF2 as a mediator of infection-induced HSPC terminal differentiation.
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Chronic pro-inflammatory signaling due to chronic infections or repetitive sterile inflammation is detrimental to HSPC self-renewal, promoting loss of quiescence and differentiation.
“Chronic pro-inflammatory signaling due to chronic infections or repetitive sterile inflammation, however, has been shown to be detrimental to HSPC self-renewal, promoting loss of quiescence and differentiation [61–65].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [61]
The Discussion (page not supplied) reports that chronic M. avium infection impairs HSC self-renewal and promotes terminal differentiation. The Results also report sustained HSC cell-cycle activity during infection, consistent with loss of quiescence. The paper does not establish the same combination of effects for repetitive sterile inflammation, so it supports the infection portion of this multi-citation claim, not its full scope. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIFN-γ signaling is necessary and sufficient for the fitness of Dnmt3a knockout hematopoiesis.
“supporting that IFN-γ signaling is necessary and sufficient for the fitness of Dnmt3a knockout hematopoiesis.”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [61]
The Results sections on IFNγ-dependent HSC engraftment and BATF2 loss of function examine infection-related HSC impairment and BATF2-knockout progenitors, respectively; no page numbers are available in our copy. A search for Dnmt3a-knockout hematopoiesis and IFNγ-related fitness found no passage addressing whether IFNγ signaling is necessary and sufficient for that fitness. (LLM, conf=0.70)
Experimental — accuracy not yet measured
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- Authors
- Matatall, K. A., Jeong, M., Chen, S., Sun, D., Chen, F., Mo, Q., Kimmel, M., & King, K. Y.
- Affiliations
- Baylor College of Medicine (US)
- Rice University (US)
- Texas A&M Health Science Center (US)
- Silesian University of Technology (PL)
- Corresponding author
- King, Katherine Y.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 17
- Issue
- 10
- Pages
- 2584-2595
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5161248
- OpenAlex
- W2560439679
- Cited by
- 262
- References
- 4
- Citations by year
- 2026: 14 · 2025: 27 · 2024: 33 · 2023: 37 · 2022: 30 · 2021: 38 · 2020: 33 · 2019: 19 · 2018: 20 · 2017: 9 · 2016: 1
- FWCI
- 15.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rice Research Repository (Rice University) (submittedVersion, cc-by-nc-nd)
- Funders
- Cytometry and Cell Sorting Core
- NIAID (P30AI036211)
- NCI (P30CA125123)
- NCRR (S10RR024574)
- Integrated Microscopy Core (HD007495, DK56338, CA125123)
- Dan L. Duncan Cancer Center
- John S. Dunn Gulf Coast Consortium for Chemical Genetics
- NIDDK (DK060445)
- NHLBI (HL128173-02, K08HL098898)
- Department of Defense (10505346)
- Caroline Wiess Law Foundation for Molecular Medicine
- Aplastic Anemia and MDS International Foundation
- March of Dimes Basil O’Connor Starter Scholar Award
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- chronic infection, hematopoietic stem and progenitor cells, Mycobacterium avium, interferon-gamma signaling, BATF2, myeloid differentiation, terminal differentiation, myelosuppression, pancytopenia, self-renewal, hematopoiesis
- MeSH terms
- Cell Self Renewal, Animals, Bone Marrow Cells, Cell Differentiation, Hematopoietic Stem Cells, Humans, Infections, Interferon-gamma, Mycobacterium avium, Signal Transduction, Cell Proliferation, Basic-Leucine Zipper Transcription Factors, Mice
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