Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation

Cell Rep. 2016 Dec 6;17(10):2584-2595. doi: 10.1016/j.celrep.2016.11.031.


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.

Keywords: bone marrow failure; chronic infection; hematopoietic stem cell; interferon gamma; pancytopenia; terminal differentiation.

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics*
  • Bone Marrow Cells / metabolism
  • Cell Differentiation / genetics*
  • Cell Proliferation / genetics
  • Cell Self Renewal / genetics
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Infections / genetics*
  • Infections / microbiology
  • Infections / pathology
  • Interferon-gamma / genetics
  • Mice
  • Mycobacterium avium / pathogenicity
  • Signal Transduction


  • BATF2 protein, mouse
  • Basic-Leucine Zipper Transcription Factors
  • Interferon-gamma