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
Sample name | Organism | Experiment title | Sample type | Library instrument | Attributes | |||||||||||||||||||||||||||||||||||||||||||||||||
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age | cell surface marker | cell type | sex | source name | strain | tissue | treatment | |||||||||||||||||||||||||||||||||||||||||||||||
ctr_hsc_l3 RNA-Seq | Mus musculus | GSM2367465: ctr_hsc_l3 RNA-Seq; Mus musculus; RNA-Seq | RNA-Seq | Illumina HiSeq 2000 | 3-4 months | SP KSL CD150+ | Hematopoietic stem cells (HSCs) | female | Murine bone marrow derived primary HSCs | C57BL/6 | bone marrow | Naïve | ||||||||||||||||||||||||||||||||||||||||||
ctr_hsc_l2 RNA-Seq | Mus musculus | GSM2367464: ctr_hsc_l2 RNA-Seq; Mus musculus; RNA-Seq | RNA-Seq | Illumina HiSeq 2000 | 5 months | SP KSL CD150+ | Hematopoietic stem cells (HSCs) | female | Murine bone marrow derived primary HSCs | C57BL/6 | bone marrow | Naïve | ||||||||||||||||||||||||||||||||||||||||||
ctr_hsc_l1 RNA-Seq | Mus musculus | GSM2367463: ctr_hsc_l1 RNA-Seq; Mus musculus; RNA-Seq | RNA-Seq | Illumina HiSeq 2000 | 5 months | SP KSL CD150+ | Hematopoietic stem cells (HSCs) | female | Murine bone marrow derived primary HSCs | C57BL/6 | bone marrow | Naïve | ||||||||||||||||||||||||||||||||||||||||||
mav_hsc_l3 RNA-Seq | Mus musculus | GSM2367462: mav_hsc_l3 RNA-Seq; Mus musculus; RNA-Seq | RNA-Seq | Illumina HiSeq 2000 | 3-4 months | SP KSL CD150+ | Hematopoietic stem cells (HSCs) | female | Murine bone marrow derived primary HSCs | C57BL/6 | bone marrow | Mycobacterium avium infection | ||||||||||||||||||||||||||||||||||||||||||
mav_hsc_l2 RNA-Seq | Mus musculus | GSM2367461: mav_hsc_l2 RNA-Seq; Mus musculus; RNA-Seq | RNA-Seq | Illumina HiSeq 2000 | 5 months | SP KSL CD150+ | Hematopoietic stem cells (HSCs) | female | Murine bone marrow derived primary HSCs | C57BL/6 | bone marrow | Mycobacterium avium infection |