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

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. [Display omitted] •Chronic M. avium infection causes pancytopenia in mice•Chronic M. avium infection depletes the hematopoietic stem cell (HSC) pool•Terminal differentiation is the major route of HSC loss during infection•The transcription factor BATF2 promotes IFN-γ-dependent HSPC differentiation Matatall et al. show that chronic infection causes pancytopenia and hematopoietic stem cell (HSC) depletion in mice. HSCs are lost through impaired self-renewal and increased terminal differentiation, which can be triggered by induction of the interferon gamma-responsive transcription factor BATF2. This study elucidates mechanisms underlying bone marrow failure during chronic infections.