title: Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation.
abstract: 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.
authors.affiliation: Section of Pediatric Infectious Diseases, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Matatall
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mira
authors.initials: M
authors.lastname: Jeong
authors.affiliation: Department of Statistics, Rice University, Houston, TX 77030, USA.
authors.forename: Siyi
authors.initials: S
authors.lastname: Chen
authors.affiliation: Institute of Biosciences & Technology, College of Medicine Texas A&M University Health Science Center, Houston, TX 77030, USA.
authors.forename: Deqiang
authors.initials: D
authors.lastname: Sun
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Fengju
authors.initials: F
authors.lastname: Chen
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.affiliation: Department of Statistics, Rice University, Houston, TX 77030, USA; Systems Engineering Group, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Kimmel
authors.affiliation: Section of Pediatric Infectious Diseases, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; BCM Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: kyk@bcm.edu.
authors.forename: Katherine Y
authors.initials: KY
authors.lastname: King
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics*; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D000066673:Cell Self Renewal / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007239:Infections / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics; D051379:Mice; D009162:Mycobacterium avium / Q000472:pathogenicity; D015398:Signal Transduction
chemical_list: C576672:BATF2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D007371:Interferon-gamma
keywords: bone marrow failure; chronic infection; hematopoietic stem cell; interferon gamma; pancytopenia; terminal differentiation