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

Area of Science:

• Hematology
• Immunology
• Infectious Diseases

Background:

• Chronic infections impact a third of the global population.
• Bone marrow suppression is a severe complication of chronic infections, increasing mortality.
• Understanding the mechanisms of infection-associated bone marrow suppression is crucial.

Purpose of the Study:

• To investigate the basis of bone marrow suppression caused by chronic infection.
• To identify the cellular and molecular mechanisms underlying hematopoietic stem and progenitor cell (HSPC) depletion during chronic infection.

Main Methods:

• Repeated infection of wild-type (WT) mice with Mycobacterium avium.
• Analysis of hematopoietic stem and progenitor cells (HSPCs) for depletion, mobilization, and apoptosis.
• Transcriptome analysis to identify key signaling pathways and transcription factors.
• Gain- and loss-of-function studies of the transcription factor Batf2 in murine and human systems.

Main Results:

• Chronic Mycobacterium avium infection led to pancytopenia and severe depletion of HSPCs in mice after 4-6 months.
• HSPCs exhibited impaired self-renewal, dependent on interferon gamma (IFN-γ) signaling, without increased mobilization or apoptosis.
• Transcriptome analysis revealed increased myeloid differentiation of HSPCs and identified the transcription factor Batf2 as a mediator of IFN-γ-induced differentiation.
• Batf2 was confirmed to play a role in myeloid differentiation in both murine and human cells.

Conclusions:

• Chronic infection can cause significant depletion of hematopoietic stem and progenitor cells (HSPCs).
• Interferon gamma (IFN-γ) signaling plays a critical role in mediating infection-induced HSPC defects.
• The transcription factor Batf2 is identified as a key mediator of IFN-γ-induced terminal differentiation of HSPCs during chronic infection.