Chronic Mycobacterium Avium Infection Leads to Cell Autonomous Exhaustion of Hematopoietic Stem Cells

Background: Chronic infections and inflammatory conditions can cause bone marrow suppression and pancytopenia, a dangerous condition that impairs recovery from infection. In some chronic infections such as tuberculosis, marrow suppression has been ascribed to myelofibrosis. However, inflammatory conditions also affect hematopoietic stem cells (HSCs) themselves. HSCs are activated to proliferate and differentiate in the setting of a Mycobacterium avium infection. These responses are mediated by interferon gamma (IFNg) signaling. We hypothesized that sustained interferon signaling during a chronic infection would impair self-renewal in HSCs and lead to premature exhaustion of the stem cell compartment.

Objective: To ascertain whether persistent interferon exposure in an animal model of chronic Mycobacterium avium infection leads to cell autonomous reduction in HSC number and competency.

Methods: We conducted sustained infection of C57Bl/6 wild type mice with M. avium over an 8-month period. At monthly intervals, we assessed HSC number and pluripotency in a mouse model of bone marrow transplantation. In order to determine whether suppression of HSC counts was due to a cell autonomous or environmental effect, we performed Mycobacterium avium infection in chimeric mice containing mixed WT and IFNg-receptor-deficient (Ifngr1^-/-) marrow.

Results: After 6 months of repeated infection with M. avium, mice became anemic and leukopenic. There was a gradual decrease in the number of committed hematopoietic progenitors and a depletion of HSCs in the bone marrow by 6 months following initial infection. The bone marrow of infected animals was hypercellular and not fibrotic. Despite the overall reduction in HSC number, HSCs that remained in chronically infected animals retained full self-renewal potential even across multiple rounds of transplantation. Whereas WT marrow was suppressed in M. avium-infected chimeras, Ifngr1^-/- marrow demonstrated enhanced engraftment, indicating an IFNg-dependent cell autonomous reduction in self-renewal potential. Transcriptional profiling of HSCs from M. avium-infected and control animals by RNAseq indicated that genes involved in the interferon gamma-mediated inflammatory response and genes associated with aging were differentially upregulated.

Conclusions: We find that chronic interferon gamma exposure can deplete the HSC pool without inducing myelofibrosis. Further, we demonstrate that IFNg-mediated impairment in HSC self-renewal is cell-autonomous. Despite a reduction in HSC number, a subset of HSCs is protected from exhaustion and maintains self-renewal potential. Serial M. avium infection may be utilized as a mouse model for bone marrow suppression associated with inflammatory conditions, as is seen in some patients with chronic infections or autoimmune disorders. In future studies, candidate genes identified by transcriptome analysis will be assessed for their contribution to HSC exhaustion in the setting of chronic inflammation.