Disseminated Mycobacterium Avium Infection Accelerates Hematopoietic Stem Cell Exhaustion,

Anemia, leucopenia, or pancytopenia is a common presenting sign in a number of chronic infectious diseases such as HIV and atypical mycobacterial infection. In order to understand the pathophysiology of pancytopenia as a complication of chronic infection, we have investigated the responses of hematopoietic stem cells (HSCs) to mycobacterial infection. We previously found that HSCs proliferate in the setting of a Mycobacterium avium infection. We hypothesized that sustained infection impairs self-renewal in HSCs and leads to premature exhaustion of the stem cell compartment.

Testing HSC self-renewal is nontrivial and requires serial bone marrow transplantation to measure HSC totipotency over time. Three successive rounds of bone marrow transplantation were conducted using HSCs from mice with M. avium infection.

HSCs from infected mice were significantly less capable of sustaining trilineage peripheral blood production after serial transplantation compared to control HSCs. These findings demonstrate that self-renewal of HSCs is compromised during chronic infection. It follows that the total number of HSCs should decline with time during sustained infection. To test this, serial monthly infection with M. avium was conducted over an 8-month period. Repeatedly infected animals showed a gradual decrease in the number of committed lymphoid and myeloid progenitors and a significant depletion of HSCs in the bone marrow by 6 months following initial infection. Transcriptional profiling of HSCs from M. avium-infected animals by RNAseq revealed previously uncharacterized potential regulators of HSC self-renewal.

Our results demonstrate that HSC self-renewal is compromised during chronic infection, leading to exhaustion of the stem cell compartment. These findings elucidate both the basis for and possible therapeutic approaches towards hematologic complications in patients with atypical mycobacterial infection, tuberculosis, HIV, and other chronic inflammatory conditions.

No relevant conflicts of interest to declare.