Abstract
How hematopoietic stem cells (HSCs) respond to inflammatory signals during infections is not well understood. Our studies have used a murine model of ehrlichiosis, an emerging tick-born disease, to address how infection impacts hematopoietic function. Infection of C57BL/6 mice with the intracellular bacterium, Ehrlichia muris, results in anemia and thrombocytopenia, similar to what is observed in human ehrlichiosis patients. In the mouse, infection promotes myelopoiesis, a process that is critically dependent on interferon gamma (IFNγ) signaling. In the present study, we demonstrate that E. muris infection also drives the transient proliferation and expansion of bone marrow Lin-negative Sca-1+ cKit+ (LSK) cells, a population of progenitor cells that contains HSCs. Expansion of the LSK population in the bone marrow was associated with a loss of dormant, long-term repopulating HSCs, reduced engraftment, and a bias towards myeloid lineage differentiation within that population. The reduced engraftment and myeloid bias of the infection-induced LSK cells was transient, and was most pronounced on day 8 post-infection. The infection-induced changes were accompanied by an expansion of more differentiated multipotent progenitor cells, and required IFNγ signaling. Thus, in response to inflammatory signals elicited during acute infection, HSCs can undergo a rapid, IFNγ-dependent, transient shift from dormancy to activity, ostensibly, to provide the host with additional or better-armed innate cells for host defense. Similar changes in hematopoietic function likely underlie many different infections of public health importance.
Highlights
Hematopoiesis, the process that supplies the host with innate and adaptive immune cells, is maintained by hematopoietic stem cells (HSCs), which are capable of both self-renewal and differentiation
We initiated the present study to address whether the altered myelopoeisis we had observed was accompanied by changes in bone marrow HSC phenotype and/or function
Our study demonstrates that HSCs can undergo a transition from a dormant state to an active state during an intracellular bacterial infection
Summary
Hematopoiesis, the process that supplies the host with innate and adaptive immune cells, is maintained by hematopoietic stem cells (HSCs), which are capable of both self-renewal and differentiation. HSCs are thought to be largely quiescent [1,2], and are commonly referred to as dormant HSCs, or as long-term reconstituting HSCs (LT-HSC), as these progenitor cells have the most robust hematopoietic potential [3]. Much is known regarding HSC potential and differentiation under homeostatic conditions, but how infections can alter the function and phenotype of LT-HSCs is not well understood. Alterations in hematopoietic stem and progenitor cell phenotype and function have been observed in bacterial infection models, and during sepsis [5,6,7], as evidenced by the apparent expansion of lineage-negative (Lin-neg), Sca-1+ c-Kit+ (LSK) bone marrow cells. It is likely that, during infection, inflammation acts to modulate hematopoiesis to promote the production of cells better able to respond to and control infection
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