The focus of our lab is on understanding how the hematopoietic system responds to, and recovers from, infection-induced stress. The hematopoietic system is maintained by the bone marrow, which produces billions of cells each day. Ultimately, it is the bone marrow-resident hematopoietic stem cell (HSC) that supports hematopoiesis throughout life, as it is able to self-renew, generating more stem cells, and produce more differentiated multipotent progenitors (MPPs). Under normal conditions, HSCs are maintained in a dormant state, and their daughter cells, the MPPs, are responsible for the daily production of lineage-specific cells (such as neutrophils and red blood cells). While a great deal is known about the mechanisms governing the generation of hematopoietic cells under homeostatic conditions, how these processes are altered by infection and inflammation are unclear.
We use a murine model of human monocytic ehrlichiosis (HME) to examine the cellular and molecular changes that occur to the hematopoietic system during stress-induced inflammation. HME is an emerging tick-borne disease caused by the pathogen Ehrlichia chaffeensis; patients exhibit anemia and thrombocytopenia. Our mouse model of HME utilizes a related pathogen, Ehrlichia muris, which causes similar changes in the peripheral blood as what is observed in HME patients. Our studies have revealed an important role for interferon gamma (IFNg)-signaling in the development of anemia, and we have also found that IFNg is critical for the production of innate myeloid cells, in particular monocytes, during infection. Mice deficient in the IFNgR are unable to control E. muris infection. Studies from other labs, and our own research, have demonstrated that IFNg can drive the activation of hematopoietic stem and progenitor cells, which may be an essential cue to promote innate immunity in response to infection. Additional projects in the lab are seeking to understand the role of type I IFNs (alpha and beta) in the activation of hematopoietic responses in response to the ehrlichia. In collaboration with other laboratories in the Center, we are also exploring other infection models to validate our finding.
Current studies in the lab:
1. How is IFNg signaling regulated in undifferentiated hematopoietic stem and progenitor cells?
2. How do changes in the HSC niche contribute to changes in bone marrow function during infection?
3. Do mature lineage cells, such as macrophages, contribute to infection-induced HSC activation?
4. What is the primary source of IFNg in the bone marrow?
Understanding how the hematopoietic system is maintained in the face of both acute and chronic infections is critical for our knowledge of innate and adaptive immunity, and will also aid in our understanding of how blood pathologies, such as anemia and cancer, arise. These studies are also relevant to the use of HSCs in transplantation therapies.
Kenny Thai, Technician
Amanda McCabe, PhD Student
Yubin Zhang, PhD, Postdoc