HSPC Function during Infection Hematopoietic stem and progenitor cells (HSPCs) has the essential role of maintaining blood production, including all cells of the immune system, throughout life. In response to stress, such as infection, HSPCs can also be directed to differentiate and rapidly mobilize from the bone marrow (BM). The long-term goal of our research is to understand how HSPC function is directed during infection to promote host defense and, in turn, how defects in immunity arise due to dysfunction of HSPCs. The objectives here are to: (1) define the biological impact of interferons (IFNs) on HSPC function and mobilization during infection and (2) determine the capacity of mobilized HPSCs to directly control infection. Infectious disease represents a major cause of mortality in the United States and around the world. A more complete understanding of HSPC function during infection will lead to novel therapies geared at increasing host defense and reducing severity of disease. Despite the fact that IFNs are produced during many infections, we know very little about how IFNs regulate HSPC function during infection, particularly when both type I (? and ?) and II (?) IFNs are present. We have new evidence that concerted type I and II IFN signaling is detrimental to hematopoietic function, and the mechanisms that underlie this defect will be addressed (Aim 1). Furthermore, an assumption in the field has been that mobilization of HSPCs from the BM to peripheral sites of infection promotes responses to infection due to in situ differentiation. However, our data supports a new paradigm whereby mobilization is highly regulated during infection, and mobilization actually depends upon the type of infectious pathogen present. Specifically, mobilization is increased in response to extracellular pathogens and decreased in response to intracellular pathogens, a process found to be dependent on IFN?. Our novel finding that IFN? can actually impede HSPC mobilization suggests that mobilization may indeed be harmful in some infection conditions. We propose to further define the mechanisms controlling HSPC mobilization during infection (Aim 2), and the impact of HSPC mobilization on pathogen growth and disease outcome (Aim 3). These studies will provide a new framework in which to understand host defense and pathology. The possibility of manipulating IFNs during acute infection to drive lineage-fate choices of activated HSPCs and/or direct HSPC mobilization has tremendous therapeutic potential. Thus, this work is significant and broadly relevant to host defense as IFNs are produced during many infections and during many chronic inflammatory diseases. These studies are also directly relevant to improving clinical strategies that use transplantation of HSPCs to treat human diseases. Whereas the depletion of IFN? will likely increase the efficacy of mobilization, treatment with IFN? may augment engraftment of HSPCs by improving the HSPC niche function.

Public Health Relevance

The proposed research will define mechanisms by which interferons contribute to host defense through their ability to regulate the function and mobilization of stem and progenitor cells. These studies will reveal critical new information about how blood stem and progenitor cells respond to infection and control of pathogen growth. As infectious disease is the second cause of mortality worldwide the proposed research is directly relevant to public health and the NIH's mission to seek fundamental knowledge about the behavior of living systems to enhance health, lengthen life, and reduce the burdens of illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM105949-01A1
Application #
8689208
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Dunsmore, Sarah
Project Start
2014-05-16
Project End
2019-02-28
Budget Start
2014-05-16
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$300,200
Indirect Cost
$110,200
Name
Albany Medical College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208
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McCabe, Amanda; Smith, Julianne N P; Costello, Angelica et al. (2018) Hematopoietic stem cell loss and hematopoietic failure in severe aplastic anemia is driven by macrophages and aberrant podoplanin expression. Haematologica 103:1451-1461
Zhang, Kangning; Xu, Xingyuan; Pasha, Muhammad Asghar et al. (2017) Cutting Edge: Notch Signaling Promotes the Plasticity of Group-2 Innate Lymphoid Cells. J Immunol 198:1798-1803
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MacNamara, Katherine C (2016) Shedding light on HSC dormancy-a role for the DARC. Stem Cell Investig 3:40
Periasamy, Sivakumar; Avram, Dorina; McCabe, Amanda et al. (2016) An Immature Myeloid/Myeloid-Suppressor Cell Response Associated with Necrotizing Inflammation Mediates Lethal Pulmonary Tularemia. PLoS Pathog 12:e1005517
McCabe, Amanda; MacNamara, Katherine C (2016) Macrophages: Key regulators of steady-state and demand-adapted hematopoiesis. Exp Hematol 44:213-22
McCabe, Amanda; Zhang, Yubin; Thai, Vinh et al. (2015) Macrophage-Lineage Cells Negatively Regulate the Hematopoietic Stem Cell Pool in Response to Interferon Gamma at Steady State and During Infection. Stem Cells 33:2294-305