Ongoing research on this topic focuses on an exploration of the unique roles of the eosinophilic leukocyte on promoting health and restoring homeostasis with an emphasis on antiviral host defense. Our first report is on a recent advance that uses ourpublished protocol for the generation of mouse eosinophils from unselected bone marrow progenitors (bmEos). This work was performed primarily by Dr. Eva M. Sturm, who joined us from the Medical University of Graz via fellowship support from the Erwin Schroedinger Foundation. Dr. Sturm utilized the bone marrow progenitor protocol to develop a powerful method for examining receptor-mediated eosinophil chemotaxis in vivo. Specifically, she demonstrated that bmEos could be adoptively transferred into recipient mice and recruited to the lungs in response to a gradient of recombinant eotaxin-2. Wild-type bmEos were readily detected in the lungs of eosinophil-deficient (del-dblGATA) recipient mice, and, as anticipated, this response was completely dependent on the presence of the eotaxin-receptor, CCR3 on the bmEos. Building on this finding, Dr. Sturm showed that fluorescently-labelled bmEos generated from GFP-positive mice responded similarly to eotaxin-2, and could be detected in lung tissue of wild-type mice, thereby expanding the utility of this system. Our next report features the responses of eosinophil progenitors to IL-33, an IL-1 family cytokine that elicits dramatic eosinophilia in vivo. We found that IL-33 promoted minimal eosinophil hematopoiesis via direct interactions with eosinophil progenitors, and moreover, IL-33 antagonizes eosinophil hematopoiesis promoted by IL-5 on cytokine-primed bone marrow progenitor cells in culture. This antagonism of IL-5 was reproduced in part by the addition of GM-CSF and was inhibited by the actions of neutralizing anti-GM-CSF antibody, which suggests the possibility of an autocrine feedback loop. Our final report is the first of a planned series of collaborations with the Lee Laboratories. As part of an effort to generate mice devoid of multiple specific granule proteins for use in our antiviral host defense studies, it was found that, unlike mice with only a single deficiency, mice with a dual deficiency of both major basic protein (MBP-1) and eosinophil peroxidase (EPX) have virtually no eosinophils whatsoever. Significantly, this blockade of eosinophilopoiesis is also observed in ex vivo cultures derived from bone marrow progenitors and is not rescued in vivo by adoptive bone marrow engraftment. These observations demonstrate a role for granule protein gene expression as an unanticipated regulator of eosinophil hematopoiesis (Doyle AD et al., 2013. Blood, in press).

Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2013
Total Cost
$545,204
Indirect Cost
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State
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Rosenberg, Helene F (2015) Eosinophil-Derived Neurotoxin (EDN/RNase 2) and the Mouse Eosinophil-Associated RNases (mEars): Expanding Roles in Promoting Host Defense. Int J Mol Sci 16:15442-55
Yamada, Kelsey J; Barker, Tolga; Dyer, Kimberly D et al. (2015) Eosinophil-associated ribonuclease 11 is a macrophage chemoattractant. J Biol Chem 290:8863-75
Dyer, Kimberly D; Rosenberg, Helene F (2015) Physiologic concentrations of HMGB1 have no impact on cytokine-mediated eosinophil survival or chemotaxis in response to Eotaxin-2 (CCL24). PLoS One 10:e0118887
Kumar, Rakesh K; Foster, Paul S; Rosenberg, Helene F (2014) Respiratory viral infection, epithelial cytokines, and innate lymphoid cells in asthma exacerbations. J Leukoc Biol :
Percopo, Caroline M; Dyer, Kimberly D; Ochkur, Sergei I et al. (2014) Activated mouse eosinophils protect against lethal respiratory virus infection. Blood 123:743-52
Percopo, Caroline M; Dyer, Kimberly D; Karpe, Kendal A et al. (2014) Eosinophils and respiratory virus infection: a dual-standard curve qRT-PCR-based method for determining virus recovery from mouse lung tissue. Methods Mol Biol 1178:257-66
Xiang, Yang; Eyers, Fiona; Young, Ian G et al. (2014) Identification of microRNAs regulating the developmental pathways of bone marrow derived mast cells. PLoS One 9:e98139
Lacy, Paige; Rosenberg, Helene F; Walsh, Garry M (2014) Eosinophil overview: structure, biological properties, and key functions. Methods Mol Biol 1178:1-12
Glineur, Stephanie F; Bowen, Aaron B; Percopo, Caroline M et al. (2014) Sustained inflammation and differential expression of interferons type I and III in PVM-infected interferon-gamma (IFNγ) gene-deleted mice. Virology 468-470:140-9
Yang, Ming; Eyers, Fiona; Xiang, Yang et al. (2014) Expression profiling of differentiating eosinophils in bone marrow cultures predicts functional links between microRNAs and their target mRNAs. PLoS One 9:e97537

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