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. Eosinophils are recruited to the airways as a prominent feature of the asthmatic inflammatory response where they are broadly perceived as promoting pathophysiology. Respiratory virus infections exacerbate established asthma;however, the role of eosinophils and the nature of their interactions with respiratory viruses remain uncertain. To explore these questions, we established acute infection with the rodent pneumovirus, pneumonia virus of mice (PVM), in 3 distinct mouse models of Th2 cytokine-driven asthmatic inflammation. We found that eosinophils recruited to the airways of otherwise nave mice in response to Aspergillus fumigatus, but not ovalbumin sensitization and challenge, are activated by and degranulate specifically in response to PVM infection. Furthermore, we demonstrate that activated eosinophils from both Aspergillus antigen and cytokine-driven asthma models are profoundly antiviral and promote survival in response to an otherwise lethal PVM infection. Thus, although activated eosinophils within a Th2-polarized inflammatory response may have pathophysiologic features, they are also efficient and effective mediators of antiviral host defense. (Percopo et al., 2014. Blood. 30;123:743-52) We have also contributed to a collaborative effort directed toward identifying microRNAs expressed during eosinophil hematopoiesis, and identifying functional links between microRNAs and target mRNAs. MicroRNAs (miRNAs) are small non-coding RNAs that regulate complex transcriptional networks. Here, we profiled miRNA expression during differentiation of eosinophils derived from bone marrow progenitors (bmEos, as per Dyer et al., J Immunol. 2008), and correlated expression with potential mRNA targets involved in crucial regulatory functions. Via this approach, we identified 68 miRNAs with expression patterns that were up- or down- regulated 5-fold or more during bmEos differentiation. By employing TargetScan and MeSH databases, we identified 348 transcripts involved in 30 canonical pathways as potentially regulated by these miRNAs, and 13 specific miRNAs that are temporally associated with the expression of eosinophil transcripts, including IL-5Rαand CCR3 and 14 miRNAs associated with the transcription factors GATA-1/2, PU.1 and C/EBPε. This is the first study to map changes in miRNA expression in whole BM cultures during the differentiation of eosinophils, and to predict functional links between miRNAs and their target mRNAs for the regulation of eosinophilopoiesis. Our findings provide an important resource that will promote further understanding of the role of these non-coding RNAs in the regulation of eosinophil differentiation and function. (Yang et al., 2014. PLoS One 9:e97537) We have also contributed several book chapters on eosinophil-related subjects and methodologies, and an invited review focused on the role of respiratory viruses in eliciting eosinophilic inflammation and asthma via epithelial cytokines (Kumar et al., 2014. J. Leukocyte Biol., In press). Finally, our program includes an ongoing collaboration with Knopp Biosciences (http://knoppbio.com/products/show.php?4) designed to explore the potential of Dexpramipexole (KNS-760764) as an agent to combat hypereosinophilia. Under terms of funded CRADA 2013-0713, we are working to examine the potential of this small molecule inhibitor in both tissue culture bone marrow eosinophil cultures and the interleukin-5 transgenic hypereosinophilic mouse models.
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