As part of our larger interest in eosinophils and their role in host defense, together with my colleagues in Australia, we have explored the possibility that eosinophils play a direct role in host defense against the prevalent respiratory pathogen, respiratory syncytial virus (RSV). Specifically, we found that virus clearance from lung tissue was more rapid in hypereosinophilic (interleukin5 transgenic) mice than in wild type mice, and that transfer of eosinophils to the lungs of RSVinfected wildtype mice accelerated virus clearance. In terms of mechanism, we demonstrated that eosinophils express TLRs that recognise viral nucleic acids, are activated and degranulate after ssRNA stimulation of the TLR7MyD88 pathway, and provide host defence against RSV that is MyD88dependent. Collectively, our results demonstrate that eosinophils can protect against RSV in vivo, as they promote virus clearance and may thus limit virusinduced lung dysfunction. The results of this work have been accepted for publication (Phipps et al. Blood 2007, in press).? ? We have also continued our exploration of eosinophil differentiation and development, specifically using the deltadblGATA model of eosinophil ablation characterized by Yu and colleagues (JEM 2002) in which a deletion of a palindromic enhancer in the hematopoietic promoter of the transcription factor, GATA1, leads to mice that are completely devoid of eosinophils. Given that these mice are devoid of esoinophils even under conditions of profound Th2 stimulation, we were surprised to find that bone marrow progenitors isolated from deltadblGATA mice could differentiate into mature eosinophils when subjected to cytokine stimulation ex vivo. Cultured deltadblGATA eosinophils contain cytoplasmic granules with immunoreactive major basic protein and they express surface Siglec F and transcripts encoding major basic protein, eosinophil peroxidase, and GATA1, 2, and 3 to an extent indistinguishable from cultured wildtype eosinophils. Fibroblast coculture and bone marrow crosstransplant experiments indicate that the deficit is an intrinsic progenitor defect, and remains unaffected by interactions with stromal cells. Interestingly, and in contrast to those from the wild type, a majority of the GATA1 transcripts from cultured deltadblGATA progenitors express a variant GATA1 transcript that includes a first exon 1E(B), located approximately 3700 bp downstream to the previously described first exon found in hemopoietic cells (1E(A)) and approximately 42 bp upstream to another variant first exon, 1E(C). Taken together, our data suggest that cultured progenitors are able to circumvent the effects of the deltadblGATA ablation by using a second, more proximal, promoter and to use this mechanism to generate quantities of GATA1 that will support eosinophil growth and differentiation. The results of this work have been accepted for publication (Dyer et al. 2007. J. Immunol., in press).? ? I also participated as lead author in a review of eosinophils and eosinophil trafficking published in Journal of Allergy and Clinical Immunology (Rosenberg et al. 2007, JACI 119:13031310) and among the contributors to the chapter Eosinophils to be published in Allergy and Allergic Disorders, 2nd edition, Blackwell Scientific Publishers.? ? Finally, my expertise in eosinophil biology and inflammation has provided me with the opportunity to participate as a member of the Editorial Boards of Blood (since 2003), Journal of Leukocyte Biology (since 1996; promoted to Associate Editor, 2006), Clinical and Vaccine Immunology (since 2003) and Faculty of 1000 Biology (since 2006). As a member of the Editorial Board of Blood, I have been given the opportunity to contribute several Inside Blood capsules profiling original publications (included in bibliography). Most recently, I have assisted in developing an original feature for the Journal of Leukocyte Biology known as Pivotal Advance, and I have taken on the role of interviews editor. We have published seven of these feature interviews in FY2007, which have become an established feature in the journal.
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