This year, together with the Domachowske laboratory (Virology, Dept. Pediatric Infectious Diseases, SUNY Upstate Medical University) we have contributed to two original reports describing translational advances. In the first of these studies, we showed that CCL3-mediated neutrophil recruitment in virus infection was actually an indirect response, and was coordinated by interferon-gamma (IFNg). Specifically, neutrophil recruitment in response to PVM infection was diminished five-fold in IFNg receptor gene-deleted mice, although neutrophils from IFNgR -/- mice expressed transcripts for the CCL3 receptor, CCR1 and responded functionally to CCL3 ex vivo. Similarly, in the absence of PVM infection, CCL3 overexpression alone could not elicit neutrophil recruitment in the absence of IFNg. Interestingly, although supplemental IFNg restored neutrophil recruitment and resulted in a sustained weight loss among CCL3-overexpressing IFNgamma -/- mice, CCL3-mediated neutrophil recruitment alone did not result in the pulmonary edema or respiratory failure characteristic of severe viral infection, suggesting that CCL3 and IFN-gamma together are sufficient to promote neutrophil recruitment but not pathologic activation. Our findings reveal a heretofore unrecognized hierarchical interaction between the IFNg and CCL3, which demonstrate that IFNg is crucial for CCL3-mediated neutrophil recruitment in vivo (Bonville et al. BMC Immunol 2009). In a second study, we explored the role of pulmonary eosinophils promoting immunopathologic responses to formalin-inactivated pneumonia virus of mice. This was described in greater detail in the Summary accompanying project AI000943-06. Among the findings from this study related specifically to virus infection, we found that PVM infection in mice vaccinated with formalin-inactivated Ags from PVM-infected cells (PVM Ags) yields Th2-skewed hypersensitivity, analogous to that observed in response to hRSV. Specifically, we detect elevated levels of IL-4, IL-5, IL-13, and eosinophils in bronchoalveolar lavage fluid of PVM-infected mice that were vaccinated with PVM Ags, but not among mice vaccinated with formalin-inactivated Ags from uninfected cells (control Ags). Interestingly, infection in PVM Ag-vaccinated mice was associated with a approximately 10-fold reduction in lung virus titer and protection against weight loss when compared with infected mice vaccinated with control Ags, despite the absence of serum-neutralizing Abs. Among the other intriguing conclusions, our results suggest that all eosinophils are not equivalent functionally, and that eosinophil-mediated antiviral activity may depend directly on the presence of specific activating cytokines (Percopo et al. J Immunol., 2009) I also contributed expertise to a study carried out by Dr. Reinout Bem, who was a visiting student in my laboratory in 2006. The results of this work indicated that mechanical ventilation enhances lung inflammation and caspase activity in a model of mouse pneumovirus infection (Bem et al. Am J Physiol. 2009) I have also two invited reviews detailing our studies and those of others on the role of eosinophils in relation to respiratory virus infection, as described in AI000941-06.
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