HUMAN PHAGOCYTE GRANULE PROTEINS

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Eosinophils are enigmatic cells with well-characterized detrimental roles as mediators of allergic diseases and asthma and beneficial features that remain controversial and poorly understood. Indeed, in light of the recent findings that have undermined the hypotheses regarding eosinophils as antiparasitic agents in vivo, it is not at all clear what (if anything) eosinophils do to promote host defense. With this in mind, we have begun to look carefully at some of the intriguing associations that link eosinophils, asthma and allergic bronchospasm, and diseases caused by respiratory viruses, most notably that caused by respiratory syncytial virus (RSV). While eosinophils are associated with bronchospasm and tissue damage, and thus have been uniformly perceived as the villains of RSV disease, we have begun to consider the possibility that eosinophilic inflammation has a "double-edged sword," similar to that studied more carefully in neutrophils. Recent work in our laboratory has clearly demonstrated that eosinophils can mediate the direct, ribonuclease-dependent destruction of isolated virions of RSV in vitro, and that one of the eosinophil secretory proteins, the eosinophil-derived neurotoxin (EDN/ RNase 2), can function alone as an independent antiviral agent. The experiments described in this proposal will address the physiology of eosinophils and their role in host defense against RSV and will also consider the pharmacologic potential and mechanism of action of EDN and related ribonucleases as antiviral agents.