Eosinophils promote host defense against H1N1 influenza

Several studies have shown that eosinophils are recruited to and degranulate into the lung parenchyma in association with severe RSV infection, and RSV-infected epithelial cells produce and secrete a variety of potential eosinophil chemoattractants. Although most of the literature on respiratory virus infection and eosinophilia focuses on RSV, pulmonary eosinophilia is likely not uniquely related to the RSV pathogen per se; one observes eosinophilia in response to RSV because it is the predominant severe respiratory pathogen among young infants. Indeed, recent evidence suggests that virus-related eosinophilia is a more widespread observation. In a recent study, a series of 40 children with both respiratory and peripheral blood eosinophilia in association with lower respiratory tract infection with pandemic H1N1 influenza A was documented. In earlier studies of young (< 3 months) infants, the reported Th2 skewed response was not unique to RSV, but also observed in response to infection with other viruses, including influenza A. Similar results were observed in a study of influenza-infected neonatal mice, in which eosinophils collected in the alveoli in association with prominent elevated levels of eotaxin. Moreover, influenza virus serves as a significant stimulus of eotaxin and RANTES in vivo and in nasal epithelial cells in culture, and results in prolonged eosinophil recruitment to the nasal epithelium in human subjects. Thus, the overall aim of this project is to explore the interactions of eosinophils with the influenza A respiratory virus pathogen in vivo. For these studies, we will use a mouse-adapted (MA) strain of H1N1 influenza (A/FM/1/47-MA) which was first developed by Brown and colleagues. This A/FM/1/47-MA strain is known to elicit dose-dependent morbidity and mortality in inbred strains of mice in association with inflammatory pathology. Moreover, Dr. Rosenberg`s group has recently demonstrated dramatic, eosinophil dependent reduction in pneumonia virus of mice (PVM) recovery from lung tissue in highly-hypereosinophilic eotaxin-2 / interleukin-5 double-transgenic (hE2-IL5tg) mice, a unique model in which eosinophils undergo degranulation in vivo, reflecting the tissue pathology characteristic of human asthma. Using wild type, single hE2 and mIL5, together with the more sophisticated double-transgenic mouse model, we will explore the antiviral features of eosinophils and their interactions with the influenza A respiratory virus pathogen in vivo with respect to virus kinetics, cytokine expression, recruitment of effector cells and host morbidity and mortality. Further examination of the interactions of eosinophils with H1N1 will have enormous significance for the field of eosinophil biology as it extends our present knowledge about the pathogenesis of severe viral infections and the mechanisms involved in antiviral host defense.