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A6234 - Priming of Innate Immune Cells by Type I and II Interferons During Infections of Influenza Virus and Streptococcus Pneumoniae
Author Block: S. Hanada, K. Carver, Z. Tsai, J. C. Deng; Division of Pulmonary and Critical Care Medicine, Veterans Affairs Healthcare System, University of Michigan, Ann Arbor, MI, United States.
RATIONALE: Neutrophils are major phagocytes and effector cells of innate immunity, with a well-established role in the clearance of bacterial pathogens from the lung. The role of neutrophils during viral infections, however, is unclear. In addition, while macrophages have been shown to be capable of polarization into distinct subtypes following activation, whether the relatively less transcriptionally active neutrophil similarly can adopt different phenotypes remains a poorly understood phenomenon. Type I and II interferons (IFNs) have important roles not only in protection against viral infections but also in regulating the host immune response to bacterial infections. We hypothesize that type I IFNs and type II IFNs promote differential priming of neutrophils during influenza infections. METHODS: We used murine models of respiratory infection by influenza, Streptococcus Pneumoniae and sequential influenza-S. pneumoniae. We isolated neutrophils from the bone marrow of the mice and examined phagocytosis, bactericidal activity, and survival of neutrophils after ex vivo stimulation with IFN-alpha, IFN-gamma, or without stimulation. We also evaluated neutrophil functions of IFN-alpha receptor (IFNAR) knock-out (KO) mice compared with wild-type (WT) mice. In addition, we examined global changes in gene expression and protein induction by neutrophils isolated from bone marrow and lung to examine site of priming during respiratory infections. RESULTS: In mice with influenza infection, bone marrow derived neutrophils displayed impaired bactericidal activity in all groups regardless of the stimulation. In neutrophils isolated from uninfected animals, the stimulation of IFN-gamma decreased phagocytosis as well as bactericidal activity. In IFNAR KO and WT mice, we found no difference in phagocytosis in two groups although neutrophils from IFNAR KO animals with severe influenza infections, paradoxically, displayed decreased bactericidal activity. Preliminary analysis of gene expression and protein data revealed that neutrophils appear to be a major source of IFN-gamma during influenza infection, which appeared to promote neutrophil survival. CONCLUSIONS: These results suggest that influenza infection has a systemic effect on bone marrow that contributes to neutrophil deactivation in bacterial clearance. Furthermore, IFN-alpha and IFN-gamma have direct but distinct effects on functions of neutrophils. Neutrophils also appear to be a primary source of IFN-gamma, suggesting the possibility of autocrine regulation of neutrophil functions.