COMPLEX INTERACTIONS OF H5N1 VIRUS WITH CYTOKINES/CHEMOKINES CONTRIBUTE TO LUNG INJURY IN AVIAN INFLUENZA

Attack rates of H5N1 remain far smaller than those of other deadly diseases such as HIV/AIDS, tuberculosis, and malaria. Even so, the H5N1 virus carries the potential for a devastating global pandemic due to its high case-fatality rate (60%), coupled with the possibility that mutant viruses could acquire the capacity for efficient human-to-human transmission. H5N1 virus appears to evade the host's innate immune system, leading to hypercytokinemia or "cytokine storm". Our recent data suggest that H5N1 virus could also escape the host's adaptive immune system by infecting and replicating in antigen- presenting dendritic cells, and by inducing rapid cell death. In most fatal cases of H5N1 infection, death results from severe pneumonia. The mechanisms by which H5N1 virus causes severe respiratory illness in humans are not yet well understood. Our in vitro study demonstrated that a significant enhancement of IP- 10 production was observed when lung epithelial cells and lung microvascular endothelial cells were exposed to the combination of H5N1 and TNF-α. This enhancement was associated with TNF-α induced retinoic acid-inducible gene-I (RIG-I) up-regulation. In the absence of H5N1 virus, the combination of TNF-α and IFN-α also elicited markedly enhanced IP-10 response in both of these cell types. Methylprednisolone, a glucocorticoid commonly used in treating H5N1 infection, had a moderate effect on this chemokine response. For example, the dose of methylprednisolone (100µg/ml) that effectively abolished TNF-α production in LPS-stimulated peripheral blood mononuclear cells reduced IP-10 production by about 35% in H5N1 + TNF-α -exposed lung epithelial cells and lung microvascular endothelial cells. These results provide increased insight into the pathogenesis of H5N1 infection, and may well also suggest new and useful therapeutic approaches. Poster # 14