Influenza virus growth in the respiratory epithelium and the subsequent release of chemotactic proteins from those cells may encourage the increased presence of macrophages and neutrophils [28, 29] . Macrophages and neutrophils can secrete chemokines and cytokines that can act in an autocrine fashion which in turn can promote the increased migration of those cells and other leukocytes into the lung tissue [30] . Elevated levels of certain chemokines and cytokines have been associated with high viral load and severe disease in H5N1 virus infected patients [26, 31] . These studies show that infection with HP 1918 and Thai/16 H5N1 viruses result in elevated amounts of pro-inflammatory chemokines and cytokines in the lungs of mice day 4 post-infection compared with TX/91 and SP/83 infected mice, a time point that correlates with rising but significantly different lung virus titers between infection groups. Elevated levels of the chemokines MCP-1 [32] and MIP1-a were observed among H5N1 and 1918 virus infected mouse lungs. Although, MIP-1a does not appear to be critical for virus replication and spread in the mouse model [10] , this chemokine exhibits a variety of pro-inflammatory activities including macrophage and neutrophil recruitment and has been associated with fatal outcomes in human H5N1 virus infections [31] . Lungs infected with the 1918 pandemic and Thai/16 H5N1 viruses also exhibited significantly higher levels of IFN-c on day 4 p.i compared to their subtype-paired LP virus counterparts. IFN-c is known to mediate the increased production of nitric oxide [33] which can subsequently result in the recruitment of more neutrophils and macrophages. Higher levels of IL-6 were measured in 1918 and Thai/16 virus infected lungs, supporting observations obtained with the 1997 H5N1 viruses [10] and has been correlated with systemic illness symptoms and fever in experimental human TX/91 infections [34] . By directly measuring cytokine protein levels, these data provide confirming evidence of a heightened lung cytokine response to 1918 and H5N1 infection in mice [13] . Interestingly, while we reveal marked similarities between the HP 1918 and Thai/16 viruses in overall lung cellularity, virus growth and patterns of immune cell sub-population dynamics over time, Thai/16 virus infection consistently resulted in higher levels of chemokines and cytokines both in mouse lungs and human macrophages. Although it has been shown recently by two independent research groups that the lack of key cytokines (through the use of single cytokine gene knockout mice) had no effect on the overall disease outcome or virus replication among H5N1 virus-inoculated mice [10, 35] , the present results along with data from others continue to indicate that pro-inflammatory cytokines correlate with disease outcome [36] . It is thought that these immune mediators do not act singularly in vivo and it will be critical to reveal these concerted interactions (both locally in the lung and systemically) to further our understanding of the pathogenesis of H5N1 infection in animal models and in human patients.