Macrophages and dendritic cells play a fundamental role in the lung at all stages of influenza virus infection [20, 37, 38] . We have provided evidence regarding the higher replication efficiency of HP influenza viruses in primary human macrophages and dendritic cells, a property that has also been demonstrated previously in other primary cells [24, 39] . Mouse macrophages were also susceptible to virus infection in vitro, however they did not support productive replication to the level observed in primary human monocyte-derived macrophages ( Figure 4B ) or lung epithelial cells [21, 24] . However, the cytopathic effects (estimated by visual examination of monolayers) among HP virus-infected mouse and human macrophages was observed in a shorter period of time compared to LP virus infected cells. Interestingly, the 1918 virus exhibited higher baseline titers in human and mouse macrophages as early as 2 hrs p.i. compared to the TX/91 H1N1 virus or the H5N1 viruses, indicating a curious property of this pandemic virus. While the importance of the binding properties of the HA molecule has been demonstrated elsewhere extensively [22, 40, 41] , further resolution of this interesting finding and its immunological importance deserves further experimentation. The role of other cell surface molecules on innate immune cells such as the mannose receptor in HP influenza infection should be investigated [42, 43] . The higher viral replication of HP viruses in dendritic cells also correlated with the severe pulmonary disease observed in mice. We also demonstrated definitively that these cells are targets of infection ex vivo by highly pathogenic influenza viruses like the 1918 pandemic virus and recent H5N1 isolates (Figure 7) . Thus, it appears that macrophages and dendritic cells may contribute to the pathogenesis of HP virus infection due to their susceptibility to influenza virus infection. An inability to mount an adaptive immune response due to direct infection of important innate immune cells such as macrophages and dendritic cells may be a critical difference in host outcome during influenza virus infection [44] . This coupled with the phenomenon of T cell depletion in infected mice [17] and human patients [9, 31] may allow for uncontrolled viral replication. While reducing viral load through anti-viral intervention remains the best treatment option for H5N1 patients, therapies that moderate immunopathology may help to reduce the high case fatality rate currently associated with virus infection [45] . (Table 1) . Low pathogenicity in this manuscript refers to the non-lethal phenotype of the seasonal H1N1 TX/91 virus and the low virulence SP/83 H5N1 isolate [18, 21] . The Thai/16 and SP/83 viruses differ from each other in 13 amino acids in 7 proteins and this sequence comparison has been published previously [18] . The A/Texas/36/91 and H5N1 viruses were grown in 10 day old embryonated hen's eggs and the 1918 viruses grown in MDCK cells. All virus stocks were titered by plaque assay on MDCK cells prior to mouse infections.