Patients who succumbed to influenza during the 1918 pandemic had severe lung pathology marked by extensive inflammatory infiltrate, indicating a robust immune response in the lung. Similar findings have been reported from H5N1-infected patients, raising the question as to why people expire in the presence of a strong immune response. We addressed this question by characterizing the immune cell populations in the mouse lung following infection with the 1918 pandemic virus and two H5N1 viruses isolated from fatal cases. Our data shows excessive immune cell infiltration in the lungs contributing to severe consolidation and tissue architecture destruction in mice infected with highly pathogenic (HP) influenza viruses, supporting the histopathological observations of lung tissue from 1918 and H5N1 fatalities. We found that certain cells of the innate immune system, specifically macrophages and neutrophils, increase significantly into the mouse lung shortly following HP virus infection. Interestingly, lung macrophages and dendritic cells were shown to be susceptible to 1918 and H5N1 virus infection in vitro or ex vivo, suggesting a possible mechanism of immunopathogenesis. Identification of the precise inflammatory cells associated with lung inflammation will be important for the development of treatments that could potentially enhance or modulate host innate immune responses. [18, 21, 22] . Generated by reverse genetics [21] . doi:10.1371/journal.ppat.1000115.t001 animals, mice infected with each of the viruses exhibited an increase in the numbers of macrophages (CD11b + , CD11c 2 , Ly6G/c 2 , CD4 2 , CD8 2 ) beginning 3 days p.i. and continuing through day 9 p.i. Strikingly, there were significantly (*p,0.05) more macrophages in HP virus-infected lungs than in LP virusinfected lungs from days 2 through 9 p.i. (Figure 2B , a). As early as 2 days p.i, there was 1-2 million more macrophages in the lungs of HP-infected lungs compared to LP infected lungs. 1918 and Thai/ 16 virus-infected lungs had twice as many and nearly 4 times as many macrophages compared to LP viruses at days 3 and 5, respectively. Numbers of lung macrophages peaked in 1918 and Thai/16 infected mice (1.5 and 1.2610 7 cells, respectively) at day 7 p.i. before waning as demonstrated at day 9 p.i.