Highly pathogenic H1N1 and H5N1 viruses exhibit early and sustained replication in murine lung tissue following intranasal infection Female BALB/c mice were infected intranasally with either highly pathogenic (HP) or low-pathogenic (LP) influenza viruses ( Table 1 , Methods) based on known LD 50 's and phenotypes of disease in mouse [21] and ferret [18, 22] models. As shown in Figure 1 Increased cellularity in lungs of mice infected with highly pathogenic H1N1 and H5N1 influenza viruses Whole lungs collected (without perfusion, therefore including the bronchoalveolar lavage contents (BAL)) from both 1918 and Thai/16 virus-infected mice showed an increase in overall tissue cellularity as early as 3 days p.i. (Figure 2A ). By day 3 p.i., lungs infected with the HP influenza viruses (containing between 4.3-5.1610 7 cells) had nearly twice as many total lung cells than were measured in the HP infection groups just 24 hours previously at day 2 p.i. (2.1-2.4610 7 cells). Significant differences (*p,0.05) were observed between HP and LP infection groups in total lung cell number at every time after day 2 p.i. Total lung cell numbers doubled in HP infection groups between days 5 and 7 p.i. and by day 7 p.i., when viral titers were high for all four viruses, total cell numbers in the lungs of mice infected with either HP H1N1 or H5N1 viruses were 6-fold higher than those in PBS-inoculated mice, and at least 3-fold higher than those found in LP virusinfected lungs (Figures 1 and 2A) . On day 7 p.i., there were as many as 1.3610 8 cells in HP-infected lungs compared with 4.0-8.0610 7 cells in LP-infected and 1.8610 7 cells in PBS-inoculated lungs.