Background: Influenza infection causes respiratory disease that can lead to death. The complex interplay between
virus-encoded and host-specific pathogenicity regulators – and the relative contributions of each toward viral
pathogenicity – is not well-understood.
Results: By analyzing a collection of lung samples from mice infected by A/Vietnam/1203/2004 (H5N1; VN1203), we
characterized a signature of transcripts and proteins associated with the kinetics of the host response. Using a new
geometrical representation method and two criteria, we show that inoculation concentrations and four specific
mutations in VN1203 mainly impact the magnitude and velocity of the host response kinetics, rather than specific
sets of up- and down- regulated genes. We observed analogous kinetic effects using lung samples from mice
infected with A/California/04/2009 (H1N1), and we show that these effects correlate with morbidity and viral titer.
Conclusions: We have demonstrated the importance of the kinetics of the host response to H5N1 pathogenesis and
its relationship with clinical disease severity and virus replication. These kinetic properties imply that time-matched
comparisons of ‘omics profiles to viral infections give limited views to differentiate host-responses. Moreover, these
results demonstrate that a fast activation of the host-response at the earliest time points post-infection is critical for
protective mechanisms against fast replicating viruses.