Specific mutations in H5N1 mainly impact the magnitude and velocity of the host response in mice

Tchitchek, Nicolas; Eisfeld, Amie J; Tisoncik-Go, Jennifer; Josset, Laurence; Gralinski, Lisa E; Bécavin, Christophe; Tilton, Susan C; Webb-Robertson, Bobbie-Jo; Ferris, Martin T; Totura, Allison L; Li, Chengjun; Neumann, Gabriele; Metz, Thomas O; Smith, Richard D; Waters, Katrina M; Baric, Ralph; Kawaoka, Yoshihiro; Katze, Michael G

Highly pathogenic avian influenza H5N1 virus is known to induce aberrant host responses leading to severe immunopathology in the lung. In particular, the potent pro-inflammatory response, commonly referred to as 'cytokine storm' , is the suspected cause of acute lung injury [32] . Genomic evidence from animal model systems shows HPAI H5N1 viruses strongly enhance cytokine and chemokine transcriptional responses compared to seasonal influenza viruses (reviewed in [33] ) and 2009 pandemic H1N1 influenza viruses [34] . Here, we utilized a mouse model to study the system dynamics of H5N1 infection, comparing and contrasting the effects of increasing dosage and different previously described and newly generated viral mutants with varying degrees of pathogenicity toward the kinetics of pulmonary responses. Using a systems approach, we present a temporal analysis of transcriptomic and proteomic profiles measured from mouse lung samples collected during the acute phase of infection in order to better understand both dose-dependent and temporal mechanisms of host responses to influenza infection.