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

The extensive systematic analysis of transcriptomic and proteomic pulmonary responses to wild-type and mutant viruses we report here provides an unprecedented opportunity to assess the effect of specific virus attenuating mutations on global host responses in vivo, as well as the opportunity to directly examine the effects of dosage on the elicited host response. Here, we sought to specifically address how the kinetics of the host responses to the different viral infections differs, and how this kinetics is related to the outcome of infection. To address this, we used a systems biology approach to analyze this dataset, and we developed a new geometrical representation method and two criteriathe magnitude and velocity coefficientsto visualize and quantify the kinetics of the host response to the different viral infections. Using this approach, we have established that it is the magnitude and velocity of the early host response, rather than engagement of specific biological pathways per se, which mainly contributes to the observed pathogenicity of influenza viruses. Importantly, we show that the molecular kinetic of the host response was associated with clinical disease severity and virus replication.