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

Previous work by Chang and coworkers, using a compendium of about 200 publicly available transcriptomic profiles of mouse lungs, showed differences in pathogenicity among respiratory viruses were explained in part by the changes in magnitude of gene expression [37] . However, due to constraints of the meta-analysis, time was not taken into consideration. Moreover, the different microarray platforms and mouse genetic backgrounds used in the different datasets introduced noise into the analysis. Here, we have expanded upon the findings by Chang et al. through a kinetic analysis that incorporates the dimension of time, uses a single mouse genetic background and isogenic respiratory viruses that differ based on mutations to known pathogenicity determinants. Transcriptomic and proteomic samples were collected in a systematic manner to generate a comprehensive dataset that provides a powerful resource for modeling pathogen-host interactions. The large sample number allows to infer co-expression and co-regulation networks for identification of unknown associations and dynamic interactions between biological components. Moreover, the extensive collection of sampled time-points allows to model causality of the biological system for discovery of novel biological events. In addition, a large panel of machine learning and data mining algorithms can be used, trained and tested based on this assembled dataset. While our study focuses on acute responses to H5N1 virus, other transcriptomic datasets, such as the one reported by Pommerenke and coworkers, encompass acute and adaptive host responses to influenza virus [38] . It will be important to consider changes during adaptive host responses to fully appreciate the impact of magnitude and velocity kinetic effects on the outcome of viral infection.