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

Several genomic studies have examined host responses to H5N1 virus in mice for a deeper understanding of molecular events impacting viral pathogenesis and dissemination. Cillóniz and coworkers demonstrated robust transcriptional changes of inflammatory response genes, including upregulation of inflammasome genes (e.g., CASP1, IL1B, and NLRP3), in response to H5N1 VN1203 compared to 1918 pandemic influenza virus at day 1 postinfection [6] . Investigation of the host response to viruses possessing specific mutations has also been investigated. For example, Fornek et al. showed that the H5N1 influenza A/Hong Kong/486/97 virus containing amino acid substitution E627K in PB2 upregulated TCR complex genes (e.g., CD3D and CD3G) in the lungs of infected mice at day 2 post-infection [11] . It must be noted that the PB2 mutation is not the only difference between these two viruses. Our kinetic analysis further supports the likelihood of impaired T cell responses to H5N1 infection. In a separate study, a recombinant virus expressing H5N1 PB1-F2 N66S compared to the wild-type recombinant virus showed differences in the timing of interferon-stimulated gene expression in mouse lung [20] . Proteomic analysis of primary human monocyte-derived macrophages infected with H5N1 virus have also been investigated and changes in protein abundance of components associated with protein synthesis machinery have been observed as early as 1 hour post-infection [39] .