Transcriptomic Characterization of the Novel Avian-Origin Influenza A (H7N9) Virus: Specific Host Response and Responses Intermediate between Avian (H5N1 and H7N7) and Human (H3N2) Viruses and Implications for Treatment Options

Josset, Laurence; Zeng, Hui; Kelly, Sara M.; Tumpey, Terrence M.; Katze, Michael G.

More than 20% of the total DE genes were specific to H7N9 infection, with genes changing only in response to H7N9 (clusters 9, 13, and 16: 1,929 genes) or genes dysregulated by all IAVs except H7N9 (clusters 2 and 24: 1,565 genes). Genes specifically induced by H7N9 were broadly enriched among genes implicated in global regulation of gene transcription and the cell cycle (Table 1 ; see also Fig. S1 to S3 in the supplemental material). Interestingly, the top predicted regulator of cluster 9 was MLL, a histone methyltransferase involved in epigenetic regulation of diverse gene types associated with cell cycle regulation and development ( Table 1) . Regulation of transcription and the cell cycle by H7N9 could be related to specific interactions between H7N9 proteins and nuclear factors. Among the genes significantly upregulated by all IAVs except H7N9 (cluster 2) were several interferon (IFN) type 1 genes (IFN-A10, IFN-A16, IFN-A21, and IFNw1), IL-27, IL-32, and IL-12A (see Fig. S4A ). Most other cytokines were induced by all IAVs and belonged to cluster 1. However, closer examination of the cytokine induction level revealed an earlier and stronger induction after H3N2 infection than with avian IAV, especially for CCL5, CXCL10, IFN-B1, IL-12A, IL-1A, and IL-6 (see Fig. S4A ). Among avian IAVs, levels for some cytokines, including CCL5, IFN-A7, and IFN-B1, were significantly lower in response to H7N9 infection than to infection with H7N7 or H5N1 (see Fig. S4A ).