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 12% of the whole DE gene list was changed similarly in response to the H7N9, H7N7, and H5N1 viruses, including Table 1 and in Fig. S1 to S3 in the supplemental material. genes up-and downregulated similarly by each of these viruses (clusters 3 and 23: 1,336 genes) and genes similarly unchanged after avian IAV infection and dysregulated only after H3N2 infection (clusters 8 and 18: 667 genes). Cluster 8 was particularly interesting, since it included several genes from the antigen presentation pathway upregulated only after H3N2 infection, including those encoding class I major histocompatibility complex (MHC) molecules (HLA-A, HLA-B, and HLA-F) and transcription factors (CIITA and NLRC5). Some genes belonging to the antigen presentation pathway were also found in cluster 14 and were downregulated after H7N9 infection but upregulated in H3N2-infected cells, and these included genes encoding class II MHC molecules (HLA-DPA1, HLA-DPB1, HLA-DRA, HLA-DRB1, HLA-DRB4, HLA-DRB5, and CD74) (see Fig. S4B in the supplemental material). Finally, more than 20% of the DE genes had similar profiles in H7N9 and H3N2 IAV versus H5N1 and H7N7 IAVs: these genes were significantly DE only after H5N1 and H7N7 infection (clusters 7 and 20: 3,388 genes). These genes could reflect adaptation of H7N9 to the human host, similar to findings for the seasonal H3N2 virus. Cluster 7 genes were significantly upregulated only in H5N1-and H7N7-infected samples and included genes from the eicosanoid signaling pathway (see Fig. S4C in the supplemental material). Upstream of this pathway, gene expression levels for PLA2G5 were 2 to 4 times more increased after H7N7 and H5N1 infection than after that with H3N2 and H7N9 at 24 hpi; PLA2G5 encodes a phospholipase A2 enzyme that catalyzes arachidonic acid production, a key inflammatory intermediate that is further catalyzed in different lipid mediators, regulating many biological processes, including inflammation and immune function. Several receptors of eicosanoids (LTB4R, TBXA2R, and PTGER3) were also more increased by H5N1 and H7N7 than by H7N9 or H3N2 IAVs. Forty-seven genes from cluster 20 were involved in chromatin modification, with the majority of genes involved in this biological process having similar profiles between H7N9 and H3N2 versus H5N1 and H7N7, but some genes were specifically upregulated only in H7N9-infected samples (cluster 9 and 13 genes) (see Fig. S5 ). This could reflect both H7N9-specific and human-IAVlike ability to modify expression of genes involved in chromatin and epigenetic regulation.