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.

To confirm these predictions, we used a second independent method which is a data-driven prediction based on the Connectivity Map (Cmap). Cmap is a database of more than 7,000 gene expression profiles, representing 1,309 compounds, and we used it to identify drugs reverting IAV signatures (Cmap score close to Ϫ1) or inducing changes similar to those induced by IAVs (Cmap score close to 1) (Fig. 4B) . Because Cmap profiles were generated using cell lines and array platforms different from those in this experiment, we used these results as a second line of validation, considering only drugs predicted in the Ingenuity Pathways Knowledge Base (IPA). Among the 26 compounds predicted to be upstream regulators of at least 1 IAV, 10 were found to be significant in Cmap. Relationships between these 10 drugs and each viral condition are depicted as a drug-virus network (Fig. 4B) . These results confirmed that SB-203580 and genistein reverted the host response to all 4 IAVs. Conversely, SB-202190 and resveratrol were found to induce gene expression changes similar to those induced by IAV. Troglitazone and LY-294002 were predicted to reverse H7N9 signatures across infection but had positive Cmap scores for some viral treatment: H5N1 at 24 hpi for troglitazone and H3N2 and H7N7 at 7 hpi for LY-294002. Finally, some drugs had strain-specific effects, such as minocycline, predicted in both IPA and Cmap to negatively regulate H7N9 signatures, or simvastatin, which induced effects opposite to those of H3N2 only.