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.

Surprisingly, the most distinct response was between H7N9 and H7N7, despite genetic similarities between HA segments. Therefore, analysis of viral sequences alone cannot predict the host response to infection. Analysis between HA and human receptors has revealed that H7N9 has a profile intermediate between those of human and avian IAVs. Here, we observed that the host response to H7N9 shared some similarities with the response to human and avian IAVs, but we also observed a large amount of specificity in the cell response to H7N9 infection. Genes significantly induced by H7N9 were involved in cell cycle regulation, transcription, and epigenetic modifications. Consistent with findings of a previous study in polarized Calu-3 cells (19), we noted that avian IAVs induced a weaker proinflammatory cytokine response than human IAV. For genes coding for type I IFN and some other cytokines, this reduced cytokine induction was even more striking in H7N9-infected than in H5N1-or H7N7-infected samples. The ability to delay the antiviral host response could also have a major impact on in vivo pathogenesis of H7N9 human infection. Finally, genes coding for antigen presentation pathway proteins were upregulated only in H3N2-infected cells, while the expression of these genes was either unchanged by avian IAVs or downregulated by H7N9 virus. Notably, downregulation of the antigen presentation pathway was also observed in nonpolarized Calu Because no vaccine for the prevention of H7N9 infections is currently available, prophylaxis and treatment rely on antivirals. Studies in mice (28) and in a patient (29) have shown low efficacy of NA inhibitors for H7N9 morbidity. Moreover, emergence of H7N9 virus resistant to NA inhibitors has been observed (18) , and one of the resistance mutations (NA-R292K) induced high-level oseltamivir resistance without impairing viral replication and in vivo virulence (30) . Finally, ribavirin, which shows in vitro activity against influenza viruses, including H7N9, is not currently approved for the treatment of influenza and has controversial efficacy in vivo (31) . Developing alternative antiviral therapeutics is therefore a priority. Genome-based drug repurposing strategies relying on the identification of drugs reversing cell responses to viral infection have successfully identified antivirals against IAVs (25) and coronavirus (24) . These strategies have the advantage of being able to screen a large number of available drugs in silico and potentially accelerate their use in clinics. Here, we used a combination of two complementary methods, a knowledge-based approach (using IPA) prioritizing drugs with published effects that are opposite to IAV-induced gene expression changes, and a databased approach using drug gene expression profiles present in Cmap to determine whether drug treatment induced transcrip- tomic changes opposite to viral infection. Twenty-six molecules were predicted by the first method to modulate the host response to at least one IAV, and out of the 10 present in Cmap, 8 were found to induce gene expression changes opposite to IAV signatures after multiple cell line treatment. Drugs that were predicted by both methods for H7N9 were the kinase inhibitors SB203580, genistein, LY-294002, and the antibiotic minocycline. In addition, the antidiabetic drug troglitazone, which was just below our threshold for IPA prediction, was found in Cmap to significantly revert H7N9 signatures at 3, 7, and 12 hpi.