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.

The in vivo pulmonary host response and outcome for influenza infection cannot be determined by directly transposing transcriptomic profiles from single cell types. The whole-lung response to infection depends on the interaction between infected cells, immune cells, and the lung microenvironment. In addition, the host response to influenza infection depends on the cell type and differentiation levels of infected cells (37) . We have highlighted in a recent review that novel mathematical models are needed to model interactions between cells and to integrate in vitro and in vivo studies (38) . By using a multivariate modeling approach, McDermott et al. were able to predict pulmonary ex-pression of conserved regulatory modules in macaques and mice in response to H5N1 infection from a regulatory model built from Calu-3 cells infected with H5N1 (39) . In addition, numerous studies have shown that cell cultures are extremely useful experimental models for extended influenza virus-host interaction studies and for the screening of potential antivirals. In particular, polarized Calu-3 cells were shown to be valuable models for the study of influenza virus and supported viral replication and type I IFN responses similarly to primary human bronchial epithelial (HBE) cells (19) . Culture systems of differentiated primary epithelial cells from humans, like HBE cells, recapitulate more closely the morphological features of the human upper airway but provide a less convenient and reproducible model for the study of influenza virus because of experiment, passage, and donor variations, inducing a variable differentiated phenotype (40) . In this study, we used Calu-3 cell cultures to rapidly characterize the emerging H7N9 virus by comparing its response to several avian and human influenza viruses and to perform in silico screening for potential antivirals. We believe that this data set is a valuable resource for further studies of H7N9 and other influenza viruses. In two ongoing studies, we have been profiling mouse and macaque pulmo- . Importantly, we found that a significant number of drugs predicted to reverse Calu-3 cell responses to H7N9, including minocycline, SB203580, KN-62, and Jak Inhibitor 1, were also predicted to reverse the mouse and macaque pulmonary response to H7N9 infection (Morrison et al., submitted). This demonstrates conserved functional responses between these models.