Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/22/2014
Publication Date: 9/1/2014
Publication URL: http://handle.nal.usda.gov/10113/59864
Citation: Morrison, J., Josset, L., Tchitchek, N., Chang, J., Belser, J., Swayne, D.E., Pantin Jackwood, M.J., Tumpey, T., Katze, M. 2014. H7N9 and other pathogenic avian influenza viruses elicit a three-pronged transcriptomic signature that is reminiscent of 1918 influenza virus and is associated with lethal outcome in mice. Journal of Virology. 88(18):10556-10568. doi: 10.1128/JVI.00570-14. Interpretive Summary: Emerging avian influenza viruses are of global concern because the human population is immunologically naïve to them. Because influenza pathogenesis is determined in part by the host response, targeting the host response is a promising approach to treating influenza. In this study the host transcriptomic response to emerging H7N9 influenza virus is characterized in mice and compared it with the responses to H7N7, H5N1 and H1N1 viruses. All three avian viruses were pathogenic in mice, and elicited a host transcriptomic signature that also occurs in response to the legendary 1918 influenza virus. This work identifies host responses that could be targeted to treat severe H7N9 influenza and identifies two FDA-approved drugs that could potentially be repurposed as H7N9 influenza therapeutics.
Technical Abstract: Modulating the host response is a promising approach to treating influenza, a virus whose pathogenesis is determined in part by the host response it elicits. Though the pathogenicity of emerging H7N9 influenza virus has been reported in several animal models, these studies have not included a detailed characterization of the host response following infection. To this end, we characterized the transcriptomic response of BALB/c mice infected with H7N9 (A/Anhui/1/2013) virus and compared it to the responses induced by H5N1 (A/Vietnam/1203/2004), H7N7 (A/Netherlands/219/2003) or H1N1 (A/Mexico/4482/2009) viruses. We found that responses to the H7 subtype viruses were intermediate to those elicited by H5N1 and H1N1 early in infection, but that they evolved to resemble the H5N1 response as infection progressed. H5N1, H7N7 and H7N9 viruses were pathogenic in mice, and this pathogenicity correlated with increased cytokine response, decreased lipid metabolism and decreased coagulation signaling. This three-pronged signature has previously been observed in mice infected with pathogenic H1N1 strains such as the 1918 virus, indicating that it may be predictive of pathogenicity across multiple influenza strains. Finally, we used host transcriptomic profiling to computationally predict drugs that reverse the host response to H7N9 infection, and identified two FDA-approved drugs that could potentially be repurposed to treat H7N9 and other pathogenic influenza viruses.