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

Abstract

Modulating the host response is a promising approach to treating influenza, caused by a virus whose pathogenesis is determined in part by the reaction it elicits within the host. Though the pathogenicity of emerging H7N9 influenza virus in several animal models has been reported, these studies have not included a detailed characterization of the host response following infection. We found that responses to the H7 subtype viruses were intermediate to those elicited by H5N1 and pdm09H1N1 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 transcription of cytokine response genes and decreased transcription of lipid metabolism and coagulation signaling genes. This three-pronged transcriptomic signature was observed in mice infected with pathogenic H1N1 strains such as the 1918 virus, indicating that it may be predictive of pathogenicity across multiple influenza virus strains. Finally, we used host transcriptomic profiling to computationally predict drugs that reverse the host response to H7N9 infection, and we identified six FDA-approved drugs that could potentially be repurposed to treat H7N9 and other pathogenic influenza viruses. IMPORTANCEEmerging avian influenza viruses are of global concern because the human population is immunologically naive to them. Current influenza drugs target viral molecules, but the high mutation rate of influenza viruses eventually leads to the development of antiviral resistance. As the host evolves far more slowly than the virus, and influenza pathogenesis is determined in part by the host response, targeting the host response is a promising approach to treating influenza. Here we characterize the host transcriptomic response to emerging H7N9 influenza virus and compare it with the responses to H7N7, H5N1, and pdm09H1N1. All three avian viruses were pathogenic in mice and elicited a transcriptomic signature that also occurs in response to the legendary 1918 influenza virus. Our work identifies host responses that could be targeted to treat severe H7N9 influenza and identifies six FDAapproved drugs that could potentially be repurposed as H7N9 influenza therapeutics.

Suboptimal Humoral Immune Response against Influenza A(H7N9) Virus Is Related to Its Internal Genes

“…As of 23 June 2015, the laboratory-confirmed case-fatality rate of A(H7N9) virus infection was 41%, which was lower than that of A(H5N1) infection (53%) but much higher than that in the 2009 pandemic caused by the A(H1N1)pdm09 virus (ϳ0.1 to 5%) (5,6). In mice, the virulence of A(H7N9) virus is between that of the highly pathogenic A(H5N1) and A(H1N1)pdm09 viruses (7,8). A transcriptomic study also showed that the perturbation of the host gene expression profile of A(H7N9) virus infection is intermediate to that of A(H5N1) and A(H1N1)pdm09 virus infections (7).…”

Gene expression signatures as a therapeutic target for severe H7N9 influenza – what do we know so far?

“…The decreased transcription of coagulation and lipid metabolism genes identified in the mouse study was not identified in Calu3 cells indicating that it is likely driven by nonepithelial cell types or by the crosstalk between multiple cell types in the lung. Strikingly, this gene expression signature also occurs in the whole lung response to the infamous 1918 H1N1 virus, indicating that it may predict pathogenicity across different strains [15]. Experiments in cynomolgus macaques confirmed the validity of the pathways and molecules identified in the H7N9 mouse model [16].…”

“…Transcriptional responses to H7N9 were intermediate to those caused by pH1N1 and H5N1 early in infection, but grew to resemble the H5N1 response as infection progressed. Infection with H5N1, H7N7 and H7N9, which are lethal in mice, increased transcription of cytokine response genes and decreased transcription of coagulation and lipid metabolism genes [15]. The decreased transcription of coagulation and lipid metabolism genes identified in the mouse study was not identified in Calu3 cells indicating that it is likely driven by nonepithelial cell types or by the crosstalk between multiple cell types in the lung.…”

“…Gene expression profiles from H7N9-infected cells and tissues can be utilized to computationally identify small molecules and FDAapproved drugs that reverse the host gene expression patterns that may drive H7N9 pathogenesis. We have characterized the transcriptional response to H7N9 infection in human airway epithelial cells, BALB/c mice and cynomolgus macaques to identify host transcriptional signatures that distinguish H7N9 from other IAVs and are predictive of influenza pathogenicity across a range of influenza serotypes and strains [14][15][16]. Our host-directed approach to drug discovery has also identified drugs that could potentially be used to treat severe influenza caused by H7N9 and other pathogenic IAVs.…”

Potential for Low-Pathogenic Avian H7 Influenza A Viruses To Replicate and Cause Disease in a Mammalian Model

“…Based on results from BALB/c mice challenged with isogenic chimeric AIVs, the H7 subtype demonstrated a potential to cause enhanced disease in mammals (17). H7N7 and H7N9 viruses of human origin can also induce a transcriptomic response resulting in increased pathogenicity in BALB/c mice (18).…”