Comprehensive Transcriptomic Analysis Identifies Cellular Immune Response Against Influenza A Virus Infection

Abstract

Influenza A virus (IAV) has the higher genetic variation and reassortment, the traditional vaccine and virus-directed antiviral strategies have hardly shown successful efficacy and even lead to serious resistance, therefor developing the broad-spectrum antiviral treatments is particularly important. Host response to IAV infection provides a promising alternative approach to find host factors that are involved in the replication of viruses as molecular drug target. In this study, in order to better illustrate how IAV infection triggers cellular response and understand virus-host interaction, we systematically studied the expression profiles of host gene in a variety of human cells (including epithelial cells, primary epithelial cells) infected with different subtypes of IAV in this research by collecting and excavating 40 microarray data from Gene Expression Omnibus (GEO). The transcriptome analysis results showed that each of influenza strains led to the certain amounts of genes differentially regulated in all cell types, especially those genes belonging to immune defense and antiviral response, but we found that the overlapping regulated genes accounted for only a few in all cell types with different subtypes of IAV infection following the the criteria of P<0.05 and |logFC|≥1.5, because of the difference of IAV strains and infected cell types. Integrative gene network analysis found that IFI6, IFIT2, ISG15, HERC5, RSAD2, GBP1, IFIT3, IFITM1, LAMP3, USP18 and CXCL10 may act as key signatures in alveolar basal epithelial cells for IAV infection, while BATF2, CXCL10, IFI44L, IL6 and OAS2 played a key role in airway epithelial cell response to different subtypes of IAV infection. In addition, we also revealed that some overlaps (BATF2, IFI44L, IFI44, HERC5, OASL, CXCL10, MX2, OAS2, XAF1, IFIT3, USP18, IFIH1, OAS1, IFIT2 and IFIT1) were commonly upregulated in human primary epithelial cells infected by different influenza strains of high or low pathogenicity. Additionally, in the phagocytes, the difference gene expression pattern in different subtypes of IAV infection was found, but phagocytes could elicit the similar defence response against virus infection. Our findings will help us understand the fundamental patterns of molecular responses induced by highly or lowly pathogenic IAV originating from different species and the overlapped genes upregulated by IAV in different cell types may be as key biomarkers to improve effective early detection and treatment. Funding Statement: This work was supported by Key Lab of Process Analysis and Control of Sichuan Universities (No.2018001), The Project-sponsored by Sichuan Province for ROCS (0903/00021728) and NSFC (81902073). Declaration of Interests: No potential conflict of interest was reported by the authors.