Influenza virus infection induces widespread alterations of host cell splicing

Influenza A viruses (IAV) use diverse mechanisms to interfere with cellular gene expression and thus limit the antiviral responses and/or promote viral replication. Although many RNAseq studies have documented IAV-induced changes in host mRNA abundance, few were designed to allow an accurate quantification of changes in host mRNA splicing. Here we show that IAV infection of human lung cells induces widespread alterations of cellular splicing, with an overall increase in exon inclusion and decrease in intron retention. Over half of the mRNAs that show differential splicing undergo no significant changes in abundance or in their 3’ end termination site, suggesting that IAV can directly manipulate cellular splicing independently of other transcriptional changes. Cross-analysis of the alternative splicing profiles of IAV-infected and RED-depleted cells demonstrates a partial phenocopying of the RED-knock down phenotype in infected cells, suggesting that hijacking of the RED factor by IAVs to promote splicing of their own mRNAs could account for a minor subset of splicing changes in infected cells. All our results can be expored through a Shiny user friendly interface (http://virhostnet.prabi.fr:3838/shinyapps/flu-splicing). RNA-seq on polyA+ RNAs from A549 cells infected with the influenza virus A/WSN/33 or mock-infected, and either untreated, transfected with a control siRNA, or transfected with a siRNA targeting the splicing factor RED. Four biological replicates (R2 to R5) were performed for each of the 6 experimental condition.