Influenza A Virus RNA Polymerase Is Enriched on the Chromatin of Innate Immune Response Genes

The influenza A virus hijacks host cell machinery by “snatching” molecular caps from cellular RNAs to prime its own transcription. While this process is typically associated with the beginning of genes, this study reveals that the viral RNA polymerase exerts a far-reaching influence on host gene expression. Using genome-wide mapping and comparative pathway analyses, we show that viral polymerase (FluPol) recruitment is decoupled from general host transcriptional activity; instead, FluPol is markedly enriched at a distinct subset of promoters and enhancers associated with defense-related pathways. Beyond the initiation site, FluPol remains associated with host transcripts throughout elongation, extending into downstream-of-gene (DoG) regions. It further accumulates at gene ends, potentially contributing to widespread defects in transcription termination. By remaining linked to host transcripts across the entire gene body, FluPol could extend its opportunity for cap-snatching and impair the recycling of cellular transcription machinery. Together, these findings demonstrate how FluPol accumulation across key cellular defense loci spans from initiation through to termination, driving host transcriptional attenuation.