Viral hijacking : How hRSV NS1 Wrests Control of Host Immune Regulation

Human respiratory syncytial virus (hRSV) infection is a significant global health and economic burden. Lower respiratory tract hRSV infections predominantly affect young children, the elderly, and those with compromised immune systems. Worldwide each year, there are over 3.6 million hRSV hospital admissions in children under age 5. Though 3 new vaccines were recently approved, none of these are approved for use in young children. Thus, new strategies are needed to combat hRSV. hRSV is a negative sense single-stranded RNA virus that targets the host transcriptional machinery upon infection to modulate gene expression, including host immune response genes. We previously demonstrated that hRSV nonstructural protein 1 (NS1) partitions to the host nucleus and binds to chromatin, the proteins associated with host genomic DNA. Using biochemical and chromatin mapping studies, we demonstrated that NS1 associates with the Mediator complex. The human Mediator complex is comprised of approximately 30 subunits, many of which bind to multiple transcription factors and relay signals that control gene transcription. These Mediator subunits bind to transcription factors at gene regulatory regions, which are distant from each other, via chromatin looping. In this way, the Mediator complex bridges the physical gap between gene regulatory control regions to modulate and refine the level and timing of gene transcription. We performed chromatin mapping and transcriptome sequencing that revealed colocalization of NS1 with Mediator complex near regulatory elements of genes differentially expressed during hRSV infection, particularly at interferon-induced viral response genes. Together, our results identify hRSV NS1 as a viral interactor of MED25 that modulates Mediator complex associated transcriptional activity in hRSV infection. Our ongoing work will further elucidate viral gene regulatory mechanisms and reveal targets for development of therapeutic strategies for hRSV infections.