Name
DDX21-Mediated Antiviral State Protects Against HSV-2 in Vaginal Epithelial Cells
Presenter
Lauren Jirik, McMaster University
Co-Author(s)
Lauren Jirik1,2, Aisha Nazli1,2, and Charu Kaushic1,2 1McMaster Immunology Research Centre, 2Department of Medicine, McMaster University, Hamilton, ON
Abstract Category
Fighting & Responding
Abstract
Herpes simplex virus type 2 (HSV-2) is the leading cause of genital herpes and one of the most prevalent sexually transmitted infections worldwide. Women, particularly in Sub-Saharan Africa, bear a disproportionate burden of infection, with seroprevalence reaching 70–80% in some regions. Importantly, HSV-2 infection increases the risk of HIV acquisition three-fold, underscoring its profound implications for global reproductive health. HSV-2 is transmitted through direct mucosal contact and initially infects genital epithelial cells, yet the innate antiviral mechanisms that protect this barrier remain poorly defined. Transcriptomic analysis of vaginal epithelial cells (VK2) revealed significant downregulation of the DEAD-box RNA helicase DDX21 following HSV-2 infection. DDX21 functions as a scaffold protein within the DDX1–DDX21–DHX36 complex, which senses double-stranded RNA and promotes type I interferon (IFN) signaling, although proviral activity has been described in other viral infections. To delineate its function during HSV-2 infection, we generated VK2 cell lines with stable DDX21 overexpression or knockdown and assessed viral replication and innate immune responses. HSV-2 replication was quantified using fluorescent imaging of GFP-tagged virus, and antiviral gene expression was measured by quantitative PCR. DDX21 overexpression significantly restricted HSV-2 replication and enhanced basal and infection-induced expression of antiviral interferon-stimulate genes, including IFIT3, ISG15, MX1, and RSAD2, establishing a primed antiviral state independent of type I IFN induction. Together, these findings identify DDX21 as a critical epithelial antiviral factor that limits HSV-2 replication by amplifying downstream ISG responses and highlight its potential as a target to strengthen mucosal immunity and reduce HSV-2 transmission.