Dengue virus-2 triggers Epstein-Barr virus replication in primary B cells by co-opting the IRE1-XBP1 signaling axis

The intricate interplay between co-infecting viral pathogens within a host can significantly influence disease outcomes. Dengue virus (DENV), a globally prevalent arbovirus from the Flaviviridae family, and Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, share extensive geographical overlap, yet their potential interactions remain largely uncharacterized. This study elucidates a novel molecular mechanism whereby DENV-2 infection triggers disruption of EBV latency. We systematically demonstrate that DENV-2 infection consistently induces EBV lytic gene expression and viral replication in diverse cellular contexts, including epithelial cell lines and, critically, in primary human B lymphocytes-the principal reservoir of latent EBV. Mechanistically, we establish that the substantial burden of DENV-2 protein synthesis and replication induces profound endoplasmic reticulum (ER) stress, activating the unfolded protein response (UPR). Through pharmacological inhibition and genetic knockdown, we dissect the three UPR branches and identify the IRE1-XBP1 signaling axis as the indispensable pathway for this phenomenon. DENV-2 infection promotes the endoribonuclease activity of IRE1, leading to the unconventional splicing of XBP1 mRNA into its transcriptionally active isoform, XBP1s. Depletion of IRE1 or XBP1 attenuated DENV-induced BZLF1 expression, whereas ectopic XBP1s expression increased BZLF1 transcription. Our findings delineate a precise virus-host-virus signaling model in which an acute RNA virus engages a cellular stress pathway to promote entry into the EBV lytic program and viral genome amplification. This provides a new paradigm for understanding the pathobiology of dengue fever and the complex dynamics of the human virome.IMPORTANCEThis research uncovers a previously unrecognized molecular dialog between two of the world's most common viral pathogens. By demonstrating that dengue virus infection can awaken dormant Epstein-Barr virus, this study provides a mechanistic basis for the long-suspected but poorly understood complications arising from viral co-infections. We pinpoint a specific cellular stress pathway, the IRE1-XBP1 axis of the unfolded protein response (UPR), as the critical molecular switch. This discovery is significant because it not only explains how an acute viral illness can trigger the reactivation of a latent, potentially oncogenic virus but also opens new avenues for therapeutic intervention. Understanding this intricate interplay could lead to novel strategies for managing severe dengue and other diseases where viral co-infection is a contributing factor to pathogenesis.