Interleukin-17 directly triggers Epstein-Barr virus lytic reactivation in latently infected human B cells.

Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus implicated in a wide spectrum of inflammatory and malignant diseases. Although EBV toggles between latent and lytic states, the host cues that control this switch remain incompletely defined. Interleukin-17A (IL-17A; hereafter IL-17), a signature Th17 cytokine, is abundant in EBV-associated tissues, and EBV products can augment IL-17 responses. Whether IL-17 directly modulates the EBV life cycle has remained unknown. Here we show that IL-17 alone is sufficient to induce EBV lytic reactivation in latently infected human B cells. Across RT-qPCR, immunoblotting, and RNA-seq, IL-17 increased the immediate-early regulator BZLF1 (Zta) and upregulated downstream early and late viral genes, consistent with activation of a transcriptome-wide lytic program. Culture supernatants from IL-17-treated cells contained elevated DNase-resistant extracellular EBV DNA, indicating productive replication with encapsidated genomes. Transcriptomic pathway analyses confirmed engagement of IL-17-linked signaling and highlighted inflammatory modules, including NF-κB and JAK-STAT. Gene Ontology analysis further enriched for regulation of B-cell receptor signaling and B-cell activation, situating IL-17 within B-cell inflammatory circuitry. Together, these findings identify IL-17 as a cytokine cue for EBV lytic entry and provide a mechanistic link between Th17-skewed inflammation and episodic EBV reactivation. This cytokine-driven pathway complements existing models centered on B-cell receptor signaling, hypoxia/HIF-1α, COX-2/PGE₂, and TGF-β and motivates testing whether modulation of the IL-17/IL-17R axis can alter EBV reactivation in IL-17-rich settings. To our knowledge, this is the first demonstration that IL-17 alone directly triggers EBV lytic reactivation in human cells. IMPORTANCE: Epstein-Barr virus (EBV) persists for life by maintaining latency with intermittent lytic reactivation, yet the physiological cues that initiate the latency-lytic switch remain poorly defined. Here we identify the Th17 cytokine interleukin-17A (IL-17) as a direct host trigger of EBV lytic reactivation in latently infected human B cells. IL-17 alone induced the immediate-early transactivator Zta, activated a transcriptome-wide lytic program, and promoted release of DNase-resistant extracellular EBV DNA consistent with encapsidated virions. Transcriptomic analyses confirmed engagement of IL-17-linked inflammatory modules and implicated convergence on signaling nodes shared with canonical B-cell receptor pathways. These findings establish a mechanistic link between Th17-skewed inflammation and EBV reactivation burden, providing a framework to interrogate how IL-17-rich microenvironments influence EBV dissemination and immunopathology and to evaluate whether targeting the IL-17/IL-17R axis can modulate EBV reactivation in disease settings.