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Peer-reviewedCC BY 4.0Journal of Virology

Interleukin-17A directly triggers Epstein-Barr virus lytic reactivation in latency I human B-cell models

  • Janardhan Avilala1,2
  • Hirotomo Dochi1,2
  • Ramsy Abdelghani3
  • David Becnel3
  • Grace Maresh4
  • Xin Zhang4
  • Li Li4
  • Mark Sides2,5
  • Gilbert Morris1,2
  • Hong Liu2,6
  • Zhen Lin1,2
6 affiliations
  1. 1Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
  2. 2Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
  3. 3Section of Pulmonary and Critical Care Medicine and Interventional Pulmonology, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
  4. 4Translational Cancer Research Laboratory, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
  5. 5Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
  6. 6Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA
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Abstract

Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus implicated in inflammatory, malignant, and autoimmune diseases. Although EBV toggles between latent and lytic states, the host cues controlling this switch remain incompletely defined. Interleukin-17A (IL-17A), a signature Th17 cytokine, is enriched in EBV-associated inflammatory settings, and EBV products can augment IL-17A responses. Whether IL-17A directly regulates the EBV life cycle has remained unknown. Here, we show that IL-17A alone is sufficient to induce EBV lytic reactivation in latency I human B-cell models. IL-17A increased BZLF1/Zta, activated the BZLF1 promoter (Zp), induced early and late lytic genes and proteins, and promoted DNase-resistant EBV DNA release and infectious virion production. Mechanistically, IL-17A activated NF-κB and ERK/p38 MAPK signaling, including phosphorylation of p65, ERK1/2, and p38. IL-17RA blockade reduced IL-17A-induced signaling and lytic reactivation, and pharmacologic inhibition of NF-κB or p38 MAPK signaling attenuated EBV reactivation. Among IL-17 family members tested, only IL-17A induced reactivation. RNA-seq provided a transcriptome-wide view of the viral and cellular response to IL-17A, revealing broad EBV lytic transcription and inflammatory, NF-κB-associated, and B-cell activation programs. IL-17A responsiveness was latency- and cell-state restricted: latency I B-cell models responded, whereas latency II/III, lymphoblastoid, and EBV-positive epithelial models did not. Subinducing IL-17A (1 ng/mL) was insufficient alone but enhanced B-cell receptor-mediated reactivation, suggesting threshold-lowering activity in inflammatory B-cell niches. Together, these findings identify IL-17A as a receptor-linked inflammatory cue for EBV lytic entry and provide the first demonstration that IL-17A alone directly triggers EBV lytic reactivation in human cells.

IMPORTANCE: Epstein-Barr virus (EBV) persists for life by maintaining latency with lytic reactivation, yet the inflammatory cues that initiate this switch remain poorly defined. Here, we identify interleukin-17A (IL-17A), a Th17 cytokine, as a direct trigger of EBV lytic reactivation in latency I human B-cell models. IL-17A activates IL-17RA-linked NF-κB/MAPK signaling, induces BZLF1/Zta and downstream lytic genes, and promotes DNase-resistant EBV DNA release and infectious virion production. IL-17RA blockade and inhibition of NF-κB/p38 MAPK signaling reduce reactivation, supporting a receptor-linked mechanism rather than nonspecific stress. Subinducing IL-17A (1 ng/mL) was insufficient to reactivate EBV alone but enhanced B-cell receptor-mediated reactivation, suggesting threshold-lowering activity in inflammatory B-cell niches. The response is restricted by latency and cell state, indicating that IL-17A signaling must be coupled to a permissive EBV lytic switch. These findings connect Th17-skewed inflammation to EBV reactivation burden and suggest that IL-17A/IL-17R signaling may influence EBV pathogenesis in inflammatory and malignant settings.

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Cite

BibTeXRIS
BibTeX
@article{avilala2026interleukin17a,
  title = {{Interleukin-17A directly triggers Epstein-Barr virus lytic reactivation in latency I human B-cell models}},
  author = {Janardhan Avilala and Hirotomo Dochi and Ramsy Abdelghani and David Becnel and Grace Maresh and Xin Zhang and Li Li and Mark Sides and Gilbert Morris and Hong Liu and Zhen Lin},
  journal = {Journal of Virology},
  year = {2026},
  month = sep,
  doi = {10.1128/jvi.00813-26},
  url = {https://doi.org/10.1128/jvi.00813-26},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Interleukin-17A directly triggers Epstein-Barr virus lytic reactivation in latency I human B-cell models
AU  - Janardhan Avilala
AU  - Hirotomo Dochi
AU  - Ramsy Abdelghani
AU  - David Becnel
AU  - Grace Maresh
AU  - Xin Zhang
AU  - Li Li
AU  - Mark Sides
AU  - Gilbert Morris
AU  - Hong Liu
AU  - Zhen Lin
PY  - 2026
DA  - 2026/09/24
JO  - Journal of Virology
DO  - 10.1128/jvi.00813-26
UR  - https://doi.org/10.1128/jvi.00813-26
AB  - Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus implicated in inflammatory, malignant, and autoimmune diseases. Although EBV toggles between latent and lytic states, the host cues controlling this switch remain incompletely defined. Interleukin-17A (IL-17A), a signature Th17 cytokine, is enriched in EBV-associated inflammatory settings, and EBV products can augment IL-17A responses. Whether IL-17A directly regulates the EBV life cycle has remained unknown. Here, we show that IL-17A alone is sufficient to induce EBV lytic reactivation in latency I human B-cell models. IL-17A increased BZLF1/Zta, activated the BZLF1 promoter (Zp), induced early and late lytic genes and proteins, and promoted DNase-resistant EBV DNA release and infectious virion production. Mechanistically, IL-17A activated NF-κB and ERK/p38 MAPK signaling, including phosphorylation of p65, ERK1/2, and p38. IL-17RA blockade reduced IL-17A-induced signaling and lytic reactivation, and pharmacologic inhibition of NF-κB or p38 MAPK signaling attenuated EBV reactivation. Among IL-17 family members tested, only IL-17A induced reactivation. RNA-seq provided a transcriptome-wide view of the viral and cellular response to IL-17A, revealing broad EBV lytic transcription and inflammatory, NF-κB-associated, and B-cell activation programs. IL-17A responsiveness was latency- and cell-state restricted: latency I B-cell models responded, whereas latency II/III, lymphoblastoid, and EBV-positive epithelial models did not. Subinducing IL-17A (1 ng/mL) was insufficient alone but enhanced B-cell receptor-mediated reactivation, suggesting threshold-lowering activity in inflammatory B-cell niches. Together, these findings identify IL-17A as a receptor-linked inflammatory cue for EBV lytic entry and provide the first demonstration that IL-17A alone directly triggers EBV lytic reactivation in human cells.  IMPORTANCE: Epstein-Barr virus (EBV) persists for life by maintaining latency with lytic reactivation, yet the inflammatory cues that initiate this switch remain poorly defined. Here, we identify interleukin-17A (IL-17A), a Th17 cytokine, as a direct trigger of EBV lytic reactivation in latency I human B-cell models. IL-17A activates IL-17RA-linked NF-κB/MAPK signaling, induces BZLF1/Zta and downstream lytic genes, and promotes DNase-resistant EBV DNA release and infectious virion production. IL-17RA blockade and inhibition of NF-κB/p38 MAPK signaling reduce reactivation, supporting a receptor-linked mechanism rather than nonspecific stress. Subinducing IL-17A (1 ng/mL) was insufficient to reactivate EBV alone but enhanced B-cell receptor-mediated reactivation, suggesting threshold-lowering activity in inflammatory B-cell niches. The response is restricted by latency and cell state, indicating that IL-17A signaling must be coupled to a permissive EBV lytic switch. These findings connect Th17-skewed inflammation to EBV reactivation burden and suggest that IL-17A/IL-17R signaling may influence EBV pathogenesis in inflammatory and malignant settings.
SN  - 0022-538X
SN  - 1098-5514
ER  -