Beyond antioxidant defense: multiple roles of the KEAP1-NRF2 pathway in EBV pathogenesis

The National Institute of Allergy and Infectious Diseases awarded East Tennessee State University $570,000 on August 14, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the role of the KEAP1-NRF2 pathway in Epstein-Barr virus pathogenesis.

The research examines how EBV exploits the master antioxidant KEAP1-NRF2 signaling pathway beyond its classical antioxidant function to promote viral persistence. The project will determine how NRF2 activation rewires cellular metabolism to support EBV latency, define the interplay between the KEAP1-NRF2 pathway and autophagy regulation, and elucidate crosstalk between NRF2 and the integrated stress response pathway that sustains viral persistence. Preliminary transcriptomic data indicate that NRF2-dependent gene regulation controls metabolic flux, lysosomal biogenesis, and stress-adaptive networks during EBV latency, with implications for understanding how chronic oxidative stress contributes to EBV-associated malignancies and pathogenesis.

The award funds research training for undergraduate students alongside the primary investigator-led inquiry. Performance occurs in Johnson City, Tennessee, with a period of performance through July 31, 2029. This project grant, classified as assistance funding, supports biomedical research in infectious diseases at an academic institution.

Abstract

Epstein-barr virus (EBV) is a ubiquitous human pathogen etiologically linked to multiple human diseases including malignancies. A hallmark of EBV latency is chronic oxidative stress (OS) driven by excessive reactive oxygen species (ROS), which contribute to genomic instability and pathogenesis. Our group was the first to discover that the master antioxidant KEAP1-NRF2 pathway is constitutively activated during EBV latency. While NRF2 is classically viewed as a cytoprotective transcription factor, our findings suggest that EBV hijacks this pathway not merely for antioxidant defense but to control broader cellular processes essential for viral persistence and pathogenesis. Preliminary transcriptomic data reveal NRF2-dependent regulation of genes involved in metabolic flux, lysosomal biogenesis, and the integrated stress response (ISR), suggesting that sustained NRF2 activation orchestrates a coordinated stress-adaptive network. The central hypothesis of this project is that EBV exploits the KEAP1-NRF2 pathway as a master signaling hub to reprogram metabolism, autophagy, and ISR-ATF4 pathway activity, thereby promoting latency stability and cell survival. To test this hypothesis, we will: 1) determine how NRF2 activation rewires cellular metabolism to meet the anabolic and bioenergetic demands of EBV latency; 2) define the interplay between the KEAP1-NRF2 pathway and tfebmediated autophagy; and 3) elucidate the crosstalk between NRF2 and the ISR-ATF4 pathway that integrates redox and translational stress responses to sustain viral persistence. Successful completion of this project will reveal novel mechanistic insights into EBV pathogenesis, providing meaningful information for future design of new therapeutic strategies for EBV-associated diseases. This R15 research enhancement award program (reap) project also provides extensive hands-on research training for undergraduate and graduate students at east tennessee state university (etsu), strengthening institutional research capacity.