Berberine Antagonizes NS1-Mediated Immune Evasion and Pathogenesis in Dengue virus infection

Background: The non-structural protein 1 (NS1) of Dengue virus is a multifunctional viral protein that plays a central role in viral replication, immune evasion, and disease pathogenesis. NS1 suppresses host innate immune responses and contributes to vascular leakage, a hallmark of severe dengue, making it an attractive antiviral target. Berberine, a natural isoquinoline alkaloid derived from medicinal plants such as Berberis vulgaris, exhibits broad antiviral and immunomodulatory activities. In our previous study, we demonstrated that Berberine directly targets NS1 and inhibits dengue virus infection. Time-of-drug-addition experiments further revealed that Berberine acts across multiple stages of infection, indicating a multifaceted antiviral mechanism. However, whether Berberine can counteract NS1-mediated suppression of host innate immune responses and pathogenic effects remains unclear.

Methods and Results: Here, we examined the effect of Berberine on NS1-mediated modulation of innate immunity and dengue virus infection. Ectopic expression of NS1 significantly enhanced viral replication, whereas Berberine treatment markedly reduced this NS1-mediated increase in infection. Gene expression analysis showed that NS1 suppressed the transcription of several key innate immune response genes, which was reversed upon Berberine treatment. Berberine also disrupted the dimeric structure of NS1, likely impairing its functional activity. In addition, Berberine significantly reduced virus-induced reactive oxygen species (ROS) generation. Recombinant NS1 protein induced vascular permeability in cellular assays, consistent with its pathogenic role; importantly, Berberine markedly attenuated NS1-induced vascular permeability.

Conclusion: Together, these findings demonstrate that Berberine exerts dual antiviral activity by inhibiting NS1-mediated viral replication and pathogenic effects while restoring host innate immune responses, highlighting its potential as a therapeutic candidate targeting NS1-driven mechanisms in dengue infection.

To be updated shortly..