Dengue Virus NS1 Binds Ephrin B1 to Trigger Endothelial Dysfunction

Pahmeier, F.; Hammond, S. R.; Flory, C.; Feng, X.; Lee, S. E.; Jimenez-Posada, E. V.; Duarte, E. M.; Cardona-Ospina, J. A.; Ball, A. H.; Lee, N. E.; Leung, K.; Tjang, L. V.; Beatty, P. R.; Biering, S. B.; Scaturro, P.; Harris, E.

doi:10.1101/2025.11.19.689067

bioRxiv · 10.1101/2025.11.19.689067

Dengue Virus NS1 Binds Ephrin B1 to Trigger Endothelial Dysfunction

Pahmeier, F.·Hammond, S. R.·Flory, C.·Feng, X.·Lee, S. E.·Jimenez-Posada, E. V.·Duarte, E. M.·Cardona-Ospina, J. A.·Ball, A. H.·Lee, N. E.·Leung, K.·Tjang, L. V.·Beatty, P. R.·Biering, S. B.·Scaturro, P.·Harris, E.

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Abstract

Dengue virus (DENV), a member of the Flaviviridae family, is the most prevalent and medically important mosquito-borne viral pathogen. Infected cells secrete the viral non-structural protein 1 (NS1) into the bloodstream, where it can interact with endothelial cells to induce vascular leak. Host factors involved in NS1-mediated endothelial dysfunction are incompletely understood, leading us to investigate the host interactome of DENV NS1 in endothelial cells via a comparative mass spectrometry approach. We identified ephrin B1 (EFNB1) as a critical host factor in NS1-mediated endothelial barrier dysfunction and show that phosphorylation of EFNB1 is necessary for induction of barrier dysfunction. Further, we map the interface of the EFNB1-NS1 complex through biochemical and computational approaches, and we show that EFNB1-Fc-fusion proteins can act as decoys to block NS1-induced barrier dysfunction in vitro and in vivo. This study provides insights into the mechanism of flavivirus NS1-mediated endothelial barrier dysfunction and new avenues to target vascular leak.

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Pahmeier, F., Hammond, S. R., Flory, C., Feng, X., Lee, S. E., Jimenez-Posada, E. V., Duarte, E. M., Cardona-Ospina, J. A., Ball, A. H., Lee, N. E., Leung, K., Tjang, L. V., Beatty, P. R., Biering, S. B., Scaturro, P., Harris, E.. 2025-11-19. Dengue Virus NS1 Binds Ephrin B1 to Trigger Endothelial Dysfunction. https://doi.org/10.1101/2025.11.19.689067

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