Ebola Virus Glycoprotein Impairs Human Retinal Pigment Epithelial Barrier Function via the PI3K/Akt-Nrf2 Pathway

Ebola virus (EBOV) causes deadly Ebola virus disease (EVD), and EVD survivors are at high risk of developing blinding ocular complications, which associate with the breakdown of human retinal pigment epithelial (RPE) barrier. Here, we demonstrated EBOV glycoprotein (GP) could directly impair RPE barrier function. EBOV GP significantly decreased expression of tight junction (TJ) proteins in RPE monolayers, resulting in an increase of monolayer permeability. EBOV GP activated PI3K/Akt pathway and induced oxidative stress in RPE cells as evidenced by an increase in the production of reactive oxygen species (ROS), decreased expression of an antioxidant factor, nuclear factor erythroid 2-related factor 2 (Nrf2), and its downstream proteins heme oxygenase 1 (HO-1) and NAD(P)H dehydrogenase (quinone) 1 (NQO1). We found activating Nrf2 could counteract EBOV GP-induced RPE barrier injury. Furthermore, GP2 subunit is the key region in the GP that impairs RPE barrier function. Destruction of RPE barrier function by EBOV GP leads to translocation of bacteria and HIV-1. We confirmed EBOV GP-mediated impairment of RPE barrier function in mice. As an Nrf2 activator, resveratrol displays protective effects on the RPE barrier function. Collectively, our study demonstrates EBOV GP impairs the RPE barrier function through PI3K/Akt-Nrf2 pathway and resveratrol is a promising therapeutic agent for EVD-associated retinal complications.