The Zika Virus Persistently Infects Retinal Pigment Epithelial Cells, Eliciting Limited Cytopathic Effects and Loss of Epithelial Characteristics Consistent with Epithelial-Mesenchymal Transition

The Zika virus (ZIKV), a pathogenic member of the orthoflavivirus family, is raising serious health concerns worldwide. Like Dengue (DENV) and Chikungunya (CHIKV) viruses, it is one of the arboviruses that poses an emerging threat to areas where its main vectors, Aedes mosquitoes, proliferate, well beyond tropical and subtropical regions. Although often asymptomatic or mild, ZIKV infection has been responsible for a worrying increase in serious congenital syndromes, including microcephaly. The ability of ZIKV to be transmitted sexually and its long persistence in body fluids suggests its incomplete clearance in particular tissues, linked to recurrent infection. Among its clinical presentations, ZIKV infection has been associated with ocular complications, including maculopathy, retinopathy, uveitis, and optic neuropathy, which can lead to lasting visual impairment. The blood-retinal barrier (BRB), primarily composed of retinal pigment epithelium (RPE) and endothelial cells, plays a crucial role in shielding the retina from pathogens. Its disruption has been linked to viral retinal infections. In vitro monitoring of infection on hTERT RPE-1 cells revealed an ability of ZIKV to persist for up to 30 days in nearly 10% of the cells. This prolonged infection was marked by low cytopathic effects but notable morphological changes throughout the cell layer, suggestive of an epithelial-mesenchymal transition (EMT). Long-lasting viral replication and production was associated with reduced expression of epithelial genes and increased expression of certain mesenchymal genes, suggesting that integrity of the RPE layer may be compromised. These results indicate that viral persistence and phenotypical transition observed in vitro in RPE cells could provide clues to understanding the late onset of ocular pathophysiological manifestations in Zika virus-related diseases.