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Vasiliki Kalatzis, Nejla Erkilic, Krishna Damodar, Jean-Pierre Molès, Chantal Fourrier-Wirth, Nicolas Nagot, Philippe Van de Perre, Yannick Simonin, Sara Salinas; ZIKA virus efficiently replicates in human retinal pigment epithelium and disturbs its permeability. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3629.
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© ARVO (1962-2015); The Authors (2016-present)
Recently, the Flavivirus Zika virus (ZIKV) has rapidly spread in the Americas and in the Caribbean islands. While a large proportion of infected persons are subjected to mild or asymptomatic disease, neurological disorders such as Guillain-Barré syndrome and microcephaly have been linked to ZIKV infections. Notably, ZIKV-associated cerebral malformations can be associated with ocular disorders and ZIKV is found in the eye anterior chamber fluid and in conjunctival swab samples of patients. Moreover, ZIKV-infected mice develop ocular disorders and viral RNA is detected in the retina, optic nerve, tears and lacrimal glands.
We, and others, have shown that the human induced pluripotent stem cell (iPSc)-derived retinal pigment epithelium (RPE) is morphologically and functionally characteristic of the RPE in vivo. It thus represents a powerful model for studying pathophysiology of the RPE, a tissue normally inaccessible for experimental manipulation. To study ZIKV ability to replicate in the human retina, we infected confluent iPSc-derived RPE with a clinical Asian lineage ZIKV isolated in French Polynesia (H/PF/2013).
We showed that ZIKV efficiently replicated in the iPSc-derived RPE. Four days post-infection (p.i.), a diffuse viral labeling was seen inside the cells. Interestingly, by 11 days p.i., the location of the intracellular virions changed to a close proximity to the cellular membrane. This coincided with a less marked ZO-1 labelling of the infected RPE compared to controls, suggesting that integrity of the cell layer could be impaired. We measured the transepithelial resistance (TER) of the RPE monolayers and showed a perturbation of the TER from 7 days p.i., consistent with an alteration of epithelium permeability. Finally, electron microscopy analyses showed an impairment of cell junctions after ZIKV infection.
Our data underline the potential permissibility of human RPE to ZIKV infection and the associated deleterious effect on permeability. Our work also draws attention to the necessity of better investigating the ocular disorders associated in ZIKV-infected patients and to evaluate the risk of transmission by eye. Lastly, it provides a further and novel example of the use of iPSc-derived retinal cells for evaluating pathophysiology.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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