Molecular Responses of Human Retinal Cells to Infection with Dengue Virus

Abstract

Recent clinical reports indicate that infection with dengue virus (DENV) commonly has ocular manifestations. The most serious threat to vision is dengue retinopathy, including retinal vasculopathy and macular edema. Mechanisms of retinopathy are unstudied, but observations in patients implicate retinal pigment epithelial cells and retinal endothelial cells. Human retinal cells were inoculated with DENV-2 and monitored for up to 72 hours. Epithelial and endothelial cells supported DENV replication and release, but epithelial cells alone demonstrated clear cytopathic effect, and infection was more productive in those cells. Infection induced type I interferon responses from both cells, but this was stronger in epithelial cells. Endothelial cells increased expression of adhesion molecules, with sustained overexpression of vascular adhesion molecule-1. Transcellular impedance decreased for epithelial monolayers, but not endothelial monolayers, coinciding with cytopathic effect. This reduction was accompanied by disorganization of intracellular filamentous-actin and decreased expression of junctional molecules, zonula occludens 1, and catenin-β1. Changes in endothelial expression of adhesion molecules are consistent with the retinal vasculopathy seen in patients infected with DENV; decreases in epithelial junctional protein expression, paralleling loss of integrity of the epithelium, provide a molecular basis for DENV-associated macular edema. These molecular processes present potential therapeutic targets for vision-threatening dengue retinopathy.

Dengue Virus Induces Increased Activity of the Complement Alternative Pathway in Infected Cells

“…The low susceptibility of HUVEC (18) and MDM (47,48) to DENV infection in vitro might account for the observed lack of detectable induction of extracellular FH in these cells. To analyze this, responses were evaluated in another EC transformed cell line (HPV E6/E7-transduced human retinal endothelial cells [HREC]), which have low susceptibility to DENV infection, and ARPE-19 retinal pigment epithelial cells, which have high susceptibility to DENV infection (49). Consistent with the results in HUVEC and MDM, the levels of FB and FH mRNA were significantly increased in DENV-infected HREC and ARPE-19 cells at 48 hpi (Fig.…”

Ocular Manifestations of Emerging Flaviviruses and the Blood-Retinal Barrier

“…Smith et al 2017 have recently shown that retinal epithelial and endothelial cells are susceptible to DENV infection with cytopathic effects in epithelial cells. The infection decreased the epithelial barrier integrity while the endothelial junctions were intact which correlated with the clinically observed loss of RPE in DENV infected patients [ 68 ].…”

Emerging infectious uveitis: Chikungunya, dengue, Zika and Ebola: A review

“…Initial studies using human retinal cells and new in vivo models, most commonly in rodents, are providing illuminating information in this regard. While this work is in its infancy, research from several groups has focused on the potential role of the human retinal pigment epithelial cell as a key cell in providing access to the eye, supporting DENV, ZIKV and EBOV replication and generating a strong innate anti‐viral response . Studies of infections induced in mice by local or systemic ZIKV inoculation demonstrate that, as well as retinal pigment epithelial cells, Mueller cells, also may be primary targets for these viruses .…”

“…While this work is in its infancy, research from several groups has focused on the potential role of the human retinal pigment epithelial cell as a key cell in providing access to the eye, supporting DENV, ZIKV and EBOV replication and generating a strong innate anti-viral response. [82][83][84] Studies of infections induced in mice by local or systemic ZIKV inoculation demonstrate that, as well as retinal pigment epithelial cells, Mueller cells, also may be primary targets for these viruses. 85,86 As these investigations expand, they may identify opportunities to develop novel anti-viral drugs targeted at key pathogenic viral and/or infected host cell molecules.…”