Ocular Manifestations of Emerging Flaviviruses and the Blood-Retinal Barrier

Abstract

Despite flaviviruses remaining the leading cause of systemic human infections worldwide, ocular manifestations of these mosquito-transmitted viruses are considered relatively uncommon in part due to under-reporting. However, recent outbreaks of Zika virus (ZIKV) implicated in causing multiple ocular abnormalities, such as conjunctivitis, retinal hemorrhages, chorioretinal atrophy, posterior uveitis, optic neuritis, and maculopathies, has rejuvenated a significant interest in understanding the pathogenesis of flaviviruses, including ZIKV, in the eye. In this review, first, we summarize the current knowledge of the major flaviviruses (Dengue, West Nile, Yellow Fever, and Japanese Encephalitis) reported to cause ocular manifestations in humans with emphasis on recent ZIKV outbreaks. Second, being an immune privilege organ, the eye is protected from systemic infections by the presence of blood-retinal barriers (BRB). Hence, we discuss how flaviviruses modulate retinal innate response and breach the protective BRB to cause ocular or retinal pathology. Finally, we describe recently identified infection signatures of ZIKV and discuss whether these system biology-predicted genes or signaling pathways (e.g., cellular metabolism) could contribute to the pathogenesis of ocular manifestations and assist in the development of ocular antiviral therapies against ZIKV and other flaviviruses.

Keywords: blood-retinal barrier; eye; flavivirus; innate response; ocular; zika virus.

Figure 1

Eye anatomy and ocular complications caused by flaviviruses. Various components of the human eye are labelled in black. The flaviviruses responsible for causing ocular manifestations are shown in green whereas specific ocular tissue pathology is highlighted in red.

Figure 2

Flavivirus replication cycle and genome structure. (A) The flavivirus enters the host cell by attaching to specific receptors (1) which then leads to its endocytosis (2) followed by fusion to a lysosome into an acidic environment (3). The genome is released from the endolysosome (4) which is then translated on the Endoplasmic reticulum membrane (5) and post translational processing is done in the Golgi apparatus (6). The mature virus then buds off from the Golgi network (7) to the extracellular space via exocytosis (8, 9). (B) The genome consists of three structural proteins (Envelope (E), Capsid (C) and pre-membrane (prM)) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NSB, and NS5).

Figure 3

Probable mechanisms for the breach of blood-retinal barriers by ZIKV. Upon infection and peak viremia, there is an increased circulation of Zika virus, ZIKV NS1 protein, and immune cells in the blood (1). The virus in the retinal blood capillaries infect the endothelial lining (2) and the immune cells reach the site of infection/inflammation by diapedesis through the capillaries (3). It is followed by infection of RPE, the cell lining the outer BRB, resulting in chorioretinal atrophy. The viral infections might cause a BRB weakening by decreasing intercellular junction integrity. Being a neurotrophic virus, at later stages ZIKV can infect retinal Muller glia or neurons inside of the eye (4). The complications are worsened with the involvement of immune cells which get activated upon infection and release a “cytokine storm” as an antiviral response which damages the host cells by altering the barrier integrity (5). The virus along with the circulating immune cells can cross the inner BRB (retinal blood vessels) and infect neuronal cells such as ganglion cells (6, 7). The Image has been created with BioRender software.