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.

Comparative Pathology of West Nile Virus in Humans and Non-Human Animals

“…Ocular manifestations seen in WNV infection, specifically those associated with the optic nerve and the retina, can be considered an extension of the brain. In one report, 80% of patients with WNV neurologic disease have chorioretinal involvement, primarily multifocal chorioretinitis, although it is often asymptomatic and self-limiting [79,80]. Additional WNV ocular manifestations vitritis, optic neuritis and retinal hemorrhage [81][82][83].…”

Zika virus: Molecular responses and tissue tropism in the mammalian host

“…Studies in mice further suggested that the neuronal cell components in the cornea and retina were more susceptible than the rod and cone photoreceptor cells to the viral onslaught . It is hypothesized that the retinal compartment of the eye could be breached by ZIKV infection of the outer layer of the BRB, ie, the retinal pigment epithelial cells or by infection of the retinal vascular endothelial cells, which constitute the inner layer of BRB …”

Molecular Mimicry between Zika virus and central nervous system inflammatory demyelinating disorders: the role of NS5 Zika virus epitope and PLP autoantigens

“…In addition, ZikV was detected by serology in cerebrospinal uid (CSF), molecular and histopathological analysis of the brain and amniotic uid of microcephalic fetuses (3,4). ZikV has also been associated to central nervous system (CNS) in ammatory demyelinating disorders (IDD) including optic neuritis (5), neuromyelitis optica spectrum disorders (NMOSD) (6), transverse myelitis and acute disseminated encephalomyelitis (ADEM) (3). Our group has recently published a case in which the coexistence of the virus in the CNS of an MS patient led to the development of an ADEM-like episode (7).…”