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.
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