Flaviviruses constitute a group of small enveloped viruses with positive-sense single stranded RNA genomes of approximately 9.0–13 kb, belonging to the Flaviviridae family. Many Flaviviruses are host-specific and capable of causing severe disease in both mammals and birds. The family Flaviviridae includes four genera: Flavivirus, Hepacivirus, Pegivirus, and Pestivirus. The term Flavivirus is derived from the Latin word flavus, meaning yellow. This name is a direct reference to the Yellow Fever virus, which was the first identified member of the Flaviviridae family and is known for causing jaundice in infected individuals. Flaviviruses are classified into four main groups based on their transmission patterns: mosquito-borne flaviviruses (e.g., Dengue virus, West Nile Virus, Japanese Encephalitis virus, Yellow fever virus, Zika virus, Murray Valley Encephalitis Virus, Kyasanur Forest Disease virus, St. Louis Encephalitis Virus), tick-borne flaviviruses (e.g., Tick-borne encephalitis virus, Omsk hemorrhagic fever virus, Louping ill virus, Kyasanur forest disease virus), Unknown vector flaviviruses (e.g., Jutiapa virus), and insect-only flaviviruses. This new classification helps in understanding their epidemiology and potential for human disease (Table 1). Unknown vector Flaviviruses, also known as no-known-vector (NKV) Flaviviruses, are a group of Flaviviruses that are primarily found in bats and rodents and are not known to be transmitted by arthropods. The terms “insect-only Flaviviruses” in current usage generally refer to viruses that naturally infect and replicate in mosquito cells in vitro, but do not replicate in vertebrate cells or infect humans or other vertebrates. In 2023, the International Committee on Taxonomy of Viruses (ICTV) changed the genus name Flavivirus to Orthoflavivirus due to the same word stem "flavi" in the taxon names, but virus names remain unchanged (Mifsud et al., 2024; Best, 2016; Postler et al., 2023).

Most Flaviviruses are primarily transmitted by hematophagous arthropods, notably mosquitoes and ticks, resulting in widespread endemic infections and, despite sharing a similar genomic organization and replication mechanisms, phylogenetically closely related Flaviviruses could induce a broad spectrum of life-threatening diseases. More than 50 % of known Flaviviruses have been associated with human disease and have a worldwide distribution, but individual species are restricted to specific endemic or epidemic areas. Flavivirus infections often manifest as either asymptomatic or as mild non-specific febrile illnesses. However, severe and potentially fatal systemic complications can occur (van Leur et al., 2021).

Flavivirus pathogenesis involves a complex interplay between viral proteins, host cells, and immune responses, leading to a wide spectrum of human diseases. The specific outcome depends on the particular virus, the host immune system status, and the route of infection. Flavivirus-induced diseases may be associated with symptoms of the central nervous system (e.g., meningitis, encephalitis, and microcephaly), congenital abnormalities, hepatitis, fever, arthralgia, rash, vascular leakage, hemorrhagic fever, gastrointestinal issues, and Guillain–Barre syndrome (Fernandez-Garcia et al., 2009). Apart from causing systemic infections, Flaviviruses have been shown to cause multiple ocular complications, with the most common being conjunctivitis, uveitis, optic nerve abnormalities and diseases in the posterior segment of the eye (e.g., retinitis) (Table 2). The incidence of Flavivirus infection between males and females is nearly similar, as transmission primarily occurs through mosquito bites. Children and the elderly are usually more vulnerable to ocular complications caused by flaviviruses, since their immune systems are either immature (children) or weakened (elderly).

There are no specific antiviral therapies for Flavivirus infections, but significant progress has been made in some Flavivirus vaccine development. While some Flavivirus vaccines like yellow fever and Japanese encephalitis vaccines are well-established, other Flavivirus vaccines are largely in developmental stages (Zhao et al., 2021). This manuscript aims to provide an overview of ocular complications associated with the most significant Favivirus-related human diseases. These viruses have evolved specific mechanisms to counteract the immune response of the host and exploit various metabolic pathways to cause disease. Moreover, we discuss the probable interactions of Flaviviruses with the immune system in ophthalmic anomalies.