Mosquito-borne Flaviviruses
Introduction
Mosquito-borne flaviviruses are important pathogens for humans causing diseases such as encephalitis, fever, and hemorrhagic fever. Mosquito-borne flaviviruses are primarily transmitted through Aedes and Culex mosquitoes. The flaviviruses that are classically regarded as neurotropic include Japanese encephalitis virus (JEV), West Nile virus (WNV), as well as Saint Louis encephalitis virus (SLEV), Murray Valley encephalitis virus (MVE).
Virology
Members of the family Flaviviridae have monopartite, linear, single-stranded RNA genomes of positive polarity, and 9.6 to 12.3 kilobase in total length. The genome encodes capsid protein (C), membrane protein (M), envelope protein (E), non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5). Mature infectious flaviviruses are icosahedral, 50nm in diameter.
Fig.1 Flavivirus genomic organization and structure. (Slon Campos, 2018)
Pathogenesis
Flaviviruses are deposited into the skin epidermis by a mosquito bite where they encounter cells permissive to infection. Following cutaneous infection, Langerhans cells migrate to local draining lymph nodes, where the virus is amplified. This results in further virus dissemination on the periphery and viremia. It is generally believed that flaviviruses can invade the central nervous system (CNS) using two major anatomical routes: (a) via the blood circulatory system (resulting in hematogenous spread to the CNS parenchyma during viremia) and (b) via the peripheral nervous system (resulting in neural spread within the axons of peripheral nerves to the CNS).
Fig.2 Pathogenesis of flavivirus neuroinvasion. (Maximova, 2018)
Epidemiology
Flaviviruses infection is an immense global health problem. Historically, epidemics of encephalitis have been recognized in Japan since the 1870s. JEV is primarily prevalent in Asia. In recent years WNV has been spreading globally and is currently endemic in Africa, the Middle East, India, Australia, central and southern Europe, and the Americas. SLEV is prevalent in North and South America. MVEV is the most important cause of arboviral encephalitis in Australia.
Fig.3 The global distribution and spread of the major Flaviviruses causing encephalitis. (Mackenzie, 2004)
Symptoms
Most symptomatic flavivirus infections result in self-limiting flu-like febrile illnesses with a headache, myalgia, arthralgia and a rash without long-term consequences. Severe and life-threatening symptoms are associated with neurological disease including encephalitis, myelitis, and brain malformations.
Prevention and Treatment
The control of encephalitis caused by flavivirus is based largely on three interventions: mosquito control, avoiding human exposure and immunization. Inactivated Vero cell culture-derived JEV vaccine (manufactured as IXIARO) is the only JEV vaccine licensed and available in the United States. There are no vaccines to prevent or medications to treat WNV, SLEV and MVE in people.
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References
- Slon Campos, J.L.; et al, The immune response against flaviviruses. Nat Immunol. 2018, 19(11): 1189-1198.
- Maximova, O.A.; Pletnev, A.G. Flaviviruses and the Central Nervous System: Revisiting Neuropathological Concepts. Annu Rev Virol. 2018, 5(1): 255-272.
- Mackenzie, J.S.; et al. Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med. 2004, 10(12 Suppl): S98-109.
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