The Immunopathogenesis of Neurotropic Flavivirus Infection

Abstract

The flavivirus genus in the Flaviviridae family comprises over 70 species, most of which are tickor mosquito-borne. They are single-stranded, plus-sense RNA viruses, responsible for significant human and animal morbidity and mortality on all inhabited continents. Medically important viscerotropic flaviviruses include dengue, found equatorially across the world, and the prototypic yellow fever virus, found in Africa and South America. Neurotropic members include tick-borne encephalitis virus (TBEV) in Europe, West Nile virus (WNV) in Africa, parts of Europe and the Indian subcontinent, as well as the USA, St Louis encephalitis virus in the USA, and Japanese encephalitis (JEV) and Murray Valley encephalitis (MVE) viruses in Australasia. Many of these have a history of emergence and re-emergence; indeed, following a novel outbreak in 1999 in New York (Lanciotti et al., 1999; CDC, 2010), WNV spread virtually throughout the Americas in less than 10 years and is the most common cause of meningoencephalitis in North America. WNV is now perhaps the most widely spread of all flaviviruses and may comprise 4 or more lineages, based on isolate homologies (C.G. Hayes, 2001; Bakonyi et al., 2005; Vazquez et al., 2010), with Lineage I and II well-defined and of obvious clinical importance in animals and humans (E.B. Hayes et al., 2005; Venter et al., 2009). WNV was first isolated in 1937 in the West Nile region of Uganda (Smithburn et al., 1940). It is a member of the Japanese encephalitis serogroup, together with JEV, Murray Valley and Saint Louis encephalitis viruses (Poidinger et al., 1996). These viruses are usually propagated in a zoonotic cycle between mosquitoes and amplifying hosts, particularly birds (or pigs in the case of JEV), with humans being incidental, since they may not develop high enough virus titres to infect arthropod vectors (C.G. Hayes, 2001). Rare cases of human-to-human WNV transmission have been documented via organ transplants and blood transfusion, as well as vertical transmission to the foetus in utero (Iwamoto et al., 2003; Lindsey et al., 2009). Although less than one percent of WNV infections develop neuroinvasive disease, in some 60% of patients presenting with central nervous system (CNS) symptoms denoting neuroinvasive disease, life-threatening encephalitis supervenes (Samuel & Diamond, 2009). The young,