title: Flaviviruses are neurotropic, but how do they invade the CNS?
abstract: Flaviruses (FV) are RNA viruses carried by mosquitoes. Neurological signs including acute encephalitis, meningitis and acute flaccid paralysis develop in a small percentage of infected individuals; long term sequlae are, Parkinsonism, dystonias and cognitive changes. FV neuroinfection is neurotropic involving subcortical nuclei (substantia nigra and thalamus) anterior horn neurons and neocortex. Glycosylation of the FV E envelope protein is one determinant of neuroinvasion, increasing both axonal and trans-epithelial transportation. Neutralizing antibodies against the E and NS proteins prevents FV uptake into several cell types, including axons. CD8+ T cells are vital for clearance of WNF infected cells from the CNS, whereas TLR-3 and TLR-7 mediated anti-virus response through increased serum inflammatory cytokines to disrupt the BBB providing infected leucocytes and free virus access to the CNS (so called Trojan horse) Cellular virus attachment factors, promoting FV cell entry are widely distributed and include DC-SIGN (that detects complex carbohydrate molecules); Glycosamino glycans (GAG), Heparan sulphate(HSPG) Semaphorin 7A, Low Density Lipid receptors (LDLR); these are not FV specific virus entry receptors. The FV also crosses epithelial and endothelial barriers by disrupting Tight Junction complexes to increase BBB permeability. This review describes the multiple pathways responsible for the neuroinvasive properties of the Flaviviruses.
authors.affiliation: Institute of Infection and Immunity, Henry Wellcome Building, University Hospital of Wales, Cardiff University, Cardiff CF14 4XN, United Kingdom. Electronic address: jwneal@doctors.org.uk.
authors.forename: J W
authors.initials: JW
authors.lastname: Neal
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D020805:Central Nervous System Viral Diseases / Q000276:immunology / Q000821:virology*; D002831:Choroid Plexus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005416:Flavivirus / Q000502:physiology*; D018177:Flavivirus Infections / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D051379:Mice; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000276:immunology / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D019108:Tight Junctions / Q000821:virology; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism; D056189:Viral Tropism; D053585:Virus Attachment; D053586:Virus Internalization
chemical_list: D016207:Cytokines; D051192:Receptors, Pattern Recognition; D051196:Toll-Like Receptor 3; D014764:Viral Proteins
keywords: Axonal transport; Blood brain barrier; Brain; Flavivirus; Inflammation; Tight junction proteins