title: Mechanism of West Nile virus neuroinvasion: a critical appraisal.
abstract: West Nile virus (WNV) is an important emerging neurotropic virus, responsible for increasingly severe encephalitis outbreaks in humans and horses worldwide. However, the mechanism by which the virus gains entry to the brain (neuroinvasion) remains poorly understood. Hypotheses of hematogenous and transneural entry have been proposed for WNV neuroinvasion, which revolve mainly around the concepts of blood-brain barrier (BBB) disruption and retrograde axonal transport, respectively. However, an over‑representation of in vitro studies without adequate in vivo validation continues to obscure our understanding of the mechanism(s). Furthermore, WNV infection in the current rodent models does not generate a similar viremia and character of CNS infection, as seen in the common target hosts, humans and horses. These differences ultimately question the applicability of rodent models for pathogenesis investigations. Finally, the role of several barriers against CNS insults, such as the blood-cerebrospinal fluid (CSF), the CSF-brain and the blood-spinal cord barriers, remain largely unexplored, highlighting the infancy of this field. In this review, a systematic and critical appraisal of the current evidence relevant to the possible mechanism(s) of WNV neuroinvasion is conducted.
authors.affiliation: School of Veterinary Science, University of Queensland, Gatton, QLD, 4343, Australia. w.suen@uq.edu.au.
authors.forename: Willy W
authors.initials: WW
authors.lastname: Suen
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, QLD, 4072, Australia. n.prow@uq.edu.au.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Prow
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, QLD, 4072, Australia. roy.hall@uq.edu.au.
authors.forename: Roy A
authors.initials: RA
authors.lastname: Hall
authors.affiliation: School of Veterinary Science, University of Queensland, Gatton, QLD, 4343, Australia. h.bielefeldtohmann1@uq.edu.au.
authors.forename: Helle
authors.initials: H
authors.lastname: Bielefeldt-Ohmann
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism / Q000821:virology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000821:virology; D049428:Blood-Nerve Barrier / Q000378:metabolism / Q000821:virology; D001921:Brain / Q000473:pathology / Q000821:virology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D018792:Encephalitis, Viral / Q000503:physiopathology / Q000821:virology*; D015967:Gene Expression Regulation, Viral; D006736:Horses; D006801:Humans; D013116:Spinal Cord / Q000473:pathology / Q000821:virology; D019108:Tight Junctions / Q000378:metabolism / Q000821:virology; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014766:Viremia / Q000503:physiopathology / Q000821:virology*; D053586:Virus Internalization; D014902:West Nile virus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity
chemical_list: D015815:Cell Adhesion Molecules; D014764:Viral Proteins; C013065:cell aggregation factors