Mechanism of West Nile virus neuroinvasion: a critical appraisal

Viruses. 2014 Jul 18;6(7):2796-825. doi: 10.3390/v6072796.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adherens Junctions / metabolism
  • Adherens Junctions / virology
  • Animals
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / virology
  • Blood-Nerve Barrier / metabolism
  • Blood-Nerve Barrier / virology
  • Brain / pathology
  • Brain / virology
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Encephalitis, Viral / physiopathology
  • Encephalitis, Viral / virology*
  • Gene Expression Regulation, Viral*
  • Horses
  • Humans
  • Spinal Cord / pathology
  • Spinal Cord / virology
  • Tight Junctions / metabolism
  • Tight Junctions / virology
  • Viral Proteins / genetics*
  • Viral Proteins / metabolism
  • Viremia / physiopathology
  • Viremia / virology*
  • Virus Internalization*
  • West Nile virus / genetics
  • West Nile virus / metabolism*
  • West Nile virus / pathogenicity


  • Cell Adhesion Molecules
  • Viral Proteins
  • cell aggregation factors