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.
Highlights
West Nile virus (WNV) continues to pose a significant disease burden in both human and animal populations, with new emerging or re-emerging strains appearing to be more neurotropic [1,2].In 2012, the Center for Disease Control and Prevention (CDC) reported the highest number of humanWNV cases in the U.S since 2003 [3]
While this study investigated the role of TLR-3 and its downstream cytokines in WNV neuropathogenesis, it did not directly demonstrate cell-free virion migration across blood-brain barrier (BBB) via the paracelluar junction
Through direct injection of WNV inoculum into the sciatic nerve, investigators have shown that transneural spread of the virus from the peripheral nervous system (PNS) to the central nervous system (CNS) could be a putative route for neuroinvasion [64,65]
Summary
Received: 28 April 2014; in revised form: 9 July 2014 / Accepted: 10 July 2014 /
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