Pathogenicity and virulence of West Nile virus revisited eight decades after its first isolation

Abstract

West Nile virus (WNV) is a flavivirus which transmission cycle is maintained between mosquitoes and birds, although it occasionally causes sporadic outbreaks in horses and humans that can result in serious diseases and even death. Since its first isolation in Africa in 1937, WNV had been considered a neglected pathogen until its recent spread throughout Europe and the colonization of America, regions where it continues to cause outbreaks with severe neurological consequences in humans and horses. Although our knowledge about the characteristics and consequences of the virus has increased enormously lately, many questions remain to be resolved. Here, we thoroughly update our knowledge of different aspects of the WNV life cycle: virology and molecular classification, host cell interactions, transmission dynamics, host range, epidemiology and surveillance, immune response, clinical presentations, pathogenesis, diagnosis, prophylaxis (antivirals and vaccines), and prevention, and we highlight those aspects that are still unknown and that undoubtedly require further investigation.

Keywords: West Nile virus; antivirals; clinical presentation; diagnosis; epidemiology; immune response; molecular biology; pathogenesis; transmission; vaccines.

Figure 1.

Structure and genome organization of WNV. A) Surface representation of WNV particle displaying the arrangement of E glycoprotein (protein data bank accession 3J0B). B) Schematic view of WNV particle. C) Crystal structure of an E glycoprotein monomer (protein data bank accession 2I69). D) WNV genome organization. The mature proteins produced by cleavage of the single ORF are denoted by boxes. See text for details

Figure 2.

Schematic view of WNV infectious cycle. The major steps of WNV infection, including receptor-mediated endocytosis, membrane fusion and genome release, intracellular membrane rearrangements associated with viral replication, immature virion budding into the ER, particle maturation through the secretory pathway, and mature virion release are schematized. See text for details. Electron micrographs to illustrate selected steps of WNV infectious cycle were reproduced under the terms of the creative commons attribution-noncommercial (CC BY-NC 4.0) from [1]

Figure 3.

Phylogenetic analysis based on complete genome nucleotide sequences of the different West Nile virus lineages. GenBank accession numbers, geographic origin and year of isolation of samples are shown. The scale bar depicts genetic distance. The Usutu virus USUV-Spa09 strain was used as out-root

Figure 4.

Schematic representation of pathogen recognition receptors (PRRs) activation implicated in WNV infection. Upon binding of viral components, PRRs activation induces a downstream signaling cascade with adaptor proteins implicated and catalytic enzyme activities that promotes the activity of transcription factors, each of which capable of inducing the expression of different target genes, such as Type I IFN genes, ISGs (IFN-stimulated genes) and pro-inflammatory cytokine coding genes. PRRs: TLRs (Toll-like receptors, like TLR-7 and TLR-3), RLR (RIG-I-like receptors, like RIG-I [retinoic acid-inducible gene I protein], and MDA5 [melanoma differentiation antigen 5]) and NLR (NOD-like receptors, like NLRP3). Adaptor proteins: MYD88 (myeloid differentiation 88), TRIF (TIR domain-containing adaptor inducing IFN-β), MAVS (mitochondrial antiviral signaling), and ASC (apoptosis-associated speck-like protein, containing a caspase recruitment domain). Transcription factors: IRF (interferon regulatory factors, like IRF7 and IRF3) and NF-κB (nuclear factor kappa B). Adapted from [265]