West Nile virus (WNV) is a mosquito borne, neurotropic, positive-stranded, enveloped RNA virus in the Flaviviridae
family. WNV is related genetically to other viruses that cause severe visceral and central nervous system (CNS) diseases in humans including dengue (DENV), yellow fever (YFV), Japanese encephalitis (JEV), and tick-borne encephalitis (TBEV) viruses. WNV is maintained in an enzootic cycle between mosquitoes and birds, but also infects and causes disease in vertebrate animals including horses and humans. WNV is transmitted primarily by Culex
species mosquitoes and the virus amplifies in bird reservoirs, with humans and horses largely considered as dead-end hosts [1
]. Although human cases occur primarily after mosquito inoculation, infection after blood transfusion, organ transplantation, and intrauterine transmission has been reported [1
]. At present, there are no vaccines or therapeutic agents approved for humans against WNV.
WNV was first isolated in 1937 in Uganda from a woman with an undiagnosed febrile illness [2
], and historically, has caused outbreaks of a relatively mild febrile illness in regions of Africa, the Middle East, Asia, and Australia [3
]. In the 1990’s, the epidemiology of infection changed. New outbreaks in Eastern Europe were associated with higher rates of severe neurological disease [4
]. In 1999, WNV entered North America, and caused seven human fatalities in the New York City area as well as a large number of avian and equine deaths. Since then, it has spread to all 48 of the lower continental United States as well as to parts of Canada, Mexico, the Caribbean, and South America. While the majority of human infections are asymptomatic, WNV can cause a severe febrile illness and neuroinvasive syndrome characterized by meningitis, encephalitis, and/or acute flaccid paralysis [5
]. Persistent movement disorders, cognitive dysfunction, and long-term disability all occur after West Nile neuroinvasive disease. West Nile poliomyelitis-like disease results in limb weakness or paralysis. Patients show markedly decreased motor responses in the paretic limbs, preserved sensory responses, and widespread asymmetric muscle denervation without evidence of demyelination or myopathy [8
]. Thus, the neurological and functional disability associated with WNV infection represents a considerable source of morbidity in surviving patients long after the acute illness [9
]. In the United States alone between 1999 and 2012, ~36,000 cases and ~1,500 deaths have been confirmed.
The risk of severe WNV infection in humans is greatest in the elderly and immunocompromised [14
]. Two studies have estimated a 20-fold increased risk of neuroinvasive disease and death in those over 50 years of age [14
]. Beyond age, a limited number of host genetic factors have been linked with susceptibility to WNV infection. A deficiency of the chemokine receptor CCR5 increases the risk of symptomatic WNV infection, as a higher incidence (4.2%) of loss-of-function CCR5Δ32 homozygotes was observed in symptomatic WNV infection cohorts compared to that in the general population (1.0%) [17
]. A nonsense mutation in the gene encoding 2'-5'-oligoadenylate synthetase/L1 (OAS) isoform is associated with WNV susceptibility in laboratory mice [18
]. Correspondingly, a hypomorphic allele of the human ortholog OAS1
is associated with both symptomatic and asymptomatic WNV infection [19
]. Finally, an association of single nucleotide polymorphisms (SNP) between symptomatic and asymptomatic WNV infections and IRF3
innate immune response and effector genes has been reported [20
]; thus, genetic variation in the interferon (IFN) response pathway appears to correlate with the risk of symptomatic WNV infection in humans. In this review, we will summarize our understanding of the host-virus interface in the CNS and how this determines WNV disease pathogenesis and clinical outcome.