West Nile virus

West Nile virus is the most widely distributed of the flaviviruses, an Orthoflavivirus maintained in nature by a cycle between Culex mosquitoes and birds and spread across Africa, Europe, the Middle East, Asia, Australasia and, since its dramatic arrival in New York in 1999, the Americas. Most human infection is silent or a mild febrile illness, but in a minority the virus is neurotropic, crossing into the central nervous system to cause meningitis, encephalitis and a poliomyelitis-like flaccid paralysis. It is a member of the Japanese encephalitis serocomplex, shares that group’s neuroinvasive tendency, and like the other encephalitic flaviviruses has no licensed human vaccine. West Nile virus holds particular importance for southern Africa, where the endemic lineage 2 strain, first characterised on the continent, causes recurrent neurological disease in horses and a recognised, probably underdiagnosed, burden of human disease.

Discovery and historical significance

West Nile virus was first isolated in 1937 from the blood of a febrile woman in the West Nile district of Uganda, from which it takes its name. For decades it was regarded as a cause of sporadic mild febrile illness across Africa, the Middle East and parts of Europe and Asia. Its status changed in 1999, when the virus emerged for the first time in the Western Hemisphere in New York City, causing an outbreak of encephalitis with associated bird and horse deaths. Over the following decade it spread across the continental United States and into Canada, Mexico and the Caribbean, becoming the leading cause of arboviral neuroinvasive disease in North America and a textbook example of arbovirus emergence in a naive ecosystem.

Classification, structure, and genome

Classification

West Nile virus belongs to the genus Orthoflavivirus (family Flaviviridae), current binomial Orthoflavivirus nilense, and sits within the Japanese encephalitis serocomplex alongside Japanese encephalitis, St Louis encephalitis and Murray Valley encephalitis viruses. It exists as a single serotype but resolves into at least five phylogenetic lineages, of which only lineages 1 and 2 cause significant human disease.

Lineage	Distribution	Notes
Lineage 1a	Americas, Europe, Africa, Middle East	The most widespread and epidemiologically important; caused the 1999 New York outbreak
Lineage 1b (Kunjin virus)	Australia	Generally milder disease
Lineage 2	Sub-Saharan Africa, including South Africa, and increasingly Europe	The endemic African lineage; drives South African disease and, since 2010, large European outbreaks

The North American strain evolved a more efficiently transmitted variant, the WN02 genotype, within a few years of arrival, illustrating how quickly the virus adapts to local mosquitoes.

Virion structure

The virion is a small enveloped particle about 50 nm in diameter. The envelope (E) glycoprotein mediates receptor binding and membrane fusion and is the dominant target of neutralising antibody, while the membrane (M) protein completes the surface. On the mature particle 90 E dimers lie flat in a smooth herringbone lattice; immature particles are spiky and carry the uncleaved precursor membrane (prM) protein.

Genome organisation

The genome is a positive-sense single-stranded RNA of about 11 kb with a single open reading frame between structured 5’ and 3’ untranslated regions. Translation gives one polyprotein cleaved into three structural proteins (capsid C, prM/M, envelope E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). NS3 provides the protease and helicase, NS5 the RNA-dependent RNA polymerase and methyltransferase, and NS1 is a secreted glycoprotein used in diagnosis.

Replication cycle

West Nile virus follows the canonical flavivirus arc. The E protein engages attachment factors such as the C-type lectin DC-SIGN (dendritic-cell-specific intercellular adhesion molecule grabbing non-integrin) and phosphatidylserine receptors, and the particle enters by clathrin-mediated endocytosis. Endosomal acidification drives E to rearrange into a fusogenic trimer that fuses the viral and endosomal membranes, releasing the nucleocapsid.

The capped genome is translated at the endoplasmic reticulum into the polyprotein, and replication proceeds in endoplasmic-reticulum-derived vesicles where NS5 copies a minus strand and then makes an excess of new positive strands, hidden from cytoplasmic sensors. Nucleocapsids bud into the endoplasmic reticulum through prM- and E-bearing membrane to form immature particles, which mature when furin cleaves prM to M in the trans-Golgi network before release. The nonstructural proteins, notably NS2A and NS4B, antagonise interferon induction and signalling, a determinant of how efficiently the virus replicates before immune control.

Pathogenesis

After a mosquito bite, West Nile virus first replicates in skin dendritic cells (Langerhans cells) and draining lymph nodes, then produces a viraemia that seeds visceral organs. In most people the infection is controlled here. In a minority the virus is neuroinvasive, entering the central nervous system, and this neurotropism defines the severe disease.

Once in the brain and spinal cord the virus infects neurons, and the destruction of anterior horn cells in the spinal cord produces the characteristic poliomyelitis-like acute flaccid paralysis, while cortical, brainstem and deep grey-matter involvement produce encephalitis. The single strongest determinant of whether infection becomes neuroinvasive is advancing age, with the risk in people over 65 many times that of young adults; immunosuppression, particularly in organ-transplant recipients infected through the graft, and several chronic diseases also raise the risk. Notably, the chance of acquiring infection is similar across ages, so age drives severity rather than susceptibility. A deficiency of the chemokine receptor CCR5 has been linked to more severe disease, evidence that a robust immune response is needed to keep the virus out of the brain.

Epidemiology

West Nile virus is maintained in an enzootic cycle between Culex mosquitoes and birds, in which wild birds develop a prolonged high-titre viraemia and act as the amplifying hosts. Humans and horses are incidental dead-end hosts: they can be infected but do not generate enough viraemia to infect biting mosquitoes, so they play no part in maintaining the cycle. Different Culex species carry the virus in different regions, and transmission peaks in late summer and early autumn when mosquito populations and bird infection are highest.

The virus can also be transmitted by routes that bypass the mosquito: blood transfusion, organ transplantation, breast milk, and rarely from mother to child in pregnancy, along with occasional laboratory-acquired infections. Organ transmission is especially dangerous because it can occur from donors without detectable viraemia and because recipients are immunosuppressed. The scale of the North American epidemic illustrates the burden: between 1999 and 2014 the United States reported more than 41,000 cases, including over 18,000 neuroinvasive cases, and serosurveys show that even in outbreak areas fewer than 10% of the population has been infected, so most transmission is silent.

Natural history

After an incubation of about 2 to 14 days, which can be longer in immunosuppressed hosts, roughly a quarter of infected people develop symptoms. Most have West Nile fever, a self-limiting illness lasting days to a few weeks, although fatigue and weakness often persist far longer than the term “mild” suggests. About 1 in 150 infected people develops neuroinvasive disease, and among those cases the case-fatality is around 10%. Recovery from neuroinvasive disease is slow and often incomplete: strength returns over months, with roughly a third making a full recovery, a third a substantial recovery, and a third left with lasting deficits, and the flaccid paralysis in particular may not resolve.

Clinical presentations and complications

West Nile fever is an abrupt febrile illness with headache, malaise, back pain, myalgia and anorexia, frequently with a non-pruritic morbilliform rash appearing as the fever settles and sparing the palms and soles. Although self-limiting, prolonged fatigue and difficulty concentrating are common in convalescence.

Neuroinvasive disease takes three overlapping forms. Meningitis presents as a typical aseptic meningitis. Encephalitis ranges from a mild confusional state to coma, often with tremor, myoclonus and parkinsonian features such as rigidity and bradykinesia. Acute flaccid paralysis is the most distinctive manifestation: an asymmetric, poliomyelitis-like weakness from anterior horn cell destruction that can occur without any meningitis or encephalitis, and the combination of encephalitis with limb weakness strongly suggests West Nile virus. Involvement of the muscles of respiration or of bulbar function carries a high risk of respiratory failure, which is the main cause of death. The cerebrospinal fluid typically shows a lymphocytic pleocytosis with raised protein.

Diagnosis

The mainstay of diagnosis is the IgM-capture ELISA on serum and cerebrospinal fluid, and because IgM does not cross the blood-brain barrier its presence in cerebrospinal fluid indicates central nervous system infection. Two cautions apply: IgM can persist for more than a year, so a positive result does not always mean recent infection, and antibody cross-reacts with other flaviviruses and with yellow fever or Japanese encephalitis vaccination, so paired sera and confirmatory neutralisation may be needed. If serum is taken within about eight days of onset the antibody may not yet be detectable, and the test should be repeated. Reverse-transcriptase PCR and virus culture on serum or cerebrospinal fluid are useful only in the brief viraemic phase, are more often positive in cerebrospinal fluid than plasma, and a negative result does not exclude infection; PCR is particularly valuable in immunocompromised patients who may have prolonged viraemia and blunted antibody.

Management

There is no antiviral of proven benefit, and management is supportive. Investigational approaches including immunoglobulin, neutralising monoclonal antibodies, interferon and ribavirin have not shown efficacy in controlled study. Severe neuroinvasive disease requires attentive supportive care, and patients with bulbar involvement or respiratory muscle weakness need intensive care and ventilatory support, since respiratory failure carries a high mortality.

Prevention and public health

Vector control

Prevention rests on reducing mosquito bites and mosquito populations. Personal measures include DEET-based repellents, long clothing and permethrin-treated gear, and screening of windows and doors, while community measures target Culex breeding by removing standing water and, in outbreaks, applying larvicides and adulticides.

Vaccination

There is no licensed human vaccine despite several candidates, including chimeric and DNA vaccines, reaching early-phase trials; the sporadic and geographically scattered nature of human disease has made large efficacy trials commercially and logistically difficult. In contrast, effective inactivated equine vaccines are licensed and have substantially reduced disease in horses.

Surveillance and notification

Because birds and horses are infected before or alongside humans, surveillance of dead birds, sentinel mosquito pools and equine cases provides early warning of local transmission and guides vector-control and blood-safety responses. In many settings blood services screen donations by nucleic-acid testing during transmission seasons to prevent transfusion transmission.

South African context

West Nile virus is endemic in South Africa, where the circulating strain is lineage 2, the African lineage that was first characterised on the continent and has since seeded outbreaks in Europe. The clinically important local reservoir of disease is in horses: lineage 2 causes recurrent, often seasonal, outbreaks of equine neurological disease, and in a national surveillance series of animals with neurological signs from 2008 to 2015, West Nile virus was found in about 7% of horses tested, of which roughly a third died. Because equine cases cluster geographically with human exposure, horses act as a sentinel for human risk.

Human disease is recognised but probably underdiagnosed. Screening of unexplained neurological cases in Gauteng has detected West Nile virus in a few percent of otherwise unsolved presentations, and most infection is mild or silent. Locally the virus is transmitted by Culex and Culiseta mosquitoes, which also transmit Sindbis virus, so the two co-circulate and overlap clinically.

Diagnostic testing is centralised at the Arbovirus Reference Laboratory of the Centre for Emerging Zoonotic and Parasitic Diseases at the National Institute for Communicable Diseases. The laboratory offers reverse-transcriptase PCR and culture on serum or cerebrospinal fluid within about the first six days of illness, and haemagglutination-inhibition and West Nile IgM and IgG ELISA on paired sera taken up to two weeks apart; paired serology is essential because of flavivirus cross-reactivity, and specimens are also screened for other arboviruses given the overlapping presentations. West Nile virus is a category 3 notifiable medical condition in South Africa, reported through the routine notification system rather than the emergency pathway used for the viral haemorrhagic fevers, and samples should be submitted with the arbovirus case investigation form, kept cold, to the reference laboratory.

References and recommended reading

• Pierson TC, Lazear HM, Diamond MS. Flaviviruses: Dengue, Zika, West Nile, Yellow Fever and Other Flaviviruses. In: Fields Virology, 7th edition, Chapter 9. Philadelphia: Wolters Kluwer; 2023. The principal source for West Nile pathogenesis, neuroinvasion and clinical disease.
• Lindenbach BD, Randall G, Bartenschlager R, Rice CM. Flaviviridae: The Viruses and Their Replication. In: Fields Virology, 7th edition, Chapter 7. Philadelphia: Wolters Kluwer; 2023. The source for virion structure, genome organisation and the replication cycle.
• Petersen LR, Barrett ADT. Arthropod-Borne Flaviviruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition, Chapter 53. Washington: ASM Press; 2016. The foundational account of West Nile lineages, transmission and clinical spectrum.
• Venter M, Human S, Zaayman D, et al. West Nile Virus Lineage 2 in Horses and Other Animals with Neurologic Disease, South Africa, 2008-2015. Emerging Infectious Diseases; 2017. The source for the South African lineage 2 equine burden and its role as a sentinel for human risk.
• National Institute for Communicable Diseases. West Nile Virus. Arbovirus Reference Laboratory, Centre for Emerging Zoonotic and Parasitic Diseases; 2021. The source for the South African testing pathway and notifiable-condition status.