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West Nile Virus
(e.g. St Louis and Japanese encephalitis virus), false-positives are possible, cell infiltrate appears diffusely throughout infected regions, although it is
and thus it is important to obtain a history of recent vaccination (e.g. yellow not clear whether these inflammatory cells eradicate infection or contribute
fever virus) or foreign travel. At present, definitive serological diagnosis of to pathogenesis by destroying infected neurons and releasing potentially
WNV infection requires a comparison of antigen or neutralization activity toxic cytokines. Of note, large Purkinje neurons in the cerebellum and motor
among related flavivirus family members. Newly developed assays that neurons in the spinal cord are highly vulnerable. Indeed, the more virulent
utilize purified WNV structural and non-structural proteins may allow North American strains of WNV cause a polio-like syndrome in humans that
distinction between natural infection, vaccination, and immunity. predominantly affects lower motor neuron function.
13–15
Virology and Pathogenesis Immune Control of West Nile Virus
The flavivirus genus is composed of approximately 73 viruses, 40 of which Although an immunocompromised status predisposes to more severe
are associated with human disease; of these, dengue, yellow fever, Japanese disease in humans, the individual risk factors are not clearly characterized.
encephalitis, tick-borne encephalitis, and West Nile encephalitis viruses are Recent epidemiological investigations have shown increased severity of
the most important globally, causing extensive morbidity and mortality.
11
infection in immunosuppressed transplant recipients,
16,17
suggesting an
Flaviviruses are enveloped RNA viruses with a single-stranded, positive- important role for adaptive immunity. Experiments in small animals suggest
polarity 11-kilobase genome. They are translated as a polyprotein and then that both innate and adaptive immune responses are required to control
WNV dissemination and disease.
18
Type I interferon (IFN) (α/β) and its
downstream effector molecules are critical components of the innate
…the more virulent North American
immune response to WNV infection. A deficiency of type I IFN signaling
in vivo results in increased viral replication, expanded tropism, and uniform
strains of West Nile virus cause a polio-like
lethality.
19
Analogously, type II IFN (IFN-γ) also limits peripheral viral
syndrome in humans that predominantly
replication and early WNV dissemination into the CNS. Development of
antiviral adaptive immunity is also necessary for protection from disease, as
affects lower motor neuron function.
passive transfer of immune antibody protected wild-type and B-cell-
deficient mice from lethal WNV infection. T cells also likely have a critical
role in limiting severe WNV disease. Cytolytic T-cell responses are required
cleaved into structural and non-structural (NS) proteins by virus- and host- for the clearance of WNV infection, as persistence within the CNS was
encoded proteases. The structural proteins include a capsid protein (C), an observed in mice that lacked either class I major histocompatibiltiy complex
envelope protein (E) that functions in receptor binding, membrane fusion, (MHC) or perforin molecules.
20,21
In mice, an additional innate resistance to
and viral assembly, and a transmembrane protein (prM) that assists in proper infection by WNV has been mapped to the flavivirus resistance gene on
folding and function of the E protein. The role of the NS proteins is not fully chromosome 5.
22,23
Susceptible mouse strains have an isoform of the 2’5’
delineated, but these proteins form the viral protease (NS2B, NS3), NTPase oligoadenylate sythetase (OAS) gene that is truncated and lacks 30% of the
(NS3), RNA helicase (NS3), and RNA-dependent RNA polymerase (NS5). C-terminal sequence.
24,25
Expression of the full-length OAS gene in
After binding to possibly multiple cell surface receptors, virus uptake occurs susceptible cells conferred partial resistance to WNV infection. Further
through endocytosis. In the endosome, an acid-catalyzed change in E studies are required to determine the mechanism by which the OAS protein
induces membrane fusion and the release of the nucleocapsid into the confers protection, and whether analogous genetic polymorphisms exist
cytoplasm. Virus assembly takes place at the endoplasmic reticulum, and that could explain differential susceptibility to flavivirus infection in humans.
viral particles are exocytosed via secretory vesicles.
Approaches To Anti-West Nile Virus Therapy
Infection experiments in animals have provided significant insight into the At present, no specific therapy has been approved for use in humans with
pathogenesis of WNV encephalitis.
12
Initial replication after mosquito WNV infection, and thus current treatment is supportive. In vitro and animal
inoculation is believed to occur in the skin in dendritic cells; these infected model studies have provided important clues to the possible novel therapies
cells migrate to draining lymph nodes, where infection and the risk of against WNV, and possibly other flaviviruses. However, the development of
dissemination are countered by the development of an early immune effective therapeutics that mitigate or abort disease may be difficult, as
response. After reaching secondary lymphoid tissues, a new round of patients with the most severe disease often have underlying immune
infection occurs, leading to entry into the circulation via the efferent deficits and present to clinical attention relatively late in the course of
lymphatic system and thoracic duct. Viremia ensues and, after spread to the disease.
8,26
Among the challenges will be the development of therapeutics
visceral organs, WNV crosses the blood–brain barrier and enters the central that efficiently cross into the CNS, clear virus from infected neurons, and
nervous system (CNS) through a poorly understood mechanism. In animal have a beneficial effect on patient outcome.
models, WNV is first identified in the CNS about three to four days after
infection. Patchy infection of neurons is observed throughout regions of the Interferon-α
cerebral cortex, hippocampus, basal ganglia, cerebellum, brain stem, and Pre-treatment of cells in vitro with type I IFN potently inhibits flaviviruses,
spinal cord. In general, histopathology and immunohistochemistry do not including WNV.
27–31
However, the inhibitory effect of IFN is markedly
suggest that astrocytes or oligodendrocytes are significantly infected in vivo. attenuated after viral replication has begun,
30,32
as flavivirus NS proteins
Neuronal infection is associated with degeneration and a loss of cell specifically inhibit type I IFN signaling pathways. Although the data are
architecture; this correlates with the development of microglial nodules that somewhat conflicting, IFN may still have therapeutic potential. Pre-
surround infected neurons. Later in the course of infection, a mononuclear treatment of rodents with IFN-α inhibited St Louis encephalitis virus
46 US INFECTIOUS DISEASE 2007