West Nile virus is a current health concern. The virus was first observed in the United States in 1999 in New York City, and within 10 years cases of West Nile virus have been found in every contiguous U. S. state, as well as parts of Mexico and Canada (Gubler, 2007). Some strains of the virus cause disease in birds, though typically birds do not become sick and serve as a reservoir for the virus. Mosquitoes spread West Nile Virus from bird to bird, and less commonly, from bird to another vertebrate such as humans. The virus itself behaves as a typical Flavivirus, and can produce a deadly illness in susceptible individuals, though most people who are infected with West Nile virus do not experience any symptoms.
West Nile virus is a Class IV virus of the genus Flavivirus. The virus is enveloped and spherical, with a diameter of 40 to 50 nm (Brinton, 2002, Lanciotti et al, 1999). West Nile virus has a positive RNA genome, and thus can be translated by cellular machinery without requiring transcription. The genome is around 11 kilobases long, and contains a cap at the 5' end, though it lacks a poly adenylation tail (Brinton, 2002). The genome contains one open reading frame; the resulting large protein is cleaved to ten smaller proteins, three of which are structural and seven non-structural (Campbell et al, 2002). A capsid protein, a premembrane protein, and an envelope protein comprise the structural proteins (Lanciotti et al, 1999). The envelope and premembrane proteins are embedded in the viral envelope and have a variety of functions ranging from determining tropism to assembly (Campbell et al, 2002).
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West Nile Virus infects birds, humans, and other mammals. A specific tissue tropism for the virus has yet to be identified, but in humans the most serious form of West Nile virus infection occurs when the virus enters the nervous system (Wu et al, 2008). The virus may first replicate in skin Langerhans dendritic cells (Byrne et al, 2001). West Nile virus's envelope protein is key in attachment stage (Chu and Ng, 2003). The envelope protein interfaces with a 105-kDa receptor on the cell's surface (Chu and Ng, 2003). The virus enters the cell via clathrin mediated endocytosis (Chu and Ng, 2004). Clathrin coated pits are common on nearly all cell types, so the virus may enter a variety of cells. Once endocytosed, the vesicle containing the virus is transported along the cytoskeleton to the lysosome, where it encounters a low pH which permits the viral capsid to escape into the cytoplasm and for the genome to be released (Chu and Ng, 2004).
As the genome of West Nile virus is similar to cellular mRNA, translation of its single open reading frame may proceed immediately following uncoating. The larger precursor protein is cleaved both by cellular proteases and by a viral serine protease, NS2B-NS3 (Brinton, 2002). As West Nile virus is an RNA virus, it supplies its own RNA-dependent RNA polymerase, NS5, which replicates the viral genome (Brinton, 2002). A negative strand intermediate complementary to the genome is created and used as a template for new copies of the genome. RNA synthesis is asymmetric; one minus-RNA strand is copied from one genomic strand one at a time, but many plus-RNA strands may be copied from a single minus-RNA strand at once (Brinton, 2002).
The capsid protein is translated near the rough endoplasmic reticulum and self-assembles around the genome in the endoplasmic reticulum (Schlick et al, 2009). The capsid protein contains hydrophobic regions that are vital for assembly of the capsid (Schlick et al, 2009). A vesicle containing the virion with the envelope and premembrane proteins on its surface travels to the Golgi, where the envelope and premembrane proteins are modified (Brinton, 2002). The vesicle containing the new virus is then exocytosed (Brinton, 2002). It takes 10-12 hours for progeny virus to be released from an infected cell (Brinton, 2002).
Infection of a cell by West Nile virus usually results in the death of the cell. The cytopathic effect of the infection includes loss of adhesion (Varma et al, 1974). However, infected cells do activate antiviral pathways to combat West Nile virus. One innate antiviral defense is interferon regulatory factor 3, which is triggered by double-stranded RNA associated with the viral genome (Fredericksen et al, 2004). Interferon regulatory factor 3 becomes active late in the viral replication cycle and cannot halt viral reproduction, but does reduce transmission of the virus to other cells (Fredericksen et al, 2004). During infection, the virus alters cellular gene expression. At first, production of proteins involved in cellular signal transduction is reduced, as are other transcription regulators and proteins involved in stress responses (Fredericksen et al, 2004). Later, these proteins are over-expressed in infected cells (Fredericksen et al, 2004).
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On a cellular level, infection with West Nile virus usually results in death, but humans infected by West Nile virus usually do not become ill. The incubation period for the virus is estimated to be between 3 and 14 days (Peterson and Marfin, 2002). The most common symptom in humans is a flu-like condition called West Nile virus fever, occurring in 20 to 30% of cases (Peterson and Marfin, 2002). Approximately 1 in 150 people infected with West Nile virus experience serious and possibly fatal illness, developing meningitis or encephalitis with rare cases of acute flaccid paralysis (Peterson and Marfin, 2002). Mortality is higher for the elderly (Peterson and Marfin, 2002). Serious illness caused by West Nile virus is thought to occur when the virus crosses the blood-brain barrier and infects the central nervous system (Samuel and Diamond, 2006).
Initial viral replication occurs in the skin and proceeds to the lymph nodes (Samuel and Diamond, 2006). From the lymph the virus reaches the blood, creating a primary viremia and causing a systemic infection (Samuel and Diamond, 2006). Under ordinary circumstances the immune system clears the virus within a few weeks (Samuel and Diamond, 2006). Rarely, West Nile virus crosses the blood-brain barrier. The precise manner by which West Nile virus infects the central nervous system is unknown, but Toll-like receptor 3 has been implicated (Wang et al, 2004). Toll-like receptor 3 is part of the innate immune system, though it appears to do more harm than good when it comes to West Nile virus; an experiment with mutant mice unable to produce any Toll-like receptor 3 showed that the mutants were more likely to survive West Nile virus infection than wild-type mice (Wang et al, 2004). When the virus reaches the brain, inflammation and neuronal death result (Wang et al, 2004). Those who survive West Nile meningitis and encephalitis experience some symptoms, including fatigue, headache, and myalgias, up to 8 months following infection (Sejvar et al, 2003). Those who suffered from acute flaccid paralysis generally do not recover limb strength (Sejvar et al, 2003). West Nile virus may persist in the kidneys for years after the initial infection, and in some cases has been isolated from urine over 6 years later (Murray et al, 2010).
Treatment for West Nile virus is unnecessary in most cases, as the majority of infected individuals experience no symptoms. To determine if an individual is infected with West Nile virus, clinicians look for an IgM antibody produced by the immune system (Peterson and Marfin, 2002). Those suffering from West Nile fever may use over-the-counter medications to combat symptoms (MayoClinic.com, 2010). For West Nile virus infections of the central nervous system, supportive therapy in a hospital is recommended (Peterson and Marfin, 2002). Researchers are investigating other possible treatments, including ribavirin, an antiviral drug, and interferons (Anderson and Rahal, 2002). At present, there is no vaccine available for West Nile virus.
The prevention of infection by West Nile virus is inextricably linked to the virus's mode of transmission. West Nile virus is transmitted by mosquitoes, and birds are its typical host. When a mosquito that ought to be feeding on birds bites a human instead, the human may be exposed to West Nile virus. West Nile virus is present in all 48 contiguous states, particularly in areas with high mosquito populations. Humans cannot transmit West Nile virus to other humans under ordinary circumstances, though the virus can be spread in blood transfusions (CDC, 2010). In order to prevent West Nile virus infection, the CDC recommends avoiding being bitten by mosquitoes by using insect repellants, remaining indoors, and removing standing water in which mosquitoes typically breed. The elderly are most susceptible to serious illness and death as a result of West Nile virus infection (Peterson and Marfin, 2002).
A 2006 study on the demographics of West Nile virus positive mosquitoes and human infections in a 2002 outbreak found that while mosquitoes positive for West Nile virus dispersed randomly, human cases tended to be higher in areas with lower socioeconomic status (Rios et al, 2006). Mosquitoes can transmit the virus vertically, and the virus can survive in overwintering mosquitoes (Bugbee and Forte, 2004). Thus far in 2010 there have been 832 human cases of West Nile virus in the U. S. and 34 deaths (CDC, 2010). When West Nile virus was first detected in the U. S. the mortality of patients was higher, suggesting that either the virus has evolved to be less lethal to humans or supportive treatment has improved (CDC, 2010).
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While West Nile virus does not cause illness in the majority of infected people, it can cause long-term health problems in some cases. West Nile virus is a small Flavivirus with a replication strategy similar to other viruses of this type. The pathogenicity of the virus varies from person to person, and more severe infections result when the virus infects the central nervous system. As there is no vaccine, and it is impossible to find and destroy all carrier mosquitoes and birds, preventative measures are limited to avoiding mosquito bites. West Nile virus represents a serious health concern and research into treatments for those infected is ongoing.