West Nile Virus Replication
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West Nile Virus Replication
WNV (West Nile Virus) is a single-stranded positive-polarity RNA virus and the etiologic agent of West Nile encephalitis. It is a member of the Japanese encephalitis virus antigenic group within the family Flaviviridae, which can cause fatal encephalitis associated with damage to the CNS (Central Nervous System) in humans and animals. Wild birds are the natural reservoir (amplifying) hosts, and WNV transmission cycle primarily involving Culex sp mosquitoes. Initially isolated in 1937, it is now recognized as one of the most widely distributed flaviviruses, endemic in Africa, Europe, the Middle East, and parts of Asia. Since 1999, the virus has been recognized in North America by causing an epizootic among birds and horses and an epidemic of meningitis and encephalitis in humans (Ref.1). Humans develop a febrile illness with a subset of cases progressing to a meningitis or encephalitis syndrome. Currently, no specific therapy or vaccine has been approved for human use.

WNV is maintained in nature by replicating alternately in a vertebrate host and a hematophagous arthropod. Arthropod vectors acquire the viral infection by biting a viremic host, and after an extrinsic incubation period during which the virus replicates in the vectors tissues, they transmit virus through salivary secretions to another vertebrate host. Virus replicates in the vertebrate host, causing viremia and sometimes illness. The primary vector for WNV in the United States is the Culex pipiens mosquito that commonly breeds in urban areas and prefers to feed on birds. At least 43 mosquito species in the U.S., including other Culex, Aedes, Anopheles, and Psorophora mosquito species, have tested positive for WNV. Mosquitoes acquire WNV when feeding on infected birds and transmit the virus to humans and other incidental hosts when the mosquito takes a blood meal. Humans and other domestic animals are considered "dead-end" hosts, as they do not contribute to the transmission cycle but can develop an illness as a result of infection. Virus disseminates during lytic infection of cells, causing viremia.

The virus binds to a specific receptor on the surface of a cell and enters the cell in a vesicle by a process similar to that of endocytosis. It is unknown exactly how the virus binds to a cell, but results strongly support the possibility that the 105-kDa protease-sensitive glycoprotein with complex N-linked sugars could be the putative receptor for WN virus. The binding is promoted through initial interaction of the E (Envelope) protein with HSHS (Highly Sulfated Heperan Sulfate) residues that are present on the surfaces of many cells. Once inside the cell, a drop in pH is believed to cause a conformation change in the E protein, which exposes a hydrophobic domain of the protein and allows fusion between the viral and host membranes. After fusion between the viral and cell vesicle membranes, the genome RNA is released into the cytoplasm of the cell for translation. The viral genome RNA is designated as a positive strand because it functions as mRNA. The single RNA strand is capped at its 5 end and serves as an mRNA template for the translation of single large polyprotein. Mature viral proteins are processed from this precursor by a viral serine protease and multiple host proteinases (Ref.2). The virion structural components are encoded in the 5 one fourth of the genome, while viral NS (Nonstructural) proteins are encoded in the remainder of the genome. The overall gene order is C-prM-E-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5. The major function of NS proteins is the replication of viral RNA. NS5 is the RNA-dependent RNA polymerase as well as a putative methyltransferase involved in the formation of the RNA cap. The N-terminal region of NS3 contains the catalytic residues of the viral serine protease, which requires the protein cofactor NS2B for activity. The remainder of NS3 comprises an RNA triphosphatase, which may contribute to RNA capping, as well as an RNA helicase with nucleoside triphosphatase activity. Several other NS proteins (NS2A, NS4A, and NS4B) are small hydrophobic proteins with unknown functions, although it has been suggested that they may serve to anchor the viral replicase to cellular membranes. Shortly after synthesis, NS1 is cleaved from NS2A by an unknown ER (Endoplasmic Reticulum)-resident host proteinase. NS1 is a glycoprotein that forms homodimers and interacts with membranes via an unknown mechanism. Despite its extracytoplasmic localization, NS1 is an essential component of the viral replicase (Ref.3). After enough E, prM (precursor of membrane protein) and C proteins have accumulated; they assemble with the new RNA genomes to produce progeny virions. The progeny virions then travel to the cell surface where they are released. The multiplication of new virions usually occurs in tissues and lymph nodes near the site of entry. After release, progeny virions move to the blood via lymphatics and are then circulated throughout the body. Plus-strand synthesis is 10 to 100 times more efficient than minus-strand synthesis. The only known function of the minus-strand RNA is as a template for the synthesis of nascent genomic RNA. Specific binding of TIA1/TIAR (closely related multifunctional RNA binding proteins) to the 3 terminus of the viral minus-strand RNA template play a positive role in virus replication. Both TIAR and TIA1 regulate the generalized translational arrest that occurs following an environmental stress. Stress-induced phosphorylation of eIF-2Alpha (eukaryotic Translation Initiation Factor-2Alpha) is followed by recruitment of poly (A)+ RNA into cytoplasmic stress granules by TIAR and TIA1 (Ref.4).

WNV can cause a broad range of clinical syndromes, including fever, encephalitis, meningitis, and meningoencephalitis, acute flaccid paralysis characteristic of a poliomyelitis-like syndrome, an enlarged liver, splenomegaly, mild nonexudative pharyngitis and myocarditis. The incubation period for the virus ranges from 3 to 14 days and symptoms last 3 to 6 days. Most people who are infected with WNV do not develop any illness. The estimates are that about 20% of those infected with the virus will develop West Nile fever. The symptoms of encephalitis are: headache, high fever, vomiting, photophobia, stiff neck, drowsiness, clumsiness, disorientation and muscle weakness progressing to convulsions, coma and paralysis. It is also common for a patient to have generalized adenopathy and an enlarged submental node. A small number of patients also developed maculopapular or morbilliform rash on the neck, trunk, arms, or legs; neurological dysfunction, myocarditis, pancreatitis, and fulminant hepatitis (Ref.5). The more severe form of the disease, encephalitis, may last several weeks and the neurological effects may be permanent. WNE crosses the blood brain barrier and infects the brain parenchyma. Advanced age is the greatest risk factor for severe neurologic disease, long-term sequelae, and death. WNV infection has no characteristic findings on routine laboratory tests, although anemia, leukocytosis, or lymphopenia may be present. Testing for IgM antibody to WNV in serum or cerebrospinal fluid (samples from the acute and convalescent phases, submitted at least two weeks apart) is the most common diagnostic method. Prevention relies on comprehensive mosquito-control programs and measures to avoid mosquito bites, including the use of mosquito repellents containing N, N-diethyl-m-toluamide (Ref.6).