West Nile virus
|West Nile virus|
|A micrograph of the West Nile Virus, appearing in yellow|
|Group:||Group IV ((+)ssRNA)|
|Species:||West Nile virus|
West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family Flaviviridae, specifically from the genus Flavivirus, which also contains the Zika virus, dengue virus, and yellow fever virus. West Nile virus is primarily transmitted by mosquitoes, mostly species of the genus Culex, but ticks have also been found to carry the virus. The primary hosts of WNV are birds, so that the virus remains within a "bird-mosquito-bird" transmission cycle.
Like most other flaviviruses, WNV is an enveloped virus, but has icosahedral symmetry. Flavivirus envelopes consist of a protein shell and a lipid membrane. The protein shell is made of two structural proteins: the glycoprotein E and the small membrane protein M. Protein E serve numerous functions, several of which include receptor binding, viral attachment, and entry into the cell through membrane fusion.
The flavivirus lipid membrane has been found to contain cholesterol and phosphatidylserine, but other elements of the membrane have yet to be identified. The lipid membrane has many roles in viral infection, including acting as signaling molecules and enhancing entry into the cell. Cholesterol, in particular, plays an integral part in WNV entering a host cell.
Within the viral envelope, the genome is contained within a protein capsid, which is one of the first proteins created in an infected cell. It has been found that the capsid prevents apoptosis by affecting the Akt pathway. The capsid is a structural protein and its main purpose is to package RNA into the developing viruses.
WNV is a positive-sense, single-stranded RNA virus. Its genome is approximately 11,000 nucleotides long and is flanked by 5' and 3' non-coding stem loop structures. The coding region of the genome codes for three structural proteins and seven nonstructural (NS) proteins, proteins that are not incorporated into the structure of new viruses. The WNV genome is first translated into a polyprotein and later cleaved by virus and host proteases into separate proteins (i.e. NS1, C, E).
Structural proteins (C, prM/M, E) are capsid, precursor membrane proteins, and envelope proteins, respectively. The structural proteins are located at the 5' end of the genome and are cleaved into mature proteins by proteases.
|C||Capsid protein; encloses the RNA genome, packages RNA into immature virions.|
|prM/M||Viruses with M protein are infectious: the presence of M protein allows for the activation of proteins involved in viral entry into the cell. prM (precursor membrane) protein is present on immature virions, by further cleavage by furin to M protein, the virions become infectious.|
|E||A glycoprotein that forms the viral envelope, binds to receptors on the host cell surface in order to enter the cell.|
Nonstructural proteins consist of NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. These proteins mainly assist with viral replication or act as proteases. The nonstructural proteins are located near the 3' end of the genome.
|NS1||NS1 is a cofactor for viral replication, specifically for regulation of the replication complex.|
|NS2A||NS2A has a variety of functions: it is involved in viral replication, virion assembly, and inducing host cell death.|
|NS2B||A cofactor for NS3 and together forms the NS2B-NS3 protease complex.|
|NS3||A protease that is responsible for cleaving the polyprotein to produce mature proteins; it can also acts as a helicase.|
|NS4A||NS4A is a cofactor for viral replication, specifically regulates the activity of the NS3 helicase.|
|NS4B||Inhibits interferon signaling.|
|NS5||The largest and most conserved protein of WNV, NS5 acts as a methyltransferase and a RNA polymerase, though it lacks proofreading properties.|
Once WNV has successfully entered the bloodstream of a host animal, the envelope protein, E, binds to attachment factors called glycosaminoglycans on the host cell. These attachment factors aid entry into the cell, however, binding to primary receptors is also necessary. Primary receptors include DC-SIGN, DC-SIGN-R, and the integrin αvβ3. By binding to these primary receptors, WNV enters the cell through clathrin-mediated endocytosis. As a result of endocytosis, WNV enters the cell within an endosome.
The acidity of the endosome catalyzes the fusion of the endosomal and viral membranes, allowing the genome to be released into the cytoplasm. Translation of the positive-sense single-stranded RNA occurs at the endoplasmic reticulum; the RNA is translated into a polyprotein which is then cleaved by viral proteases NS2B-N23 to produce mature proteins.
In order to replicate its DNA, NS5, a RNA polymerase, forms a replication complex with other nonstructural proteins to produce an intermediary negative-sense single-stranded RNA; the negative-sense strand serves as a template for synthesis of the final positive-sense RNA. Once the positive-sense RNA has been synthesized, the capsid protein, C, encloses the RNA strands into immature virions. The rest of the virus is assembled along the endoplasmic reticulum and through the Golgi apparatus, and results in non-infectious immature virions. The E protein is then glycosylated and prM is cleaved by furin, a host cell protease, into the M protein, thereby producing an infectious mature virion. The mature viruses are then secreted out of the cell.
Studies of phylogenetic lineages have determined that WNV emerged as a distinct virus around 1000 years ago. This initial virus developed into two distinct lineages. Lineage 1 and its multiple profiles is the source of the epidemic transmission in Africa and throughout the world. Lineage 2 was considered an African zoonosis. However, in 2008, lineage 2, previously only seen in horses in sub-Saharan Africa and Madagascar, began to appear in horses in Europe, where the first known outbreak affected 18 animals in Hungary. Lineage 1 West Nile virus was detected in South Africa in 2010 in a mare and her aborted fetus; previously, only lineage 2 West Nile virus had been detected in horses and humans in South Africa. A 2007 fatal case in a killer whale in Texas broadened the known host range of West Nile virus to include cetaceans.
Since the first North American cases in 1999, the virus has been reported throughout the United States, Canada, Mexico, the Caribbean, and Central America. There have been human cases and equine cases, and many birds are infected. The Barbary macaque, Macaca sylvanus, was the first nonhuman primate to contract WNV. Both the American and Israeli strains are marked by high mortality rates in infected avian populations; the presence of dead birds—especially Corvidae—can be an early indicator of the arrival of the virus.
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