Lassa virus (LASV) is an Old World arenavirus that causes Lassa hemorrhagic fever, a type of viral hemorrhagic fever (VHF) in human and non-human primates. Lassa virus is an emerging virus and a select agent, requiring Biosafety Level 4-equivalent containment. It is endemic in West African countries, especially Sierra Leone, the Republic of Guinea, Nigeria and Liberia, where the annual incidence of infection is between 300,000 and 500,000 cases, resulting in 5,000 deaths per year. Recent discoveries on the Lassa Virus within the Mano River Region is that evidence has been discovered that will require to expand the endemicity zone between the two known Lassa endemic regions indicating that LASV is more widely distributed throughout the Tropical Wooded Savanna ecozone in West Africa. Currently, there are no approved vaccines against Lassa fever for use in humans.
Structure and genome
Lassa viruses are enveloped, single-stranded, bisegmented, ambisense RNA viruses. Their genome is contained in two RNA segments that code for two proteins each, one in each sense, for a total of four viral proteins. The large segment encodes a small zinc-binding protein (Z) that regulates transcription and replication, and the RNA polymerase (L). The small segment encodes the nucleoprotein (NP) and the surface glycoprotein precursor (GP, also known as the viral spike), which is proteolytically cleaved into the envelope glycoproteins GP1 and GP2 that bind to the alpha-dystroglycan receptor and mediate host cell entry.
Lassa fever causes hemorrhagic fever frequently shown by immunosuppression. Replication for Lassa virus is very rapid, while also demonstrating temporal control in replication. The first replication step is transcription of mRNA copies of the negative- or minus-sense genome. This ensures an adequate supply of viral proteins for subsequent steps of replication, as the NP and L proteins are translated from the mRNA. The positive- or plus-sense genome, then makes viral complementary RNA (vcRNA) copies of itself. The RNA copies are a template for producing negative-sense progeny, but mRNA is also synthesized from it. The mRNA synthesized from vcRNA are translated to make the GP and Z proteins. This temporal control allows the spike proteins to be produced last, and therefore, delay recognition by the host immune system.
Nucleotide studies of the genome have shown that Lassa has four lineages: three found in Nigeria and the fourth in Guinea, Liberia, and Sierra Leone. The Nigerian strains seem likely to have been ancestral to the others but additional work is required to confirm this. One book that explains about this disease is The Lassa Ward by Ross I. Donaldson. He describes what it is like being a doctor and taking care of the Sierra Leone people who have contracted the virus.
The Lassa virus gains entry into the host cell by means of the cell-surface receptor the alpha-dystroglycan (alpha-DG), a versatile receptor for proteins of the extracellular matrix. It shares this receptor with the prototypic Old World arenavirus lymphocytic choriomeningitis virus. Receptor recognition depends on a specific sugar modification of alpha-dystroglycan by a group of glycosyltransferases known as the LARGE proteins. Specific variants of the genes encoding these proteins appear to be under positive selection in West Africa where Lassa is endemic. Alpha-dystroglycan is also used as a receptor by viruses of the New World clade C arenaviruses (Oliveros and Latino viruses). In contrast, the New World areanviruses of clades A and B, which include the important viruses Machupo, Guanarito, Junin, and Sabia in addition to the non pathogenic Amapari virus, use the transferrin receptor 1. A small aliphatic amino acid at the GP1 glycoprotein amino acid position 260 is required for high-affinity binding to alpha-DG. In addition, GP1 amino acid position 259 also appears to be important, since all arenaviruses showing high-affinity alpha-DG binding possess a bulky aromatic amino acid (tyrosine or phenylalanine) at this position.
Unlike most enveloped viruses which use clathrin coated pits for cellular entry and bind to their receptors in a pH dependent fashion, Lassa and lymphocytic choriomeningitis virus instead use an endocytotic pathway independent of clathrin, caveolin, dynamin and actin. Once within the cell the viruses are rapidly delivered to endosomes via vesicular trafficking albeit one that is largely independent of the small GTPases Rab5 and Rab7. On contact with the endosome pH-dependent membrane fusion occurs mediated by the envelope glycoprotein.
Currently there is no US licensed vaccine for humans against the Lassa virus. Evaluation of Lassa virus vaccine immunogenicity in the CBA/J-ML29 mouse model is ongoing. A single intraperitoneal immunization of CBA/J mice with ML29 protected animals against a lethal homologous intracerebral challenge with 588 LD. Lassa fever is one of the most prevalent viral hemorrhagic fevers in West Africa responsible for thousands of deaths annually.
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