Virology

Lassa virus

Members of the virus families Arenaviridae (Lassa, Lujo, Junin, Guanarito and Machupo), Filoviridae (Ebola and Marburg), and Bunyaviridae (Rift Valley Fever and Crimean Congo hemorrhagic fever) are the agents of greatest concern to public health and bioterrorism.

Lassa virus is a member of the Arenavirus family. It is round, oval, or pleomorphic, 110 to 130 nm in diameter, and enveloped. Its genome consists of two single-stranded RNA segment - the large L segment and the small S segment. The large segment encodes the viral polymerase and zinc binding protein and the small segment encodes the structural proteins - nucleoprotein and glycoprotein precursor.

The viral envelope is acquired when new particles bud off through the host cell plasma membrane and it carries club-shaped surface projections that are about 10 nm long. Sandy-appearing granules ("Arena" is the Latin root meaning sand) resembling ribosomes are believed to be found within the unstructured interior of new viruses. However, these RNAs do not seem to have a required role in virus replication and new work by the VHFC sheds doubt on whether these sandy granules are indeed host ribosomes.

Lassa viral RNA is present in two distinct segments, designated L and S. The RNAs of Lassa and other Arenaviruses are "ambisense", as is the case for members of one genus of the Bunyaviridae. In these viruses, the 3′ half of the genome is of negative polarity and the 5′ half is positive. This results in some viral proteins being encoded in subgenomic, virus-complementary mRNA species, whereas other proteins are encoded in subgenomic, virus-sense mRNA sequences. The ambisense strategy of replication is relatively rare amongst viruses and is shared by all members of the Arenavirus family.

Replication of Lassa virus
Figure 1. Lassa virus is a membrane-bound RNA virus containing the glycoproteins (GP1 and GP2), the matrix protein (Z), the polymerase (L) and nucleoprotein (N/NP). Inside the virion the two viral RNA segments L and S can be found. The replication strategy of Lassa is a called 'ambisense', where two RNA strands code for genes in both the sense and the anti-sense direction. Image courtesy of expasy.org

Very little is known about the replication and life-cycle of Lassa virus. Most of what we know, come from studies using the proto-typical, but mostly non-pathogenic Lymphocytic choriomeningitis virus (LCMV). The virus replicates in a wide variety cell types (believed to be primarily dendritic cells) after having entered the cell via it's receptor alpha-dystroglycan (DAG1). Interestingly, a gene LARGE that modifies DAG1 and is required for Lassa viral entry was discovered by VHFC researchers to be under positive selection in the West African population. This means that over evolutionary time, certain populations may have responded to the severity of Lassa fever by developing a degree of genetic resistance to Lassa virus infection. After cellular entry, replication and transcription of the viral genome occurs in the cytoplasm. The S segment of the viral genome encodes in the negative sense a nucleoprotein (NP), and in the positive sense a precursor glycoprotein (GPC), which is later cleaved into two structural glycoproteins (GP1 and GP2). The L segment encodes in the negative sense an RNA-dependent RNA polymerase (L), and in the positive sense a zinc-binding protein (Z) that binds to the viral replication complex. Upon completion of replication the virus buds from the plasma membrane, incorporating host lipids into the viral membrane.

Lassa Fever Phylogeny
Figure 2. A phylogenetic tree showing the relationship between all the 'Old World' (e.g. Lassa and LCMV) and 'New World' (e.g. Junin and Machupo) Arenaviruses. Members known to cause hemorrhagic fever (HF) are shown in red. In the New World Arenaviruses Junin causes Argentine HF, Guanarito: Venezuelan HF, Machupo: Bolivian HF and Sabia: Brazilian HF

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