page_title: Lassa mammarenavirus
section_title: Life cycle
hierarchical_section_title: Lassa mammarenavirus / Virology / Life cycle
context_page_description: Lassa mammarenavirus is an arenavirus that causes Lassa hemorrhagic fever,
  a type of viral hemorrhagic fever, in humans and other primates. Lassa mammarenavirus 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.
  As of 2012 discoveries within the Mano River region of west Africa have expanded the endemic zone between the two known Lassa endemic regions, indicating that LASV is more widely distributed throughout the tropical wooded savannah ecozone in west Africa. There are no approved vaccines against Lassa fever for use in humans.
context_section_description: The life cycle of Lassa mammarenavirus is similar to the Old World arenaviruses. Lassa mammarenavirus enters the cell by the receptor-mediated endocytosis. Which endocytotic pathway is used is not known yet, but at least the cellular entry is sensitive to cholesterol depletion. It was reported that virus internalization is limited upon cholesterol depletion. The receptor used for cell entry is alpha-dystroglycan, a highly conserved and ubiquitously expressed cell surface receptor for extracellular matrix proteins. Dystroglycan, which is later cleaved into alpha-dystroglycan and beta-dystroglycan is originally expressed in most cells to mature tissues, and it provides molecular link between the ECM and the actin-based cytoskeleton. After the virus enters the cell by alpha-dystroglycan mediated endocytosis, the low-pH environment triggers pH-dependent membrane fusion and releases RNP (viral ribonucleoprotein) complex into the cytoplasm. Viral RNA is unpacked, and replication and transcription initiate in the cytoplasm. As replication starts, both S and L RNA genomes synthesize the antigenomic S and L RNAs, and from the antigenomic RNAs, genomic S and L RNA are synthesized. Both genomic and antigenomic RNAs are needed for transcription and translation. The S RNA encodes GP and NP (viral nucleocapsid protein) proteins, while L RNA encodes Z and L proteins. The L protein most likely represents the viral RNA-dependent RNA polymerase. When the cell is infected by the virus, L polymerase is associated with the viral RNP and initiates the transcription of the genomic RNA. The 5’ and 3’ terminal 19 nt viral promoter regions of both RNA segments are necessary for recognition and binding of the viral polymerase. The primary transcription first transcribes mRNAs from the genomic S and L RNAs, which code NP and L proteins, respectively. Transcription terminates at the stem-loop (SL) structure within the intergenomic region. Arenaviruses use a cap snatching strategy to gain the cap structures from the cellular mRNAs, and it is mediated by the endonuclease activity of the L polymerase and the cap binding activity of NP. Antigenomic RNA transcribes viral genes GPC and Z, encoded in genomic orientation, from S and L segments respectively. The antigenomic RNA also serves as the template for the replication. After translation of GPC, it is posttranslationally modified in the endoplasmic reticulum. GPC is cleaved into GP1 and GP2 at the later stage of the secretory pathway. It has been reported that the cellular protease SKI-1/S1P is responsible for this cleavage. The cleaved glycoproteins are incorporated into the virion envelope when the virus buds and release from the cell membrane.
caption: Lassa virus life cycle
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