Lassa mammarenavirus

This article is about the hemorrhagic fever-causing Lassa virus. For the rabiform virus, seeLyssavirus.

Lassa mammarenavirus
TEMmicrographofLassa mammarenavirusvirions
Virus classification
(unranked):	Virus
Realm:	Riboviria
Kingdom:	Orthornavirae
Phylum:	Negarnaviricota
Class:	Ellioviricetes
Order:	Bunyavirales
Family:	Arenaviridae
Genus:	Mammarenavirus
Species:	Lassa mammarenavirus
Synonyms
Lassa virus

Lassa mammarenavirus(LASV) is anarenavirusthat causesLassa hemorrhagic fever, a type ofviral hemorrhagic fever(VHF), in humans and otherprimates.Lassa mammarenavirusis anemerging virusand aselect agent,requiringBiosafety Level 4-equivalent containment.It is endemic in West African countries, especiallySierra Leone,theRepublic of Guinea,Nigeria,andLiberia,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 theMano Riverregion of westAfricahave expanded the endemic zone between the two known Lassa endemic regions, indicating that LASV is more widely distributed throughout the tropical woodedsavannahecozone in west Africa.There are no approved vaccines against Lassa fever for use in humans.

Discovery

In 1969, missionary nurse Laura Wine fell ill with a mysterious disease she contracted from an obstetrical patient in Lassa, a village inBorno State,Nigeria.She was then transported toJos,where she died. Subsequently, two others became infected, one of whom was fifty-two-year-old nurse Lily Pinneo who had cared for Laura Wine.Samples from Pinneo were sent toYale UniversityinNew Havenwhere a new virus, that would later be known asLassa mammarenavirus,was isolated for the first time byJordi Casals-Ariet,Sonja Buckley,and others.Casals contracted the fever, and nearly lost his life; one technician died from it.By 1972, the multimammate rat,Mastomys natalensis,was found to be the main reservoir of the virus in West Africa, able to shed virus in its urine and feces without exhibiting visible symptoms.

Virology

Structure and genome

Lassa virus structure and genome.Figure by Fehling et al., 2012

Lassa virusesare enveloped, single-stranded, bisegmented,ambisenseRNA viruses.Their genomeis 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 smallzinc fingerprotein (Z) that regulates transcription and replication, and theRNA polymerase(L). The small segment encodes thenucleoprotein(NP) and the surfaceglycoproteinprecursor (GP, also known as theviral spike), which is proteolytically cleaved into the envelope glycoproteins GP1 and GP2 that bind to thealpha-dystroglycanreceptor and mediate host cell entry.

Lassa fever causes hemorrhagic fever frequently shown by immunosuppression.Lassa mammarenavirusreplicates very rapidly, and demonstrates temporal control in replication.The first replication step is transcription ofmRNAcopies 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 aretranslatedfrom 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.

Receptors

Entry mechanisms of Old World and New World arenaviruses.

Lassa mammarenavirusgains entry into the host cell by means of the cell-surface receptor thealpha-dystroglycan(alpha-DG),a versatile receptor for proteins of theextracellular matrix.It shares this receptor with the prototypicOld World arenaviruslymphocytic choriomeningitis virus.Receptor recognition depends on a specific sugar modification of alpha-dystroglycan by a group ofglycosyltransferasesknown as the LARGE proteins. Specific variants of the genes encoding these proteins appear to be under positive selection inWest Africawhere 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 arenaviruses of clades A and B, which include the important virusesMachupo,Guanarito,Junin,andSabiain addition to the non pathogenic Amapari virus, use thetransferrin receptor 1.A small aliphaticamino acidat 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 useclathrincoated 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,dynaminandactin.Once within the cell the viruses are rapidly delivered toendosomesvia vesicular trafficking albeit one that is largely independent of the smallGTPasesRab5andRab7.On contact with the endosome pH-dependent membrane fusion occurs mediated by the envelope glycoprotein, which at the lower pH of the endosome binds the lysosome proteinLAMP1which results in membrane fusion and escape from the endosome.

Life cycle

Lassa virus life cycle. Figure by Fehling et al., 2012

The life cycle ofLassa mammarenavirusis similar to the Old World arenaviruses.Lassa mammarenavirusenters the cell by thereceptor-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 theantigenomicS and L RNAs, and from the antigenomic RNAs, genomic S and L RNA are synthesized. Both genomic and antigenomic RNAs are needed fortranscriptionandtranslation.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 viralpromoterregions of both RNA segments are necessary for recognition and binding of the viralpolymerase.The primary transcription first transcribesmRNAsfrom 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 acap snatchingstrategy to gain the cap structures from the cellular mRNAs, and it is mediated by theendonucleaseactivity 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 isposttranslationally modifiedin theendoplasmic reticulum.GPC is cleaved into GP1 and GP2 at the later stage of the secretory pathway. It has been reported that the cellularproteaseSKI-1/S1P is responsible for this cleavage. The cleavedglycoproteinsare incorporated into thevirionenvelope when the virus buds and release from the cell membrane.

Pathogenesis

False colorScanning electron micrographof Lassa virus (in orange) budding off an infected cell

Lassa feveris caused by theLassa mammarenavirus.The symptoms include flu-like illness characterized by fever, general weakness, cough, sore throat, headache, and gastrointestinal manifestations. Hemorrhagic manifestations include vascular permeability.

Upon entry, theLassa mammarenavirusinfects almost every tissue in the human body. It starts with themucosa,intestine, lungs and urinary system, and then progresses to the vascular system.

The main targets of the virus areantigen-presenting cells,mainlydendritic cellsand endothelial cells. In 2012 it was reported howLassa mammarenavirusnucleoprotein (NP) sabotages the host'sinnate immune systemresponse. Generally, when a pathogen enters into a host,innate defense systemrecognizes thepathogen-associated molecular patterns(PAMP) and activates an immune response. One of the mechanisms detects double stranded RNA (dsRNA), which is only synthesized bynegative-sense viruses.In the cytoplasm, dsRNA receptors, such asRIG-I(retinoic acid-inducible gene I) andMDA-5(melanoma differentiation associated gene 5), detect dsRNAs and initiatesignaling pathwaysthat translocateIRF-3(interferonregulatory factor 3) and othertranscription factorsto the nucleus. Translocated transcription factors activate expression of interferons 𝛂 and 𝛃, and these initiateadaptive immunity.NP encoded inLassa mammarenavirusis essential inviral replicationand transcription, but it also suppresses host innate IFN response by inhibiting translocation of IRF-3. NP ofLassa mammarenavirusis reported to have anexonucleaseactivity to only dsRNAs.the NP dsRNA exonuclease activity counteracts IFN responses by digesting the PAMPs thus allowing the virus to evade host immune responses.

See also

• Coalition for Epidemic Preparedness Innovations