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The Molecular Biology & General Background of the Lassa Virus

The Molecular Biology & General Background of the Lassa Virus. Presented by Ryan Cordell. Presentation Overview. General Virus Background General Morphology of the Virus Ambisense RNA Genome Viral Proteins Virus Life Cycle Treatment Weaponization. Lassa Fever Background.

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The Molecular Biology & General Background of the Lassa Virus

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  1. The Molecular Biology & General Background of the Lassa Virus Presented by Ryan Cordell

  2. Presentation Overview • General Virus Background • General Morphology of the Virus • Ambisense RNA Genome • Viral Proteins • Virus Life Cycle • Treatment • Weaponization

  3. Lassa Fever Background • Found in West Africa • 100K – 300k Cases/year • 1% of infections result in death • Early symptoms resemble flue or enteritis • Three-week incubation period

  4. General Characteristics Virus • Member of the Arena Virus Family • Spherical viral particles • Particle diameter is 110-130 nm • Lipid membrane coat • Virion consists of two nucleocapsids

  5. Club-shaped projections on virion surface Virion Composition: 70% Protein weight 2% Genome weight 8% Carbohydrates 20% Lipids 40-45% Guanine & Cytosine content Thermal inactivation point is 56 oC Inactivated at < pH 5.5 and > pH 8.5 General Characteristics Cont’d

  6. RNA Genome:Coding Region • Composed of 2 strands: S-RNA & L-RNA • L:S ratio is 2:5 in virion & infected cell • Both strands are ambisense • S-RNA is 3.4 kb and codes for 2 proteins • Nucleoprotein (NP) • Glycoprotein (GPC) • L-RNA is 7 kb and codes for 2 proteins • Viral RNA-dependent RNA polymerase (L) • Zinc RING-finger motif protein (Z)

  7. RNA Genome:Coding Region

  8. RNA Genome:Noncoding Region • No overlap between (+) & (-) ambisense genes • Noncoding intergenic region found between genes • Intergenic region forms stable hairpin loop in both L & S strands • 17 of 19 nt on the 3’ end are conserved between L & S

  9. Viral Proteins

  10. Viral Proteins:Nucleocapsid Protein (NP) • MW 60-68 kDa • 1st protein expressed in infected cell • Most abundant structural protein • Major protein component of nucleocapsids • NP can be cross-linked to carboxy-terminus of GP2 (essential to virion assembly)

  11. Viral Proteins:Viral RNA-Dependent RNA Polymerase (L) • MW 180-250 kDa • Actual L-protein can be detected in virions • 2nd protein produced in infected cell

  12. Viral Proteins:Envelope Glycoprotein (GPC) • MW 79-80 kDa • Post-translationally cleaved to release GP1 & GP3

  13. Viral Proteins:Glycoprotein - 1 • MW 40-46 kDa • 4-11 N-linked glycosylation sites • Assemble into homotetrameric complexes • Complexes held together with disulfide bonds

  14. Viral Proteins:Glycoprotein - 2 • MW 35 kDa • 1-4 potential N-linked glycosylation sites • Membrane spanning domain • Interacts with NP in order to assemble virion • Assemble into homotetrameric complexes • Stalk of glycoprotein spike • Acts as viral fusion protein under acidic conditions

  15. Viral Proteins:Zinc RING-finger Protein (Z) • MW 11 kDa • Contains a RING-finger motif and binds to zinc • Relatively large amount of Z-mRNA can be found in the virion • Might serve as a cofactor in replication and/or transcription • Actual function is not known

  16. Virus Life Cycle

  17. Virus Life Cycle • Virion comes into contact with cell • GP1 bind to cellular receptor (Dystroglycan) • Virion enters cell via smooth-walled clathrin-free vesicle • Acidification of endosome leads to nucleocapsid delivery • GP1 dissociates from GP2 • GP2 fusion peptide is exposed • Core unit is delivered into cytosol

  18. Virus Life Cycle Cont’d • NP is expressed in large quantities • Replication of L & S strands ensues • GPC is expressed leading to GP1 & GP2 • GP1 & GP2 homotetrameric complexes migrate to cell surface • NPs combine with genomic RNA to from a string of bead like structures • NP cross-links to carboxy terminus of GP2 • Complete virus forms and buds off from cell

  19. Lassa Virus

  20. Treatment • Ribavirin for infected individuals (mech not known) • Vaccines have been successfully tested in animals but not in humans

  21. Weaponization • No current human vaccine • Poorly understood by medical community • Rarity = unexpected • Can’t survive in open for long • Only 1 known animal reservoir • Simplistic genome • Stable replication

  22. The End

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