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Bunyaviridae

Bunyaviridae. Clayton M. Johnston. Bunyaviridae. Largest family of mammal affecting viruses (250 viruses) Arthropod- or rodent-borne vectors Most are amplified in vertebrate hosts. Bunyaviridae. Structure. Virion Structure Genomic Structure Structural Proteins. Virion Structure.

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Bunyaviridae

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  1. Bunyaviridae Clayton M. Johnston

  2. Bunyaviridae • Largest family of mammal affecting viruses (250 viruses) • Arthropod- or rodent-borne vectors • Most are amplified in vertebrate hosts

  3. Bunyaviridae

  4. Structure • Virion Structure • Genomic Structure • Structural Proteins

  5. Virion Structure • Spherical • 80-120 nm diameter • Enveloped • Helical nucleocapsid • NO matrix protein

  6. Genomic Structure • (-) sense • Linear ssRNA • Three segments: • Large (L) codes for viral polymerase • Medium (M) codes for G1 and G2 glycoproteins • Small (S) codes for nucleocapsid

  7. Structural Proteins • Membrane Glycoproteins • Nucleocapsid Protein • Viral Polymerase

  8. Structural Proteins Membrane glycoproteins (G1 and G2) Polymerase (L) Nucleocapsid proteins (N)

  9. Membrane Glycoproteins • G1 and G2 • Integral membrane proteins • Important in cell entry and pathogenesis

  10. Nucleocapsid Protein • Complexes with genomic vRNA in virus, as well as with cRNA after infection, but not with mRNA • Necessary for virus replication and packaging

  11. Viral Polymerase • RNA-dependent RNA polymerase • Complexed with ribonucleocapsid in virion • Endonuclease activity to cleave host mRNA • Transcriptase activity for making cRNA and mRNA from vRNA • Helicase activity to unwind vRNA during transcription

  12. Viral Replication • Receptor mediated endocytosis • Occurs in cytoplasm • Budding at Golgi apparatus or cell membrane

  13. Hantavirus Replication Cycle • Attachment • Entry and Uncoating • Primary Transcription • Translation • Genome Replication • Secondary Transcription • Virion Assembly • Virion Release

  14. Attachment • Viral G1 and G2 glycoproteins interact with cell surface receptors • Pathogenic hantavirus bind β3 integrins • Non-pathogenic hantaviruses bind β1 receptors

  15. Entry and Uncoating • Virus particles bound to integrin receptors are taken in by receptor mediated endocytosis • Newly formed vesicles are acidified • Acidic environment changes confirmation of G1 and G2 glycoproteins • Viral and cell membranes fuse • Genomic material and polymerase are released into cytoplasm

  16. Attachment and Entry

  17. Primary Transcription • Transcription of negative sense vRNA to mRNA • Viral polymerase transcribes nucleoprotein-coated vRNA • Capped oligonucleotides from cell’s own mRNA are used to prime transcription (similar to Influenza virus)

  18. Translation • L and S segments of mRNA are translated on free ribosomes in cytoplasm • M segment mRNA is translated on ER-bound ribosomes

  19. Translation

  20. Genome Replication • vRNA is used as a template by viral polymerase to make cRNA • cRNA is used as a template to make more negative sense strands of vRNA

  21. Secondary Transcription • Extra vRNA synthesized during replication is used as template to make mRNA • Since more template is present after vRNA is replicated, more mRNA can be transcribed, and more viral proteins can be made • Persistent infection

  22. Virion Assembly • Membrane-bound G1 and G2 peptides are transported to Golgi apparatus and carbohydrates are attached by N-linked glycosylation • vRNA complexes with N nucleocapsid protein, forms looped panhandle structure, and complexes with polymerase

  23. Virion Assembly

  24. Nucleocapsid complexes bud into the Golgi membrane with G1 and G2 embedded Virion particle is formed inside Golgi apparatus Virions are transported to cell membrane by vesicles and released by exocytosis G1 and G2 embed into cell membrane through Golgi vesicles Virions bud from cell membrane, not through Golgi apparatus Virion ReleaseTwo Mechanisms

  25. Attachment Entry Uncoating Release Transcription Replication Assembly Translation

  26. LaCrosse EncephalatisBunyavirus • Mostly infects children younger than 16 • Ades mosquitoes are the common vector • Squirrels and chipmunks are the amplifying host • Most common bunyavirus infection in the United States

  27. LaCrosse EncephalatisBunyavirus • Targets the brain • Symptoms may include: • Fever • Convulsions • Drowsiness • Focal neurological signs

  28. Rift Valley FeverPhlebovirus • Most spread by sandfly or Ades species of mosquitoes • Causes abortion in livestock • Highly infectious by aerosolized blood • Distribution follows that of the host vectors • Immunization of livestock is the most effective way to control and prevent the disease

  29. Rift Valley FeverPhlebovirus • Febrile disease in humans • Targets the liver • Symptoms often include: • Fever • Encephalitis • Retinal vasculitis (which may lead to blindness)

  30. Rift Valley FeverDistribution Map

  31. Crimean-Congo Hemorrhagic FeverNairovirus • Transmitted by ticks • Appears in the Middle East and Africa • Targets the liver and vascular endothelium • Symptoms include: • Headache • Pain in limbs • Often bleeding from many orifices

  32. Crimean-Congo Hemorrhagic FeverNairovirus

  33. Hantavirus • Enveloped • ssRNA • Virions 98 nm in diameter • Genome consists of three RNA segments

  34. TransmissionVectors • Transmitted via aerosolized rodent urine, feces, and saliva • Deer mouse (Peromyscus maniculatus) • Cotton rat (Sigmodon hispidus) • White-footed mouse (Peromyscus leucopus) • Striped field mours (Apodemus agrarius) • Bank vole (Clethrionomys glareolus) • Rat (Rattus)

  35. Hemorrhagic Fever with Renal SyndromeHantavirus • Liver and vascular enothelium are targeted • Symptoms include: • Hemorrhage • Acute renal failure • Fever • Over 15% mortality rate

  36. Hantavirus Pulmonary SyndromeHantavirus • Lungs are targeted • Symptoms include • Fever • Acute respiratory distress • Over 50% mortality rate • Shock and cardiac complications often contribute to death

  37. Prevention and Control • Vaccines • Hygiene • Vector Control

  38. Vaccines • E. coli expressed truncated nucleocapsid as an immunogen • Naked DNA • Recombinant non-pathogenic virus • Rodent brain-derived • Cell culture derived • Inactivated virus – being tried out in China

  39. Hygiene • Prevent aerosolization of virus from roden excrement • Dampen surfaces with bleach before cleaning • Control rodents and human contact with rodents

  40. Host Defenses and Immune Response • Interferon is produced • Humor antibody has been shown to be related to the disappearance of virus from blood • Cytotoxic T-cells attack infected host cells • Inflammatory response

  41. Treatment • Early aggressive intensive care • Early use of inotropic agents (Dobutamine) • Early ventilation • Careful monitoring: • Oxygenation • Fluid balance • Blood pressure

  42. Treatment • General care, alleviation of symptoms • Ribavirin (Hemorrhagic Fever with Renal Syndrome) • ECMO (Hantavirus Pulmonary Syndrome)

  43. Ribavirin • Administered intravenously • Shown to be effective against Hemorrhagic Fever with Renal Syndrome • Not shown to be effective against Hantavirus Pulmonary Syndrome causing strains

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