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Rabies, Slow Virus Infections and Prions

Rabies, Slow Virus Infections and Prions. Chapter 42. Rhabdoviruses. Features Bullet-shaped (75 x 180 nm) Enveloped Single stranded RNA genome, 12 kb Many viruses with broad host ranges Classification Family Rhabdoviridae Genus Lyssavirus (including Rabies virus) Vertebrates

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Rabies, Slow Virus Infections and Prions

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  1. Rabies, Slow Virus Infections and Prions • Chapter 42

  2. Rhabdoviruses • Features • Bullet-shaped (75 x 180 nm) • Enveloped • Single stranded RNA genome, 12 kb • Many viruses with broad host ranges • Classification • Family Rhabdoviridae • Genus Lyssavirus (including Rabies virus) • Vertebrates • Invertebrates • Plants • Genus Vesiculovirus (Vesicular stomatitis-like viruses)

  3. Rabies Virus • Rabies virus replication • Spike protein mediates attachment (nicotinic acetylcholine receptor) • Viral RNA polymerase transcribes a monocistronic mRNA • Five polypeptides are encoded by the genome • N • L (polymerase) • P (polymerase) • M • G • The N assembles with the polymerase and RNA in progeny virus (spiral configuration) • Virus exits by budding • G protrudes from plasma membrane • M binds to inner PM leaflet

  4. Rabies Virus • Animal susceptibility • All warm-blooded animals can be infected with varying susceptibility • High - wolves, coyotes, foxes, dogs • Intermediate - skunks, raccoons, bats • Low - opossums • Virus occurs in saliva, nervous system, urine, lymph, milk • Recovery is rare and only occurs in bats; fatal in nearly all others • Vampire bats can transmit virus for months

  5. Rabies Virus • Pathogenesis • Requires several weeks for infection to become apparent • Transmission through bite or scratch from infected animal • Replication in muscle and connective tissues at site of inoculation • Enters peripheral nervous system at neuromuscular junctions • Spreads up the peripheral nerves to the central nervous system • Encephalitis • Virus grows to high titers in the salivary glands • Rabies patients must be restrained • Negri bodies appear in neuron cell bodies • Clinical spectrum • Prodrome - nausea, headaches, fever, sore throat, photophobia • Acute neurologic phase - apprehension, nervousness, hallucinations, behavioral anomalies, salivation, perspiration, hydrophobia, photophobia • Coma - seizures and death (99+%) Negri bodies

  6. Rabies Virus • One survival using novel medical treatment • NEJM. 2005. 352:2508-2514 • 15 year old Jeanna Giese bitten by a bat • Presented with clinical rabies after one month • Treatment • Induced coma • Administered high doses of ketamine to suppress brain activity • Required mechanical ventilation • Administered heparin • Administered ribavirin, an antiviral, to protect the heart from rabies-induced cardiomyopathy • Days 8-10 showed improvement in cardiovascular and neurological functions • By day 23 she could sit up in bed, but neurological manifestations persisted • Required prolonged physical therapy, but is continuing to recover • This treatment failed for a Texas boy

  7. Rabies Virus • Laboratory diagnosis • PCR • Serology (IFA) • Animal control • Rabid or suspected rabid animals are killed and examined by histopathology for Negri bodies and viral antigen • Vaccination of pets is required by law in most states • Immunity and protection • Vaccines • First one developed by Pasteur by using spinal cords from infected dogs • Today’s principal vaccine is the human diploid cell vaccine (HDCV) made in the WI-38 fibroblast cell line • Virus is inactivated by βPL • Post-exposure prophylaxis • One dose of hyperimmune antiserum • Five immunizations over 28 days

  8. Rabies Virus • Epidemiology • Enzootic in wild and domesticated animals • In the U.S., edible vaccines are dispersed to control wild animal rabies • More than 200 people die from rabies in China each month • Reservoirs might be bats • But the slow-growing nature of rabies virus also contributes to its persistence in nature

  9. Prion Diseases • Proteinacious infectious agents • Diseases are transmissible spongiform encephalopathies (TSEs) • There are also inherited spongiform encephalopathies • Human • Creutzfeldt-Jakob Disease - sporatic • New Variant CJD - from beef (“mad cow disease”) • Kuru - ritualistic cannibalism (consuming brains of infected dead) • Fatal familial insomnia • Animal • Bovine spongiform encephalopathy (“mad cow” disease) • Scrapie - sheep • Chronic wasting disease - deer, elk, moose

  10. Prion Diseases • Pathogenesis • Poorly understood • The prion protein is a normal cellular protein, encoded by the PRPC gene • The gene is found on the short arm of chromosome 20 • It is thought to be involved in ion transport • It is prominently expressed in the CNS • Some mutant alleles occur in familial enecphalopathies • Protein folding • The properly-folded protein is termed PrPc • The misfolded protein is termed PrPSc • It is unknown why the protein misfolds • However, once misfolded, it can cause misfolding of other copies of PrPc • The misfolded protein is highly resistant to heat and protease digestion • TSEs have been transmitted by autoclaved surgical instruments • The misfolded proteins apparently elude the ubiquitin/proteosome system • Cells export the misfolded protein, which then forms extracellular plaques • These plaques interfere with neuronal communication Normal Misfolded

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