Rabies, Slow Virus Infections and Prions

Chapter 42

Rhabdoviruses

• • • • • • Features Bullet-shaped Enveloped (75 x 180 nm) 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)

• • • • •

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

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

• • • • • • •

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

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 Required mechanical ventilation Administered heparin to suppress brain activity 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

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

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

Prion Diseases

• • Proteinacious infectious agents Diseases are transmissible spongiform • • encephalopathies • (TSEs) There are also inherited spongiform encephalopathies • • • Human Creutzfeldt-Jakob Disease New Variant CJD - sporatic 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

• • • • • • • Pathogenesis Poorly understood

Prion Diseases

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 The misfolded protein is termed PrP c protein is termed PrP Sc Normal Misfolded It is unknown why the protein misfolds However, once misfolded, it can cause misfolding of other copies of PrP c 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