Rabies, Slow Virus Infections and

PrionsChapter 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

• 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

• 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

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 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

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

• 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

Rabies Virus

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

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