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
• Invertebrates
• Plants
• Genus Vesiculovirus (Vesicular
stomatitis-like viruses)
 Rabies
• Rabies virus replication Virus
• 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
• Pathogenesis
Rabies Virus
• 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
Negri bodies
• Coma - seizures and death (99+%)
 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
 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 - 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
• Pathogenesis
Prion Diseases
• 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 Normal Misfolded
• 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