Rabies, Slow Virus
Infections and Prions
Chapter 42
Rhabdoviruses
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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)
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Vertebrates
Invertebrates
Plants
Genus Vesiculovirus (Vesicular
stomatitis-like viruses)
Rabies
Virus
• Rabies virus replication
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Spike protein mediates
attachment (nicotinic
acetylcholine receptor)
Viral RNA polymerase
transcribes a monocistronic
mRNA
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Five polypeptides are encoded by
the genome
N
L (polymerase)
P (polymerase)
M
G
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The N assembles with the
polymerase and RNA in progeny
virus (spiral configuration)
Virus exits by budding
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G protrudes from plasma membrane
M binds to inner PM leaflet
Rabies Virus
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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
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Pathogenesis
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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
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Rabies patients must be restrained
Negri bodies appear in neuron cell bodies
Clinical spectrum
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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
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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
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Induced coma
Administered high doses of ketamine to suppress brain activity
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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
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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
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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
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Virus is inactivated by βPL
Post-exposure prophylaxis
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One dose of hyperimmune antiserum
Five immunizations over 28 days
Rabies Virus
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Epidemiology
Enzootic in wild and domesticated animals
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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
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But the slow-growing nature of rabies virus also contributes to its persistence
in nature
Prion Diseases
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Proteinacious infectious agents
Diseases are transmissible spongiform
encephalopathies (TSEs)
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There are also inherited spongiform
encephalopathies
Human
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Creutzfeldt-Jakob Disease - sporatic
New Variant CJD - from beef (“mad cow disease”)
Kuru - ritualistic cannibalism (consuming brains of
infected dead)
Fatal familial insomnia
Animal
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Bovine spongiform encephalopathy (“mad cow”
disease)
Scrapie - sheep
Chronic wasting disease - deer, elk, moose
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Pathogenesis
Poorly understood
The prion protein is a normal cellular protein, encoded by the
PRPC gene
Prion Diseases
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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
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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
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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