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 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 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
Todays principal vaccine is the human diploid cell vaccine (HDCV)
made in the WI-38 fibroblast cell line
Virus is inactivated by PL

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
 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
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
These plaques interfere with neuronal communication