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

 Pathogenesis

Rabies Virus

Requires several weeks for infection to become apparent

Enters peripheral nervous system at neuromuscular

junctions

Transmission through bite or scratch from infected animal

Replication in muscle and connective tissues at site of
inoculation

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

Kuru - ritualistic cannibalism (consuming

brains of infected dead)

New Variant CJD - from beef (mad cow

disease)

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

The properly-folded protein is termed PrPc

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 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