152 Virus Involved in the Bloodstream, CNS and other Sterile Sites I:

Rabies

Rabies

One of the oldest recognized infectious diseases

rabid dog

In The Iliad (700 BC), Hector is compared to a —-

Chinese

—- scholars warned of the dangers of rabid dogs in 500 BC

Celsus

1st century AD, —- described clinical aspects of human infection:
■ patient is tortured by thirst and invincible repulsion toward water
■ recommended excision of the bitten tissue, cauterization of the wound, and dunking the victim into a pool

dog saliva

1804, Zinke used —- for transmission.

Galtier

1879, —- is credited with experimental rabies transmission to rabbits, and from rabbit to rabbit

Pasteur's vaccine

July 6, 1885, is a milestone in the history of rabies
o 9-year-old Joseph Meister was bitten at multiple sites by a rabid dog and received the first postexposure prophylaxis with —-.

Negri

1903, a clear description of viral and neuronal interactions was made by —-, with the detection of cytoplasmic inclusions (Negri bodies) in neurons of rabid animals

human diploid cells

In the 1960s, a rabies virus grown in —- was used to produce a safe and efficacious vaccine

Rhabdoviridae

Rabies family:

Rhabdoviridae

a family of characteristically bullet-shaped RNA viruses

Lyssavirus

Rabies Genus:

Lyssavirus

○ infect vertebrates
○ seven species are known

-ssRNA genome

Rabies genome structure

nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and polymerase (L)

The rabies genome encodes five proteins:

RNA transcriptase

Rabies has a —- that is responsible for the production of viral mRNAs in infected cells.

L protein

responsible for the production of viral mRNAs in infected cells

(G) spikes of the virus

Responsible for viral attachment to cellular receptors and fusion activity

Matrix protein (M)

○ Major structural protein of the virus
○ Stabilizes the structure of the virion

Nucleoprotein (N)

Encapsidates and protects the RNA from degradation by RNAase enzymes

True

TRUE OR FALSE. Rabies can be transmitted via infected transplant donors.

10 days - 1 year (Avg. 1-3 months)

Incubation period of rabies

False

TRUE OR FALSE. The number of bites does not affect the rate of transmission of rabies.

Insidious

Rabies onset is usually —-

prodromal

1 - 10 day —- period of malaise, fever, headache, hypersalivation

○ Furious rabies
○ Paralytic (‘dumb’) rabies

Subsequent course (Two Forms) of rabies

Furious Rabies

‘Stage of Excitement’

‘Stage of Excitement’

Anxious and apprehensive expression
Fast pulse
Rapid breathing

Furious Rabies

● Cranial nerve and other paralyses are frequent
● Usually from dogs

Hydrophobia

What is the classical sign of furious rabies?

Paralytic (‘Dumb’) Rabies

● Characterized by ascending paralysis
● Spinal cord and medulla are more affected than the brain

vampire bat bites

Paralytic (‘Dumb’) Rabies is associated more with —- rather than dogs

Paralytic (‘Dumb’) Rabies

● Less dramatic
● Lasts as long as a month

up to 8 months

RABIES IN ANIMAL
Incubation in dogs:

behavioral changes

First sign of rabies in dogs

True

TRUE OR FALSE. Most rabid cats enter a furious phase.

epithelial or striated muscle cells
mucosal cells

In humans, rabies virus first replicates in the —- of the bite site or in the —- of the respiratory tract

peripheral nervous system

In humans, the virus accesses the —- via neuromuscular spindles

cholinesterase-positive binding sites

In humans, the virus specifically binds to —- at neuromuscular junctions

3mm/day

In humans:
Centripetal progress of the virus along the axons of the peripheral nerve has been estimated experimentally in mice as —-

neuronal axons of the peripheral nerves

In humans:
Once the virus has replicated in the spinal cord and throughout the CNS, may spread along —- to other tissues (includes salivary glands and hair bearing tissues)

encephalitis

In humans, the victim dies of

saliva

In Animals, A rabid animal transmits rabies virus through —- into a bite wound.

spinal cord

In Animals, The virus travels up peripheral motor nerves to the —-, where it rapidly divides and spreads through the nervous system.

lower motor neuron paralysis, behavior changes, and the cranial nerve deficits

In animals, the spreading virus produces —- typically encountered during the various stages of infection.

1. Adsorption
2. Penetration
3. Uncoating
4. Transcription
5. Translation
6. Processing
7. Replication
8. Assembly
9. Budding

CYCLE OF INFECTION AND REPLICATION

Adsorption

(receptors and virion interaction)

Penetration

(virus entry)

Uncoating

(envelope removal)

Transcription

(synthesis of mRNAs)

Translation

(synthesis of structural proteins)

Processing

(G-protein glycosylation)

Replication

(production of genomic RNA from intermediate strand)

Budding

(complete virions)

carnivores

What are the vectors of rabies?

○ Urban rabies
○ Sylvatic Rabies

Rabies has 2 epidemiological forms:

Urban Rabies

● Domestic cats and dogs
● Main reservoirs and transmitters
● Most important sources of human infection
○ Usually found in developing countries due to low vaccination rate

Sylvatic Rabies

● Various wildlife species
○ Wolves: eastern Europe
○ Red fox: western Europe
○ Mongooses and vampire bats: Caribbean
○ Skunks and racoons: USA and Canada
○ Vampire bats: Latin America

Virus isolation
Immunofluorescence in cells to demonstrate rabies antigen
Cytoplasmic inclusions (Negri bodies)

LABORATORY DIAGNOSIS

Virus isolation

○ Brain tissue, saliva, CSF, or urine samples are injected intracerebrally into newborn mice
○ Needs category IV lab and expertise in maintaining cultures

Immunofluorescence in cells to demonstrate rabies antigen

○ Obtained from corneal impressions or hair-bearing skin
○ Central feature of laboratory diagnosis

Cytoplasmic inclusions (Negri bodies)

○ Usually used
○ Less sensitive, but useful post-mortem technique
○ Named after Italian physician who discovered them
○ Tissue is taken from Ammon’s horn region of the hippocampus (brain) and stained with Mann’s stain

quaternary ammonium compound

rabies virus is susceptible to this compound

soap and water, alcohol, iodine, or a quaternary ammonium compound

Wound from the bite should be thoroughly washed with

90%

Good wound care is the cornerstone of rabies prevention since it reduces risk by

Anti-tetanus treatment

should be give to those not immunized against rabies within the past 3 years

Pasteur vaccine

Historical interest only

Semple vaccine

● Phenol-inactivated virus vaccine prepared in brains of rabbits, sheep, or goats
● Widely used in developing countries
● Inexpensive

neuroparalytic reactions

Semple vaccine is liable to cause

Duck embryo vaccine

● Virus inactivated with beta-propiolactone
● Free from neural tissue, but cause allergic reactions and a relatively ineffective antigen
● Discontinued

Human diploid cell strain virus (HDCS)

● Virus inactivated with beta-propiolactone
● Few side-reactions
● Most widely used in developed countries
● Expensive

Not needed

Determine the treatment needed:
Indirect contact only
Animal appears healthy or has signs of rabies

Start vaccine immediately, stop if animal is normal after 10 days

Determine the treatment needed:
Licks to skin
(a) Under observation for at least 10 days after the contact

Full course of vaccine immediately

Determine the treatment needed:
Licks to skin
(b) Escaped

Start vaccine, stop if lab test for animal is negative

Determine the treatment needed:
Licks to skin
(c) Killed

Schedules as for ‘licks to skin’ + human rabies immunoglobulin (HRIG), 20 international units/ kg body weight, of which half is infected around the bite/s and half is given intramuscularly

Determine the treatment needed:
Bites

Category I(No Exposure)

● Touching or feeding animals
● Animal licks on intact skin

Category II (Exposure)

● Nibbling of uncovered skin
● Minor scratches or abrasions without bleeding

Category III (Severe Exposure)

● Single/ multiple transdermal bites or scratches
● Contamination of mucous membrane or broken skin with saliva from animal licks
● Exposures due to direct contact with bats

● Washing exposed skin surfaces
● No PEP

Category I (No Exposure) pep measures

● Wound washing
● Immediate vaccination

Category II (Exposure) pep measures

● Wound washing
● Immediate vaccination
● Administration of rabies immunoglobulin

Category III (Severe Exposure) pep measures

Europe

Chicken heads impregnated with live attenuated rabies vaccine and tetracycline are dropped by helicopter into remote mountainous areas