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La rage

Rabies
• Maladie infectieuse

• Inoculable par morsure ou griffure

• Zoonose

• Maladie professionnelle

• Evolution mortelle
LA RAGE

DEFINITION
C’est une maladie infectieuse, virale, inoculable le plus souvent par morsure, commune à
l’homme et aux mammifères : c’est une ZOONOSE

ZOONOSE
C’est d’ailleurs la zoonose la plus grave et la plus redoutée au Monde.
La rage est due à la multiplication dans l’organisme (et surtout dans le système nerveux)
d’un virus appartenant à la famille des rhabdoviridés.
La rage provoque une encéphalomyélite qui conduit inéluctablement à la mort des
animaux et des personnes après l’apparition des symptômes.

LES VECTEURS DE LA RAGE


Dans le Monde, les principaux vecteurs sont les chiens .
En Europe le renard a été un vecteur et un réservoir important de la
maladie.
La chauve-souris peut également être vecteur du rhabdovirus dans
différentes régions du monde.
La rage est une infection grave aigue du
cerveau causée par le virus de la rage. La
rage animale existe sous deux formes : la
forme "furieuse", où la fureur prédomine,
et la forme "paralytique", plus difficile à
reconnaître, où l’animal a l'air affaibli et
pitoyable. Pour cette raison il ne faut
jamais caresser d’animaux sauvages,
apparemment dociles (singes, p.ex. en
visitant des temples, renards,…).
Etiologie
Dans les pays tropicaux, la transmission à
l’homme se fait le pus souvent par
morsure de chiens errants mais également
par des chats, des singes et des chauves-
souris. Un grand nombre d’autres animaux
à sang chaud peuvent occasionnellement
la transmettre. Dans beaucoup de pays en
voie de développement la rage représente
un problème majeur. Il n’existe aucun
traitement curatif de la rage déclarée :
l’issue est fatale à 100 % dès l’apparition
des premiers signes.
Rabies virus structure

Matrix protein
Envelope
Glycoprotein

Nucleocapsid protein
Structure of Rabies Virus
Clinical forms of rabies
• encephalitic = furious
– ~ 80%

• paralytic = dumb
– ~ 20%
Rabies attacks the
Central Nervous System

• Watch as the rabies


virus from an exposure
on the leg spreads up
the spinal cord to the
brain and throughout the
rest of the body.

Rabies virus entering


the body.
 Shape: bullet
 Genome: -ssRNA
 enveloped virus
 CPE: Negri body
DISTRIBUTION GÉOGRAPHIQUE

• La rage sévit de façon enzootique, avec


une intensité variée sur tous les continents
et dans la plupart des pays.

• Rares sont les pays indemnes de manière


régulière. Exemples : Grande-Bretagne,
Suède, Japon,Taïwan.
Geographic distribution of rabies - 2000

No information: DRC, Benin ,Burkina, Sierra Leone, Liberia, Gambia,


Mauritania, Somalia, Yemen, Malaysia, Laos, Myanmar, Vietnam
Cambodia, North Korea
Rabies widely spread in Asia and
Africa
• Rabies is widely distributed across the
globe. More than 55 000 people die of
rabies each year. About 95% of human
deaths occur in Asia and Africa.
• Most human deaths follow a bite from an
infected dog. Between 30% to 60% of the
victims of dog bites are children under the
age of 15.
What is Rabies
• Rabies is a zoonotic disease (a disease that is
transmitted to humans from animals) that is
caused by a virus. Rabies infects domestic and
wild animals, and is spread to people through
close contact with infected saliva (via bites or
scratches). The disease is present on nearly
every continent of the world but most human
deaths occur in Asia and Africa (more than
95%). Once symptoms of the disease
develop, rabies is fatal.
Rabies- A Zoonotic Disease
• Rhabdovirus family;
genus Lyssavirus
• Enveloped, bullet-shaped
virions
• Slow, progressive
zoonotic disease
• Primary reservoirs are
wild mammals; it can be
spread by both wild and
domestic mammals by
bites, scratches, and
inhalation of droplets.

18
Rabies – A fatal Zoonotic Disease
Rhabdoviruses
• A Bullet shaped virus/
Enveloped
• Contains ss RNA virus
• Rhabdoviridae – infects
mammals.
• Important virus
Lyssa virus- Rabies
virus
Lyssa means Rage.
Rabies virus
• Bullet shaped virus
• Size is 180 x 75 nm
• Has Lipoprotein
envelop
• Knob like spikes
/Glycoprotein S
• Genome un segmented
• Linear negative sense
RNA
What is a Fixed Virus
• One whose virulence and
incubation period have
been stabilized by serial
passage and remained
fixed during further
transmission.
• Rabies virus that has
undergone serial passage
through rabbits, thus
stabilizing its virulence
and incubation period and
called as fixed virus
What is a Street Virus
• Virus from a naturally
infected animal, as
opposed to a laboratory-
adapted strain of the
virus.
• The virulent rabies virus
from a rabid domestic
animal that has
contracted the disease
from a bite or scratch of
another animal, and
called as street virus.
Any mammal can get rabies.
• Raccoons,
skunks, foxes and
bats

• Dogs, cats,
cattle and ferrets

• Humans too
What kind of animals
get Rabies?
• The rabies virus can infect all
mammals.

• Mammals are warm-blooded


animals that have hair and
mammary glands to produce
milk for their babies.

• Animals like frogs, birds, and


snakes do not get rabies.
Spread of Virus
• From Brain virus
spread to
Salivary glands,
Conjunctival cell
released into tears
Kidney
Lactating glands
and Milk after
pregnancy
IMPORTANCE
• L’importance de la rage est, avant tout,
médicale : tous les cas de rage humaine
sont d’origine animale. Et la rage,
lorsqu’elle est cliniquement déclarée chez
l’Homme, est toujours mortelle, après
une évolution relativement courte d’un
tableau clinique dramatique au cours
duquel la conscience est conservée
jusqu’à une phase avancée.
• L’importance de la rage est, également,
économique : dans certains pays, les
pertes en animaux peuvent être élevées :
on a rapporté que plusieurs dizaines de
milliers de bovins meurent de rage chaque
année en Amérique du Sud.
• Par ailleurs, les dépenses engagées pour
la lutte contre la rage peuvent être très
élevées: traitements - vaccins
Rabies Virus
• Belongs to the genus Lyssavius (lyssa:
rage in Greek)
• Include members of the Rabdoviridae
family: Rabies, Makola, Duvenhage
• Enveloped bullet-shaped virus
• 5 structural proteins
• SS RNA, non-segmented, non-polar
• 12,000 nucletides
Rabies Virus
• Envelope contains G-protein spikes,
which bind to cells
• Nucleocapsid core: Matrix (M)
protein, viral nucleoprotein (N), viral
RNA
• Transcriptase (L) protein, non-
structural protein (NS)
Rabies/Vector transmission
• Spill over: Rabid animals transmit rabies
among same & other species
• Compartmentalisation Concept: specific
virus variants within a genotype
perpetuate among particular hosts in
different geographic areas
• Localized viral evolution: geographic
barriers
• Occasional: emergence of viral variants
with extended host range
Rabies/Vector transmission
• The dog is the most common cause of
Rabies transmission worldwide, Cats 2nd
• In developed countries: dogs immunized,
other species of wild animals are
reservoirs
• Bats: always considered rabid
• In the past: < 10% of animal rabies in
USA and Canada
Variants of bat rabies virus has become
the most common cause of rabies death
Rabies/Vector transmission
• Australia: previously Rabies free
• Endemic in 1996
• Mainly animal infection: any animal may
get infected
• Animal to human transmission
• Rabies control requires knowledge of
animal reservoir, geography of infection
• Some animal are more infectious than
others
• A single animal species is the source of
infection in a certain area
Rabies/Vector transmission
North America
• Maintained by wild carnivores mainly
raccoons, skunks and different bat sp.
• Central USA, Canada: Striped skunk
• Mid-Atlantic, SE USA: Raccoon
• NY, Quebec, Ontario: Red Fox
• Northwest: Arctic fox
• Arizona: Gray Fox
• Texas: Gray fox
Rabies surveillance in
animals/USA
• > 92% wild animals, 7.4% domestic
species
• Raccoons: 36.3% most common
• Skunks: 30.5%
• Bats: 17.2%
• Foxes: 6.4%
• Cats: 3.8%
• Dogs: 1.2%
Rabies/Vector transmission

• Caribbean: Mongoose
• Europe: Red fox
• Iran: Wolf
• Africa: Jackal
Global distribution of mammalian rabies reservoirs and vectors
Rupprecht CE, The Lancet Infectious Diseases Vol 2 June 2002
Rabies
Structure
• The Rabies virion is bullet shaped and contains
a non-segmented, negative stranded RNA
genome that encodes five proteins. It is
approximately 180nm long and 75nm wide. Its
RNA measures at 3000nm.
• The RNA is encased by nucleoprotein, which is
covered by the ribonucleoprotein (RNP) helical
core. Phosphoprotein and polymerase are
associated with the RNP. A matrix protein
covers the RNP and is surrounded by an
envelope.
• The surface of the envelope is covered by
around 400 spike-like glycoprotein10nm long.
Replication
• Attachment: the virus attaches
to the nerve cell.
• Penetration: the virus enters
the cell
• Uncoating: the envelope is
removed.
• Transcription and translation:
the virus replicates.
• Budding: the new virus leaves
the host cell and attaches to
other nerve cells and spreads
from brain to the rest of the
body by the nerves.
Raccoons are social animals
Well adapted to living at high
population densities (urban/suburban)
Prefer forested habitat
Skunks are another major reservoir of rabies virus in the USA
Rabies in animals/USA
• Skunks are solitary animals
• Lower densities than raccoons
• Prefer grassland, agricultural
areas, interfaces
• Skunks and raccoons coexist in the
same geographic areas
• Cross-species transmission between
skunks & raccoons due to aberrant
behavior of rabid animals
A productive pathogenesis cycle of animal rabies: virus entry into peripheral nerves via a bite,
movement to the central nervous system resulting in encephalitis, and transit to the salivary
glands, mediating infection of another host. Rupprecht CE et al, The Lancet Infectious Diseases Vol 2 June 2002
Foxes maintain rabies from Arctic areas to temperate and tropical latitudes
Gray fox: A surge of rabies cases among gray foxes in Texas in 2002
Arctic fox
The Jackal is an important candid reservoir of rabies in the old world
Mongoose and related species are important in parts of Africa, Asia
& the Caribbean. Transported from Asia for snake control in sugar-
cane plantations.
Rabid wolves are associated with severe bites and human deaths
Wolves may not serve as true rabies reservoirs
Hosts 6/7 lyssavirus genotypes

Widespread throughout North


America, Latin America

Infection rates in bats varies


(4% to > 15%)

Humans encounter bats that are


sick, incapacitated
Primary reservoir for rabies in
Different bat species vary in All continents.
their human interaction
Rabies/Bats
• At least 39 cases in USA
• Only 9 (23%) has hx. of bite
• 20 (51%): known or likely contact
with bats
• Bite is most likely mode of
transmission
• Bat rabies viruses vary in their
virulence properties
• Minor lesions should not be ignored
Rabies/Dogs
• IP: usually < 10 days
• May be one year
• Change in disposition,
restlessness, fear
• “Furious” or “dumb” syndrome
• Death within 10d of symptoms
• Wild animals: similar symptoms,
lack of fear of man
Rabies/Vector transmission
A rabid dog displaying the
classic form of paralytic rabies,
including cranial-nerve deficits
and hypersalivation
Rupprecht CE, The Lancet Infectious Diseases Vol 2
June 2002
Rabies/transmission
• Infected animal saliva inoculated by bite
or scratch
• Infected saliva: contact with mucous
membrane, transdermal exposure
• Virus shed in the saliva during, before or
after clinical symptoms
• Human-Human: few reported cases
following corneal transplantation
• Aerosol transmission: caves containing
bats, lab work accident
Rabies/Pathogenesis
• Risk of acquisition:
• bite 5-80%
• Scratch 0.1-1.0%
• Lyssavirus genotype dependent
• Dog: Nicotinic acetylcholine receptor on
muscle
• Bat: Unknown receptor on epidermis
/dermis
• Skunks: rabies virus antigens and
genome can persist for months in
muscle: host clearance, treatment
Rabies/Pathogenesis
• Budding from the plasma membrane of
muscle cells into unmyelinated nerve
endings
• Retrograde axoplasmic flow to the CNS
• Virus replication in dorsal root ganglia
(DRG) and anterior horn cells
• Immune response to virus in DRG:
neuropathic pain (Bat>dog)
• Prophylaxis at this stage cannot prevent
death
Rabies/Pathogenesis
• Direct access of virus to peripheral
nerves
• Travel to CNS at rate of 8-20mm/day
• Neuromuscular junction is the major site
of entry into neurons
• Receptors on nerves that are used by the
virus: Nicotic acetylcholine, neural
adhesion molecule (CD56), NGF (p75
neurotrophin) receptor
• Viral spread to other neural cells via G-
protein
Rabies/Pathogenesis
CNS infection
• Virus reaches CNS: rapid dissemination
• Preferential localization in brain stem,
thalamus, basal ganglia, spinal cord
• Clinical manifestations of rabies are not
totally explained by host, viral strain,
virus localization
• Development of paralytic rabies is more
likely after bite by vampire bat
• Paralytic rabies may have genetic
predisposition
Rabies/Pathogenesis
CNS infection
• Eventually, the virus spreads centrifugally
from the CNS to the heart, skin,
salivary and serous glands in the tangue
• All major organs may contain the virus
(except blood)
• Organs from patients with unexplained
neurologic disease may transmit rabies by
transplantation
Rabies
• Viral induced neurological disease of warm-
blooded animals.
• Recorded as far back as the 12th century BC in
Mesopotamia
• Worldwide occurrence except for rabies free
islands and states,
• 1. Hawaii, 2. Guam 3. Australia 4. England 5.
Japan 6. New Zealand
Rabies

• Causative Agent-Virus
• Rhabdoviridae Family (Rhabdo means Rod) A Large
Rod shaped Virus with one flat end and one round
end. Shaped like a bullet.
• Labile Virus which doesn’t persist long in the
environment.
• Sunlight, warm temperatures, drying, heat and
common disinfectants destroy its infectivity.
Electron Microscope View
Negatively Stained Rabies Virus
Rabies Virus Cross Section
• Rabies Virus
Rabies Virus
• Cross Sectional
Transmission of Rabies
• Usually thru infected saliva entering bite wounds.
Virus migrates up peripheral nerves to the spinal
cord and ends up in the brain.
• Aerosol transmission has been documented from
caves with large populations of infected bats.
• Organ donations—documented from early corneal
transplantation. In 2004 four US citizens died
from rabies acquired via organ transplantation
from the same donor.
Incubation of Rabies
• Averages three to eight weeks
• Can be as short as 1 week or up to 1 year
• Bite location and amount of virus present are the
two most important factors in incubation of the
virus.
• Virus migrates from peripheral nerves to the spinal
cord and ends up in the brain. The Virus replicates
in neurons and migrates out of the brain into the
salivary glands
Clinical Signs of Rabies

• Normally has 3 defined stages

• 1. Prodromal Phase—Behavioral changes


– A. Friendly animals become shy and fractious
– B. Wild animals loose their fear of humans
– C. Nocturnal animals come out in the day
– This stage lasts 1-3 days
Clinical Signs of Rabies
• 2. Hyperactive Stage
– A. Easily Excited
– B. Bite anything close by
– C. Bite imaginary objects
– This is considered the furious stage of rabies. It lasts 1-4
days.

– In some cases the animal does not exhibit the Hyperactive


stage. These animals appear to be in a stupor. This is
called “dumb” rabies
Clinical Signs of Rabies
• 3. Paralytic Stage
• Viral damage to motor neurons results in paralysis.
This is usually seen first in the hind legs. In
coordination is one of the first signs of the paralytic
stage of Rabies.
• Paralysis of the throat causes drooling and the
inability to swallow. Loss of Jaw tone, dropped
Jaw.
• This stage lasts 1-2 days and is followed by death
due to respiratory failure
Rabid Fox
CDC
Rabid Racoon
CDC
Dumb Rabies
CDC
• Zoonose virale transmise par morsure,
morsure
atteignant la quasi totalité des espèces de
mammifères et inexorablement mortelle

• L’excrétion virulente commence dans la salive


avant les premiers signes de la maladie, ce qui
conduit à mettre sous surveillance tout animal
mordeur

• L’expression clinique est peu caractéristique,


d’où la nécessité d’une observation de
l’évolution de la maladie et d’examens de
laboratoire pour parvenir à un diagnostic de
certitude
Questions?