Rhabdoviridae

VIRUSES

Introduction

Rabies is a neurological killer that has evolved a fool-proof technique of transmission, and it cleverly evades the species barrier to present a potent threat to mammalian life. While the simplicity of the virus ensures its transmission, it also contributes to its weakness: its monoclonal antigenicity means that a single vaccination covers all strains of the disease. Though rabies is considered endemic in parts of the developed and undeveloped world, vaccination schemes have rendered the disease controllable to a satisfactory degree. Nonetheless, infection is still largely fatal and the disease should not be taken lightly.

Morphology

• Large, enveloped, negative-sense RNA virus
• Bullet-shaped with short glycoprotein spikes

Types and Subtypes

Two Genera:

1. Lyssaviruses: 7 genotypes
   1. Genotype 1 is classical rabies
   2. Genotypes 2-7 more limited in distribution
   3. Genotype 4 infects insectivorous bats
2. Vesiculoviruses are all exotic to the UK:
   1. Vesicular Stomatitis Virus
   2. Ephemeral Fever
   3. Fish Rhabdoviruses, such as viral hemorrhagic syndrome and infectious haematopoetic necrosis virus

Virulence and Pathogenesis

• Rabies is moderately resistant: it can survive well in dark places at low temperatures for several days
• Infection occurs through a penetrating bite in which virus is transmitted via saliva
• Incubation period is variable but can be long (10 days to 12 months), and increases with distance of the bite to the CNS
  • 80% show signs within 4 months
• Primary replication of the virus occurs in the muscle
• The virus gains access to nervous tissue and travels toward the brain, where it continues to replicate
• It then migrates down cranial nerves to infect salivary glands and the cornea
• Virus is shed in saliva and tears and can be shed BEFORE the onset of classical signs
• The onset of clinical signs in dogs and cats includes:
  • Behavioral changes
  • Pyrexia
  • Salivation
  • Dilation of pupils
• Two forms of the virus exist:
  • Furious form:
    • Common to cats and dogs
    • Abnormal aggression, salivation, and attack without provocation
    • Disordered wandering, "copulatory" movements.
    • Incoordination, convulsions, coma and death within 3-10 days
  • Dumb form
    • May or may not follow Furious form
    • Common to ruminants and horses
    • Ruminal tympany, tenesmus, diarrhoea
    • Paralysis of lower jaw, drooling saliva, tremors and progressive paralysis
    • In dogs, a change in voice may be observed (bellowing)
• Human infection is characterized by hydrophobia

Epidemiology

• Rabies is a NOTIFIABLE zoonosis
• Rabies is found worldwide, though currently considered exotic to the UK and Australia

Host Range:

• All mammals are susceptible
  • Very susceptible: foxes, jackals, wolves
  • Susceptible (10,000x virus necessary to infect): cats, rodents, bats, skunks, cattle, mongooses
  • Moderately susceptible (100,000x virus necessary to infect): dogs, sheep, goats, horses, primates
• Isolates can show to some species specificity in their reservoir host

Reservoir species by region:

Region	Reservoir Species
Europe	Red fox
Russia, Turkey, Middle East	Dog, Raccoon
USA	Raccoon, Fox, Skunk
Africa	Dog, Jackal, Mongoose
Asia	Dog, Mongoose
South America	Dog, Vampire bat
Worldwide	Insectivorous Bats

• The current position of DEFRA holds bat lyssaviruses to be present in the UK
• Human infection and death an occur after infection with bat rabies
  • Nocturnal bat bites account for 50% of human cases in the USA
• Humans develop disease but excrete little virus
• Immune recovered animals are rare, but are not shown to be infections

Diagnosis

• Isolate and monitor for clinical signs
• In the field:
  • Remove brain core sample via straw through occipital foramen in the direction of an eye
  • Place contents in a 50% glyerol/PBS for FAT or virus isolation, or in 10% formaldehyde for histology
  • Whole head can also be removed and sent to lab
• In the lab:
  • Fluorescent Antibody Test (FAT) on smears or frozen sections of hippocampus or cerebellum should show presence of Negri bodies
    • Being replaced by testing for monoclonal antibodies to nucleoprotein
  • Histological detection of Negri bodies using Mann's or silver stains
  • Intracerebral inoculation of mice followed by FAT testing of brain smears of affected mice
  • RT-PCR on brain or saliva can be performed to determine genotype

Rabies Control

For countries where rabies is considered exotic:

• 6 month quarantine of carnivores and ruminants (Norway, Sweden, Portugal, Australia, New Zealand)
• In the UK, this has been replaced by the Pet Travel Scheme (PETS)

For virus-endemic countries:

1. Control in pets:
   • Annual Vaccination:
     • Antigenicity allows a single antigenic type to vaccinate
     • Inactivated virus or canarypox recombinant viruses
   • Control of stray population
   • Muzzling in public
2. Control of wildlife reservoir hosts:
   • Feeding vaccinated bait
   • Secondary consequence of increasing reservoir host population (eg European foxes)
3. Control in humans
   1. Prevention by vaccination with a single booster if bitten
      • The current vaccine is grown in human diploid cells (HDCV) and is BPL-inactivated, and therefore costly
      • Developing countries utilize older vaccines passaged from a 1939 case ("Flury" vaccines)
   2. If bitten and unvaccinated:
      • Clean and disinfect wound
      • Human anti-rabies immunoglobulin administered around bite
      • Intramuscular vaccination program: 2 dose-1 dose-1 dose at 0, 7, and 14 days post-bite

For more on Rabies control in Europe, see here