Rabies

 

• Also known as hydrophobia is an acute, highly fatal viral disease of the central nervous system, caused by Rhabdovirus - transmitted by bites or licks of rabid animals, especially from the saliva..
• Rabies is characterized by acute inflammation of the brain and spinal cord (encephalomyelitis)
• It is primarily a zoonotic disease of warm-blooded animals, particularly  dogs, cats etc.
• It is the only communicable disease of man that is almost always fatal.
• About 50,000 death occur due to rabies, annually. India alone accounts for 20,000 death per year.
• The causative agent Rhabdovirus is a bullet shaped neurotropic RNA containing virus.

• It belongs to the family Rhabdoviridae - (Lyssavirus genus) [Rhabdos (G)= rod ]
• Rhabdovirus ssRNA genome
• Infect mammals, reptiles, birds, fishes etc

 

Structure

• Rhabdovirus - large rod or bullet shaped enveloped virus, measuring 7 X 180nm diameter (50-95 nm diameter, 130-139nm length)
• Bullet shaped-one end conical/rounded and the other end planar/concave

• Envelope- The lipid bilayer envelope derived from the host cell membrane contains
• Numerous knob like spikes present on the envelope, these are made up of virus encoded glycoprotein, (G-spikes).
• These glycoproteins are found to bind specifically to host cellular receptor and are responsible for neurotropism in infected cells. Thus, glycoprotein is necessary for viral attachment & also induce protective antibodies.
• Closely associated with G-protein is a second membrane known as matrix protein (M protein) which has a role in viral budding.
• Nucleocapsid- The nucleocapsid is spiral or helical composed of RNA, phosphorylated nucleoprotein and RNA dependent RNA polymerase I.
• The viral genome consists of unsegmented, linear, negative sense single stranded RNA.

 

Antigenic Components

Rabies virus particles contain two distinct, major antigens

(1)   Glycoprotein (G protein)   antigen from the virus membrane

(2)   an internal nucleoprotein antigen

(3)   Two membrane proteins, glycolipids, RNA dependent RNA polymerase are also antigenic in nature

 

1. Glycoprotein (G protein) antigen

• The glycoprotein is the only antigen capable of inducing the formation of virus-neutralizing antibodies- (the presence of virus neutralizing antibodies in the blood of man and animals is considered an index of protection against infection with rabies virus).
• Thus, G protein antigen is important in pathogenesis, virulence and immunity

(1)   Mediates binding of virus to acetyl choline receptors in neural tissues- causes neurotrophism of virus

(2)   Induces protective antibodies (hemagglutination inhibiting and neutralizing antibodies)

(3)   Stimulates cytotoxic T cell immunity

• Purified glycoprotein is a safe, effective subunit vaccine

 

2. Nucleoprotein antigen

• Induces complement fixing antibodies- Not protective in nature
• Important in diagnostic immunofluorescence testing

 

Resistance

• The rabies virus can be inactivated by lipid solvents (soap solutions, ether, chloroform, acetone), 1% sodium hypochlorite, 2% glutaraldehyde, 45-75% ethanol, iodine preparations, quaternary ammonium compounds, phenol, formalin, beta propionolactone  or a low pH.
• The virus is also susceptible to ultraviolet radiation or heat of 1 hour at 50°C.
• It is rapidly inactivated in sunlight, and it does not survive for long periods in the environment except in a cool dark area.
• Preserved at -70°C or by lyophilisation.

Host/Source of Infection

All warm blooded animals including man are susceptible to rabies.

The source of infection to man is the saliva of rabid animals.

Rabies in man is a dead-end infection.

Laboratory staff working with rabies virus, veterinarians, dog handlers, hunters face bigger risks of rabies.

Animals reported in India, include

Domestic:-Dogs & Cats, Sheep & Goats, Pigs, Donkeys, Horses, Camels

Wild:-Foxes & Jackals, Monkeys, Mongoose, Bears

 

Mode of transmission

1. Animal Bite: People are infected following a deep bite or scratch by an infected animal.

• Dogs are the main host and transmitter of rabies.
• Bats are the source of most human rabies deaths in the USA and Canada.

2. Licks-Licks on broken skin and mucosa can transmit the disease.

3. Aerosol- by inhalation of aerosol infected with virus

• In lab, personnel can become infected
• In caves, where rabid bats are present

4. Person to person (rare) - Human-to-human transmission is possible through corneal grafting because rabies antigen has been detected in the corneal cells of patients

 

Epidemiological cycles

• Rabies is maintained in two epidemiological cycles, - urban and sylvatic.
• In the urban rabies cycle, dogs are the main reservoir host. This cycle predominates in areas of Africa, Asia, and Central and South America where the proportion of unvaccinated and semi-owned or stray dogs is high. It has been virtually eliminated in North America and Europe; although sporadic cases occur in dogs infected by wild animals.

• The sylvatic (or wildlife) cycle is the predominant cycle in Europe and North America. It is also present simultaneously with the urban cycle in some parts of the world. The epidemiology of this cycle is complex; factors affecting it include the virus strain, the behavior of the host species, ecology and environmental factors.

Street Virus and Fixed Virus

The virus is excreted in the saliva of the affected animals.

The virus recovered from naturally occurring cases of rabies is called "street virus". It is pathogenic for all mammals and shows a long variable incubation period. It is capable of producing Negri bodies (intracytoplasmic eosinophilic inclusion body) in the neurons which is pathognomonic of rabies. Cause fatal encephalitis in 1-12 weeks.

pathognomonic (characteristic or indicative of a particular disease or condition)

Fixed virus- street virus when attenuated in the lab, after several serial intracerebral passages in rabbit brain is least virulent, more neurotropic and has short fixed incubation period (2-5) days. Virus isolated at this stage is called a fixed virus. It does not form Negri bodies. It no longer multiplies in extra-neural tissues. It has lost its pathogenicity on human being but retains its antigenicity. The fixed virus is used in the preparation of ant rabies vaccine. Intracerebral inoculation causes fatal encephalitis in a short period (2-5 days)

 Growth in Laboratories

• Chick embryos- virus inoculated in yolk sacs-serial propagation led to the development of attenuated vaccine strains Flury and Kelev
• Duck eggs- strains adapted to duck eggs, used in inactivated vaccine production
• Tissue culture- Primary and continuous cell cultures such as chick embryo fibroblast, porcine/hamster kidney- strains with not much cytopathic effects, but in low yield. Fixed virus strains adapted for growth in human diploid cell lines, chick embryo and Vero cell cultures- used in vaccine production

 Rabies- (Rabidus (L)=mad) 

Disease transmitted by the bite of “mad dogs”. 

Rabies virus demonstrated in the brain of infected animals by Pasteur in 1881. 

He obtained fixed virus by serial intracerebral passages in rabbits- pieces of spinal cord from rabbits dried for various periods- used as vaccine- In 1885, Joseph Meister (9-year-old)- course of 13 inoculations- first successful vaccination. 

Rabies in man is called hydrophobia-patient exhibits fear of water- incapable of drinking though subject to intolerable thirst (attempts to drink-painful spasms of pharynx and larynx- choking& gagging, dread at the sight and sound of water)

 Pathogenesis

• Rabies virus is excreted in saliva of rabid animal so, human acquire virus by the bite of rabid animals.
• Virus multiplies in muscle or connective tissue at the site of inoculation and then enter peripheral nerves at neuromuscular junction and spread up to the CNS.
• It spreads from the site of infection centripetally via the peripheral nerves towards the central nervous system.
• Following infection of the central nervous system, the virus spreads centrifugally in peripheral nerves to many tissues, including salivary glands. 

• Virus, however, can also enter directly into CNS without local multiplication.
• It multiplies in the grey matter in brain and propagates through efferent nerves to salivary gland and other tissues like kidney, heart, cornea, retina, pancreas.
• The highest titre of virus is seen in submaxillary gland (salivary gland)

The virus is neurotropic. Presence of virus in saliva and the irritability/aggression brought on by encephalitis ensure transmission and survival of virus in nature

• Rabies virus produces a specific eosinophilic cytoplasmic inclusion with basophilic granules called the Negri bodies in the brain of animals
• The Negri body is filled with viral nucleocapsid and forms the pathognomonic basis of rabies diagnosis.

Incubation period

Susceptibility to rabies infection and incubation period may depend on host age, genetic makeup, immunity, viral strain involved, inoculum size and the distance virus has to travel from the point of entry to CNS.

The incubation period in man is highly variable, commonly 1-3 months but may be as short as  weeks to as long as many years. It is usually shorter in children than in adults.

   The incubation period depends on the

• Site of the bite,
• severity of the bite,
• number of wounds,
• amount of virus injected,
• species of the biting animal,
• protection provided by the clothing and
• treatment undertaken, if any.

In general, incubation period tends to be shorter in severe

• exposures and bites on face, head, neck and upper extremities
• and bites by wild animals.

Clinical spectrum of rabies can be divided into three phases.

Prodromal phase: It lasts for 2-10days and is characterized by any of the following non-specific symptoms, malaise, anorexia, headache, photophobia, nausea and vomiting. There is pain and tingling or numbness at the site of the bite.

Acute neurological (Encephalitic) phase: It lasts for 2-7 days and is characterized by the presence of nervous system disorder like nervousness, apprehension, hallucination, lacrimation, pupillary dilation, and increased salivation, hydrophobia and painful throat muscles. 

Widespread excitation and stimulation of all parts of nervous system involving, the sensory system, the motor system, the sympathetic and mental system.

The patient is intolerant to noise, bright light (photophobia) or air (aerophobia).

Mental changes include fear of death, anger, irritability and depression. 

Swallowing liquid become unsuccessful. At later stage the mere sight or sound of water may provoke spasm of the muscles of deglutition. This characteristic symptom of hydrophobia (fear of water) is pathognomic of human rabies and is absent in animals.

The duration of illness is 2 to 3 days, but may be prolonged to 5-6 days in exceptional cases.

Coma and death:  Neurological phase is followed by coma and death. Death is due to respiratory arrest, convulsion or choking.

Paralytic rabies: In about 20% cases, muscle weakness is prominent - flaccid paralysis at the site of bite, quadriparesis (weakness in both arms and both legs) and facial weakness in 2-10days. Ultimately, multi organ failure, death. 

Lyssaphobia/Hydrophobiophobia -Persons exposed to real/imaginary risk of rabies. Psychological disorder- anxiety, irritability and exaggerated hydrophobia; afebrile- need sedation and reassurance

Rabies in Dogs

Incubation period- 3-6 weeks. 

Prodromal stage - Alert/troubled appearance, restlessness, snapping at imaginary objects, licking, gnawing at the site of bite etc.

Then, dogs may manifest either of the two types of rabies- dumb or furious rabies. Both equally infectious

Dumb rabies- paralytic form- animal lied huddled- no feeding- may not bite, but attempts to feed can be dangerous.

Furious rabies- Runs wild, bite without provocation and indiscriminately. Lower jaw drops- saliva drooling from mouth- paralysis, convulsions and death follow

Rabid dogs usually die in 3-5 days.