Rabies pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The rabies virus is categorized as a Lyssavirus. The molecular biology of rabies consists of bullet shaped virus with helical symmetry that has a length of approximately 180 nm. Rabies typically has its greatest effect on the brain. It is typically defined by encephalitis and myelitis. It is very important to avoid being bitten by a rabid animal because the virus is typically transmitted through the saliva of an infected organism.

Pathophysiology

The organism causing rabies is called Rabies virus (RV), a negative-stranded RNA virus of the rhabdovirus family. Rabies is an acute encephelomyelitis that causes disease in the human host via two features associated with the Rabies virus (RV):

• Neurotropism
• Neuroinvasiveness

Transmission

Common route of tranmission

• Various carnivorous animal species have been identified as the source of Rabies virus (RV)

• In Africa and Asia, domestic dogs are the main reservoirs of infection from Rabies virus
• In the United States, racoons, foxes, skunks, coyotes, possums and bats rather than dogs spread the infection through bites
• Three stages of rabies have been known to occurr in dogs. The first stage is a one to three day period characterized by behavioral changes and is known as the prodromal stage. The second stage is the excitative stage, which lasts three to four days. It is this stage that is often known as furious rabies due to the tendency of the affected dog to be hyper-reactive to external stimuli and bite at anything near. The third stage is the paralytic stage and is caused by damage to motor neurons. Incoordination is seen due to rear limb paralysis and drooling and difficulty swallowing is caused by paralysis of facial and throat muscles. Death is usually caused by respiratory arrest.
• Transmission of the Rabies virus starts when a human is bit by an animal harboring the virus in its salivary glands
• The RV remains cell-free after initial inoculation because rigorous wound cleaning may reduce the chances of infection
• RV infects peripheral nerves and then reaches the central nervous system (CNS) via retrograde axonal transport

The infectious path of rabies virus in a raccoon

Less common routes of transmission

• Less common routes of transmission include:
  • Contamination of mucous membranes (i.e., eyes, nose, mouth)
  • Aerosol transmission
  • Corneal and other organ transplantation from infected donor

Virology

The rabies virus (RV) belongs to the genus Lyssavirus. This genus of RNA viruses also includes the Aravan virus, Australian bat lyssavirus, Duvenhage virus, European bat lyssavirus 1, European bat lyssavirus 2, Irkut virus, Khujand virus, Lagos bat virus, Mokola virus and West Caucasian bat virus. Lyssaviruses have helical symmetry, so their infectious particles are approximately cylindrical in shape.

• The virus has a bullet-like shape with a length of about 180 nm and a cross-sectional diameter of about 75 nm
• One end is rounded or conical and the other end is planar or concave
• The lipoprotein envelope carries knob-like spikes composed of Glycoprotein G. Spikes do not cover the planar end of the virion (virus particle)
• Beneath the envelope is the membrane or matrix (M) protein layer which may be invaginated at the planar end. The core of the virion consists of helically arranged ribonucleoprotein
• The genome is unsegmented linear antisense RNA. Also present in the nucleocapsid are RNA dependent RNA transcriptase and some structural proteins

 
Longitudinal and cross-sectional schematic view of rabies virus

Pathogenesis

Incubation period and eclipse phase

• The incubation period may vary from a few days to several years, but is typically 1 to 3 months
• After gaining entry into human host, the RV enters into an eclipse phase, during which, the host immune defenses may confer cell-mediated immunity against viral infection because RV is a good antigen

Neuromuscular junction invasion

• The neuromuscular junction is the major site of entry into neurons
• The RV uses the acetylcholine receptors and other receptors such as the neutral cell adhesion molecule (NCAM) to gain entry into the neuron via endocytosis
• Fusion of the viral membrane with endosomal membranes liberates the viral nucleocapsid into the cytosol, where transcription and replication occur

Inter-neuronal spread

• The main mechanism involved in the neuroinvasion of RV is trans-synaptic neuronal spread
• The following proteins lead to the spread of virus between the neurons, once the virus gains entry into the body:
  • Rabies virus G protein: RV to spread from the post-synaptic site to the pre-synaptic site
  • Rabies virus P protein: important determinant of retrograde transport of the virus within axons

CNS invasion

• Trans-synaptic neuronal spread leads to spread of infection to the CNS from the peripheral nerves
• RV forms cytoplasmic inclusion bodies called Negri bodies in the neurons, which are composed of the viral N and P proteins (all viral RNAs genome, antigenome, and every mRNA have been known to be found inside the inclusion bodies- suggesting that they play a role in viral replication and life cycle)
• RV infects neurons and leads to degeneration of the neuronal processes by disrupting cytoskeletal integrity
• The hypothalamus has been known to be affected most severely by RV infection

Microscopic Pathology

Histologic examination of biopsy or autopsy tissues is occasionally useful in diagnosing unsuspected cases of rabies that have not been tested by routine methods. When brain tissue from rabies virus-infected animals are stained with a histologic stain, such as hematoxylin and eosin, evidence of encephalomyelitis may be recognized by a trained microscopist. This method is nonspecific and not considered diagnostic for rabies.

Before current diagnostic methods were available, rabies diagnosis was made using this method and the clinical case history. In fact, most of the significant histopathologic features (changes in tissue caused by disease) of rabies infection were described in the last quarter of the 19th century. After Louis Pasteur's successful experiments with rabies vaccination, scientists were motivated to identify the pathologic lesions of rabies virus.

Histopathologic evidence of rabies encephalomyelitis (inflammation) in brain tissue and meninges includes the following:

1. Mononuclear infiltration
2. Perivascular cuffing of lymphocytes or polymorphonuclear cells
3. Lymphocytic foci
4. Babes nodules consisting of glial cells
5. Negri bodies

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