Rabies virus
Encyclopedia
Neurotropic virus
A neurotropic virus is a virus which is capable of infecting nerve cells, or which does so preferentially. Such viruses thereby largely evade the usual immune response—which acts only within the blood system.- Terminology :...
that causes fatal disease in human and animals. Rabies transmission
Rabies transmission
Rabies may be transmitted through the saliva of animals.Transmission between humans is extremely rare, although it can happen through transplant surgery, or, even more rarely, through bites, kisses or sexual relations....
can occur through the saliva of animals.
The rabies virus has a cylindrical morphology and is the type species
Type species
In biological nomenclature, a type species is both a concept and a practical system which is used in the classification and nomenclature of animals and plants. The value of a "type species" lies in the fact that it makes clear what is meant by a particular genus name. A type species is the species...
of the Lyssavirus
Lyssavirus
Lyssavirus is a genus of viruses belonging to the family Rhabdoviridae, in the order Mononegavirales. This group of RNA viruses includes the Rabies virus traditionally associated with the disease.-Structure:Viruses typically have either helical or cubic symmetry...
genus
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...
of the Rhabdoviridae
Rhabdoviridae
Rhabdoviruses are viruses belonging to the family Rhabdoviridae, which is in the order Mononegavirales. The name is derived from the Greek rhabdos meaning rod referring to the shape of the viral particles. Rhabdoviruses infect a broad range of hosts throughout the animal and plant kingdoms...
family. These viruses are enveloped
Viral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...
and have a single stranded RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
genome with negative-sense. The genetic information is packaged as a ribonucleoprotein
Ribonucleoprotein
Ribonucleoprotein is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together. A few known examples include the ribosome, the enzyme telomerase, vault ribonucleoproteins, and small nuclear RNPs , which are implicated in pre-mRNA splicing and...
complex in which RNA is tightly bound by the viral nucleoprotein. The RNA genome of the virus encodes five genes whose order is highly conserved. These genes code for nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and the viral RNA polymerase (L).
All transcription and replication events take place in the cytoplasm inside a specialized “virus factory“, the Negri body
Negri bodies
Negri bodies are eosinophilic, sharply outlined, pathognomonic inclusion bodies found in the cytoplasm of certain nerve cells containing the virus of rabies, especially in Ammon's horn of the hippocampus. Often also found in the cerebellar cortex of postmortem brain samples of rabies victims.They...
(named after Adelchi Negri
Adelchi Negri
Adelchi Negri was an Italian pathologist and microbiologist who was born in Perugia. He studied medicine and surgery at the University of Pavia, where he was a pupil of Camillo Golgi . After graduation in 1900, he became an assistant to Golgi at his pathological institute...
). These are 2–10 µm
Micrometre
A micrometer , is by definition 1×10-6 of a meter .In plain English, it means one-millionth of a meter . Its unit symbol in the International System of Units is μm...
in diameter and are typical for a rabies infection and thus have been used as definite histological proof of such infection
Pathognomonic
Pathognomonic is a term, often used in medicine, that means characteristic for a particular disease. A pathognomonic sign is a particular sign whose presence means that a particular disease is present beyond any doubt...
.
Structure
Lyssaviruses have helical symmetry, so their infectious particles are approximately cylindrical in shape. They are characterized by an extremely broad host spectrum ranging from plants to insects and mammals; human-infecting viruses more commonly have cubic symmetry and take shapes approximating regular polyhedraRegular polyhedron
A regular polyhedron is a polyhedron whose faces are congruent regular polygons which are assembled in the same way around each vertex. A regular polyhedron is highly symmetrical, being all of edge-transitive, vertex-transitive and face-transitive - i.e. it is transitive on its flags...
.
The virus has a bulletlike 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
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
envelope carries knob-like spikes composed of Glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
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
Ribonucleoprotein
Ribonucleoprotein is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together. A few known examples include the ribosome, the enzyme telomerase, vault ribonucleoproteins, and small nuclear RNPs , which are implicated in pre-mRNA splicing and...
.
Life cycle
After receptor binding, rabies virus enters its host cells through the endosomalEndosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...
transport pathway. Inside the endosome, the low pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
value induces the membrane fusion process, thus enabling the viral genome to reach the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
. Both processes, receptor binding and membrane fusion, are catalyzed by the glycoprotein G which plays a critical role in pathogenesis (mutant virus without G proteins cannot propagate).
The next step after entry is the transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of the viral genome by the P-L polymerase (P is an essential cofactor for the L polymerase) in order to make new viral protein. The viral polymerase can only recognize ribonucleoprotein
Ribonucleoprotein
Ribonucleoprotein is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together. A few known examples include the ribosome, the enzyme telomerase, vault ribonucleoproteins, and small nuclear RNPs , which are implicated in pre-mRNA splicing and...
and cannot use free RNA as template. Transcription is regulated by cis-acting sequences
Cis-regulatory element
A cis-regulatory element or cis-element is a region of DNA or RNA that regulates the expression of genes located on that same molecule of DNA . This term is constructed from the Latin word cis, which means "on the same side as". These cis-regulatory elements are often binding sites for one or...
on the virus genome and by protein M which is not only essential for virus budding but also regulates the fraction of mRNA production to replication.
Later in infection, the activity of the polymerase switches to replication in order to produce full-length positive-strand RNA copies. These complementary RNAs are used as templates to make new negative-strand RNA genomes. They are packaged together with protein N to form ribonucleoprotein
Ribonucleoprotein
Ribonucleoprotein is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together. A few known examples include the ribosome, the enzyme telomerase, vault ribonucleoproteins, and small nuclear RNPs , which are implicated in pre-mRNA splicing and...
which then can form new viruses.
Infection
In September 1931, Dr. Poupe Charles Jones of TrinidadTrinidad
Trinidad is the larger and more populous of the two major islands and numerous landforms which make up the island nation of Trinidad and Tobago. It is the southernmost island in the Caribbean and lies just off the northeastern coast of Venezuela. With an area of it is also the fifth largest in...
in the West Indies, a Government Bacteriologist, found Negri bodies
Negri bodies
Negri bodies are eosinophilic, sharply outlined, pathognomonic inclusion bodies found in the cytoplasm of certain nerve cells containing the virus of rabies, especially in Ammon's horn of the hippocampus. Often also found in the cerebellar cortex of postmortem brain samples of rabies victims.They...
in the brain of a bat with unusual habits. He said that a rabies virus was key to the curing of Lyssophobia. In 1932, Dr. Russ Pfister first discovered that infected vampire bats could transmit rabies to humans and other animals.
From the wound of entry, the rabies virus travels quickly along the neural pathways to the noncentral nervous system (nCNS). The retrograde axonal transport
Axoplasmic transport
Axoplasmic transport, also called axonal transport, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other cell parts to and from a neuron's cell body, through the cytoplasm of its axon...
of the rabies virus to the CNS is the key step of pathogenesis during natural infection. The exact molecular mechanism of this transport is unknown although binding of the P protein from rabies virus to the dynein
Dynein
Dynein is a motor protein in cells which converts the chemical energy contained in ATP into the mechanical energy of movement. Dynein transports various cellular cargo by "walking" along cytoskeletal microtubules towards the minus-end of the microtubule, which is usually oriented towards the cell...
light chain protein DYNLL1
DYNLL1
Dynein light chain 1, cytoplasmic is a protein that in humans is encoded by the DYNLL1 gene.-Interactions:DYNLL1 has been shown to interact with DLGAP1, MYO5A, DYNC1I1, BCL2L11, NRF1, IκBα, PAK1, DLG4 and TP53BP1.-Further reading:...
has been shown. P also acts as an interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
antagonist, thus decreasing the immune response of the host.
From the CNS, the virus further spreads to other organs. The salivary glands located in the tissues of the mouth and cheeks receive high concentrations of the virus, thus allowing it to be further transmitted due to projectile salivation. Fatality can occur from two days to five years from the time of initial infection. This however depends largely on the species of animal acting as a reservoir
Natural reservoir
Natural reservoir or nidus, refers to the long-term host of the pathogen of an infectious disease. It is often the case that hosts do not get the disease carried by the pathogen or it is carried as a subclinical infection and so asymptomatic and non-lethal...
. Most infected mammals die within weeks, while strains of a species such as the African Yellow Mongoose
Yellow Mongoose
The Yellow Mongoose , sometimes referred to as the Red Meerkat, is a small mammal averaging about 1 lb in weight and about 20 in in length...
(Cynictis penicillata) might survive an infection asymptomatically for years.
Antigenicity
Upon viral entry into the body and also after vaccination, the body produces virus neutralizing antibodies which bind and inactivate the virus. Specific regions of the G proteinhave been shown to be most antigenic in leading to the production of virus neutralizing antibodies. These antigenic sites, or epitopes, are categorized into regions I-IV and minor site a. Previous work has demonstrated that antigenic sites II and III are most commonly targeted by natural neutralizing antibodies. Additionally, a monoclonal antibody with neutralizing functionality has been demonstrated to target antigenic site I. Other proteins, such as the nucleoprotein, have been shown to be unable to elicit production of virus neutralizing antibodies. The epitopes which bind neutralizing antibodies are both linear and conformational.