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Rabies virus ( Lyssavirus rabies) is a neurotropic virus that causes rabies in animals, including humans. It can cause violence, hydrophobia, and fever. Rabies transmission can also occur through the saliva of animals and less commonly through contact with human saliva. Rabies virus, like many Rhabdoviridae, has an extremely wide host range. In the wild it has been found infecting many mammalian species, while in the laboratory it has been found that birds can be infected, as well as cell cultures from mammals, birds, reptiles and insects. (2025). 9780470023860, Wiley. ISBN 9780470023860 Rabies is reported in more than 150 countries and on all continents except Antarctica. The main burden of disease is reported in Asia and Africa, but some cases have been reported also in Europe in the past 10 years, especially in returning travellers.
Rabies virus has a cylindrical morphology and is a member of the Lyssavirus genus of the Rhabdoviridae family. These viruses are Viral envelope and have a single stranded RNA genome with negative-sense. The genetic information is packaged as a ribonucleoprotein 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). The complete genome sequences range from 11,615 to 11,966 nt in length.
All transcription and replication events take place in the cytoplasm inside a specialized "virus factory", the Negri bodies (named after Adelchi Negri). These are 2–10 micrometre in diameter and are typical for a rabies infection and thus have been used as pathognomonic.
The rabies genome encodes five proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and polymerase (L). All rhabdoviruses have two major structural components: a helical ribonucleoprotein core (RNP) and a surrounding envelope. In the RNP, genomic RNA is tightly encased by the nucleoprotein. Two other viral proteins, the phosphoprotein and the large protein (L-protein or polymerase) are associated with the RNP. The glycoprotein forms approximately 400 trimeric spikes which are tightly arranged on the surface of the virus. The M protein is associated both with the envelope and the RNP and may be the central protein of rhabdovirus assembly. CDC Rabies virus Structure 26 May 2016
Rabies virus has a bullet-like shape with a length of about 180 nanometer 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 Invagination at the planar end. The core of the virion consists of helically arranged ribonucleoprotein.
| +List of Rabies virus ORFs (3′ to 5′) |
| Coats the RNA. |
| L cofactor and various regulatory functions. Has many isoforms from multiple initiation. |
| Keeps nucleoprotein condensed. Important for assembly; has roles in regulation. |
| Spike. Uses muscular nAChR, NCAM, and p75NTR as receptors. |
| RNA replicase of the Mononegavirales type. |
Rabies virus is estimated to cause around 55,000 deaths per year across the world and has a death rate of nearly 100%. These statistics coupled with the fact that there is currently no specific treatment, or antiviral drug makes research on the virus of vital importance for the scientific community in order to possibly lower the current death rate. The rabies virus phosphoprotein and polymerase are both important targets for and are currently used to create the vaccine used for domestic and wild animals. A lot of research is being done to better understand the specific roles and functions of the L-P protein because there is significant evidence already that it could be one of the most important proteins to target for future drugs.
There are five proteins that are coded for by the rabies virus genome—phosphoprotein (P), polymerase (L), matrix protein (M), nucleoprotein (N), and glycoprotein (G). These five proteins are transcribed into mRNA in different quantities. The protein transcribed the most is the nucleoprotein, then the phosphoprotein, then the matrix protein, then the glycoprotein and finally the polymerase. Of those proteins, the ones that may be the most important for the functions of the virus are the L-P protein complex. These two proteins are required for the production of all of the proteins utilized by the rabies virus and they interact with many of the other proteins to complete the functions needed by the virus to infect cells, replicate and complete other vital functions. When the structure of the L-P protein was analyzed using UCSF Chimera, it was found that it contained two zinc molecules as well as 2 five-membered rings. The secondary structures were also analyzed, and it was found that there were three different kinds-coil, helix and strand.
The next step after its entry is the transcription 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 and cannot use free RNA as template. Transcription is regulated by cis-acting sequences 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 which then can form new viruses.
Rabies virus initially replicates in muscle tissue following a bite before entering neurons through their nerve endings and spreading to the nervous system. The retrograde axonal transport of Rabies virus to the central nervous system (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 light chain protein DYNLL1 has been shown. P also acts as an interferon 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. Most infected mammals die within weeks, while strains of a species such as the African yellow mongoose ( Cynictis penicillata) might survive an infection asymptomatically for years.
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The incubation period for this virus, in some cases, can last anywhere from weeks to months. This does not depend on specific form of the virus. This long incubation period is most likely due to the presence of microRNA, which slow down viral replication in the muscles. However, when the patient starts to exhibit prodromal symptoms (fever, flu) and gastrointestinal symptoms, the virus has widely spread. Prodromal symptoms are noted within the first 2–10 days after incubation and include fever and fatigue. They can also involve the respiratory system, causing sore throat and cough, the gastrointestinal system, causing anorexia, nausea, vomiting, abdominal pain, diarrhea, and central nervous system. The central nervous system is the most prevalent in some cases and includes symptoms like headache, vertigo, anxiety, nightmares, depression, and more. The neurological dysfunction starts when the central nervous system begins to slow and not function properly.
This leads to different categorization of these Rabies viruses. A fixed classification denotes that the virus was adapted by passage in animals or cell culture. Wild type classification, more generally known as street type, implies the virus was adapted through other means, such as a bite. To differentiate street rabies variants, monoclonal antibodies identified origins in host reservoirs throughout the world. This suggested sources of exposure even when the bite was missing from patient history.
Bat rabies in North America appears to have been present since 1281 AD (95% confidence interval: 906–1577 AD).
The rabies virus appears to have undergone an evolutionary shift in hosts from Chiroptera () to a species of Carnivora (i.e. raccoon or skunk) as a result of a homologous recombination event that occurred hundreds of years ago.Ding NZ, Xu DS, Sun YY, He HB, He CQ. A permanent host shift of rabies virus from Chiroptera to Carnivora associated with recombination. Sci. Rep. 2017;7:1–9. doi: 10.1038/s41598-016-0028-x. This recombination event altered the gene that encodes the virus glycoprotein that is necessary for receptor recognition and binding.
Recent research is focused on stabilizing the trimeric pre-fusion form of the rabies virus glycoprotein (RABV-G), which is the most immunogenic conformation of the protein. Mutations like H270P and H261L enhance the stability of this form, making it a more effective immunogen. This approach aims to develop vaccines that are both more cost-effective and have better protective coverage, addressing the ongoing global need for rabies prevention.
Interestingly, the rabies virus vaccine that was created using the SAD-B19 complex, which includes the L-P protein, was utilized in the creation of a vaccine for SARS-CoV-2. The S1 protein from SARS-CoV-2 was inserted into the rabies virus vaccine vector to create a new vaccine that was shown to be effective in protecting against COVID-19. Rabies virus has also been used to create a vaccine against Ebola, called FiloRab1, and it was found to be 100% effective for nonhuman primates.
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