Rabies virus
Rabies virus, scientific name Rabies lyssavirus, is a neurotropic virus that causes rabies in animals, including humans. Rabies transmission can occur through the saliva of animals and less commonly through contact with human saliva. Rabies lyssavirus, like many rhabdoviruses, 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.[2] Rabies is reported in more than 150 countries and on all continents except Antarctica.[3] 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.[4]
This article is about the virus. For the disease, see Rabies. For other uses, see Rabies (disambiguation).
Rabies lyssavirus has a cylindrical morphology and is a member of the Lyssavirus genus of the Rhabdoviridae family. These viruses are enveloped 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).[5] The complete genome sequences range from 11,615 to 11,966 nt in length.[6]
All transcription and replication events take place in the cytoplasm inside a specialized "virus factory", the Negri body (named after Adelchi Negri[7]). These are 2–10 μm in diameter and are typical for a rabies infection and thus have been used as definite histological proof of such infection.[8]
Life cycle[edit]
After receptor binding, Rabies lyssavirus enters its host cells through the endosomal transport pathway. Inside the endosome, the low pH value induces the membrane fusion process, thus enabling the viral genome to reach the cytosol. 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).[5]
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.[8]
Signs and symptoms[edit]
The first symptoms of rabies may be very similar to those of the flu, including general weakness or discomfort, fever, or headache. These symptoms may last for days. There may be also discomfort or a prickling or itching sensation at the site of bite, progressing within days to symptoms of cerebral dysfunction, anxiety, confusion, and agitation. At the onset of these progressive symptoms, the disease begins to worsen. As the disease progresses, the person may experience delirium, abnormal behavior, hallucinations, and insomnia. Rabies lyssavirus may also be inactive in its host's body and become active after a long period of time.[28]
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.[29] 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 systems like headache, vertigo, anxiety, nightmares, depression, and more. The neurological dysfunction starts when the central nervous system begins to slow and not function properly.[30]
Classification and antigenic types[edit]
The Lyssavirus genome includes a variety of viruses ranging from the rabies virus to genetically and anti-genetically rabies-like related viruses. These viruses include Lagos Bat, Mokola, and Duvenhage viruses, as well as European bat viruses.[30] Through other anti-genetic characterization, over 350 rabies viruses of just the Americas were discovered. Four phylogenetic groups were associated with these viruses. Additionally, other areas of ciruculation for the virus, such as E. fuscus, were found through this discovery.[31] Although these viruses are from the same genome, cross-protection studies show that animals that had taken the Lyssavirus vaccine for traditional rabies were not fully protected when exposed to other types of Lyssavirus.
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.[32] This suggested sources of exposure even when the bite was missing from patient history.
Antigenicity[edit]
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 protein have 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.[33] Additionally, a monoclonal antibody with neutralizing functionality has been demonstrated to target antigenic site I.[34] Other proteins, such as the nucleoprotein, have been shown to be unable to elicit production of virus neutralizing antibodies.[35] The epitopes which bind neutralizing antibodies are both linear and conformational.[36]
Evolution[edit]
All extant rabies viruses appear to have evolved within the last 1500 years.[37] There are seven genotypes of Rabies lyssavirus. In Eurasia, cases are due to three of these: genotype 1 (classical rabies) and to a lesser extent genotypes 5 and 6 (European bat lyssaviruses type-1 and -2).[38] Genotype 1 evolved in Europe in the 17th century and spread to Asia, Africa, and the Americas as a result of European exploration and colonization.
Bat rabies in North America appears to have been present since 1281 AD (95% confidence interval: 906–1577 AD).[39]
The rabies virus appears to have undergone an evolutionary shift in hosts from Chiroptera (bats) to a species of Carnivora (i.e. raccoon or skunk) as a result of an homologous recombination event that occurred hundreds of years ago.[40] This recombination event altered the gene that encodes the virus glycoprotein that is necessary for receptor recognition and binding.
Application[edit]
Rabies lyssavirus is used in research for viral neuronal tracing to establish synaptic connections and directionality of synaptic transmission.[41]
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.[42]