Rhabdoviruses are causative agents of rabies and vesicular stomatitis

Rabies is an acute infectious disease caused by a rhabdovirus that occurs when a person is bitten by a sick animal or when the saliva of a sick animal comes into contact with damaged skin or mucous membranes. This infection of the central nervous system is almost always fatal.

The first mentions of a disease transmitted through a dog bite and very similar in description to rabies are found in cuneiform clay tablets of Ancient Mesopotamia, dating back to the 3rd millennium BC. The virus was isolated and attenuated by passages on the brain of a rabbit in 1882 by I. Pasteur.

Vesicular stomatitis - a disease of horses, cattle and pigs, sometimes humans, which proceeds benignly - is also caused by a rhabdovirus. This virus is weakly pathogenic for humans. It has been studied better than all rhabdoviruses.

[ 1 ], [ 2 ], [ 3 ]

Life cycle

Rhabdoviruses are a family that includes three genera: Vesiculovirus (10 mammalian viruses, the typical one being the vesicular stomatitis virus, or VSV); yssavirus (6 serologically related viruses, the typical one being the rabies virus); Sigmavirus (the only representative being the sigma-Drosophila virus). Six viruses that cause fish diseases and 13 viruses that affect plants remain unclassified. Rhabdoviruses are characterized by a rod-shaped or bullet-shaped virion: 60-400 nm long and 60-85 nm wide. The particles are surrounded by a two-layer lipid membrane-like membrane with protruding spikes 10 nm long and 3 nm wide. Under the membrane is a ribonucleocapsid with a helical type of symmetry, in which stripes are visible under an electron microscope. The genome of rhabdoviruses is represented by a negative single-stranded linear non-fragmented RNA molecule with a molecular weight of 3.8 MDa; five genes encoding the synthesis of structural proteins have been found, and the order of their arrangement has been determined. At the 3'-end is the gene of the nucleocapsid protein N (50 kDa). It is followed by the gene of the NSV protein (30 kDa), one of the components of the viral transcriptase, which is part of the nucleocapsid. The next gene codes for the matrix protein M (30 kDa) and lining the bilayer lipid membrane from the inside. Next comes the gene of the protein G (65 kDa), the external glycoprotein of the viral supercapsid. At the 5'-end is the gene of the high-molecular component of the viral transcriptase, the protein L (160 kDa).

The interaction of rhabdoviruses with cells and their reproduction occur according to the following scheme: adsorption of the virus on the cell (glycoprotein G) - penetration into the cell by endocytosis - fusion with the lysosome membrane - deproteinization of the virus. Under the action of virion transcriptase (RNA polymerase), cRNA is formed, which serves as a matrix for the synthesis of vRNA and performs the function of mRNA. Then virus-specific proteins are synthesized on the ribosomes of the host cell. Proteins M and G are embedded in the plasma membrane. The nucleocapsid formed during the interaction of vRNA with proteins N, L and NS, passing through the membrane, is enveloped by a supercapsid. The mature virion separates from the cell by budding.

The rabies virus is very similar to the vesicular stomatitis virus in its structure and intracellular reproduction features. An important feature of these viruses is the pronounced inhibition of protein biosynthesis processes in the host cell by blocking the initiation of translation. There are several serovariants of vesicular stomatitis viruses that differ in the G protein, which is also a protective antigen.

The viruses reproduce well in chicken embryos, newborn hamster kidney cells, and in human diploid cell cultures. In cell cultures, the vesicular stomatitis virus usually causes cytopathic effects and cell death, and sometimes symplastogenesis.

The rabies virus has a wide range of hosts. All warm-blooded animals are sensitive to it. The degree of pathogenicity of different strains of rabies viruses for different animals is not the same. In some species of bats, the virus has adapted only to the salivary glands, without causing signs of disease; infection of other animals always leads to death.

Strains of rabies viruses circulating in nature among animals are called street strains. They cause diseases with a fairly long incubation period and usually form specific inclusion bodies in the cytoplasm of cells. Infected animals may experience a long period of agitation and aggressiveness. The virus can penetrate the salivary glands and the central nervous system. Successive passages in the brain of rabbits lead to the formation of a fixed virus that is unable to reproduce further in any cells except nerve cells. The fixed virus reproduces quickly, the incubation period is short, inclusions in cells are rarely found. This virus is pathogenic only for rabbits.

The rabies virus is not very stable in the external environment, it is quickly inactivated when exposed to ultraviolet rays or sunlight. When boiled, it dies after 2 minutes, at 60 °C - after 5 minutes. It is quickly inactivated by solutions of lysol, chloramine, phenol, fat solvents and trypsin. In animal corpses, especially at low temperatures, it survives for up to 4 months.

Immunity

Since rabies is fatal, post-infection immunity has not been studied. It has been established that antibodies can form during the disease and after vaccination. Post-vaccination immunity lasts up to 1 year.

Epidemiology of rabies

Rabies is a typical zoonotic disease. The main source and reservoir of the virus are wild and domestic carnivores: dogs, cats, wolves, jackals, foxes, skunks, mongooses, bats. The disease is usually transmitted through a bite or by drooling on damaged skin or mucous membranes, as the virus multiplies in the salivary glands of the animal. A sick animal is contagious not only during the illness, but also during the incubation period of 2-3 days, sometimes more, before the first signs of the disease appear.

[ 4 ], [ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ]

Symptoms of rabies

Primary reproduction of the rabies virus occurs in muscle tissue near the entry gates, then the pathogen penetrates into the receptors of peripheral sensory nerves and enters the central nervous system via the endoneurium of Schwann cells or perineural spaces. There, the virus reproduces in the neurons of the hippocampus, medulla oblongata, cranial nerves, and sympathetic ganglia, causing inflammatory, dystrophic, and necrotic changes in the nervous system. During this period, the virus also reproduces in the cells of the salivary glands.

The shortest incubation period occurs with bites to the head and hands, longer - with bites to the lower extremities; in general, it varies from 8 to 90 days. Three stages are distinguished in the development of the disease: precursors (depression), excitement, paralysis. At first, anxiety, fear, anxiety, unpleasant sensations in the area of the bite appear. After 1-3 days, pronounced excitement, spasms of the respiratory and swallowing muscles occur, pronounced hydrophobia appears (hydrophobia is the second name for this disease). Aggression, auditory and visual hallucinations are characteristic of this period. Then paralysis develops, and after 5-7 days from the onset of the disease, death occurs from paralysis of the cardiac or respiratory centers.

Laboratory diagnostics of rabies

Rabies is diagnosed using virusoscopic, biological and serological methods. Brain tissue (cerebral cortex and cerebellum, Ammon's horn, medulla oblongata) and salivary gland tissue are examined in histological sections or smears of dead animals and humans. Specific eosinophilic inclusions (Babesh-Negri bodies) are found in the pyramidal cells of the brain tissue. They are located in the cytoplasm near the nucleus and are clusters of viral nucleocapsids. Their appearance is due to the difficult maturation of virions in nerve cells. Babesh-Negri bodies are detected using special staining methods (Romanovsky-Giemsa, Mann, Turevich, Muromtsev, etc.). They have a characteristic granular structure with basophilic granules on an acidophilic background, their size is 4-10 μm. The disadvantage of this method is that it can only be used after the death of a person or animal.

Viral antigen can be detected in the same preparations using direct or indirect immunofluorescence reaction.

The rabies virus can be isolated from the saliva of sick people or animals, as well as from fresh autopsy material (brain tissue, submandibular salivary gland tissue) by intracerebral infection of white mice and rabbits or hamsters - intramuscularly. The animals develop paralysis followed by death. The brain of a dead animal should be examined to detect Babes-Negri bodies or viral antigen using the immunofluorescence reaction.

Antibodies can be detected in vaccinated individuals using neutralization, complement fixation, immunofluorescence, and immunosorbent reactions (RIM and IFM).

Specific prevention and treatment of rabies

Rabies prevention consists of combating rabies in animals and preventing the development of the disease in people who have been bitten or licked by a sick animal. The program for eliminating rabies in land animals must be considered in two aspects:

1. eradication of urban canine rabies and
2. improvement of natural foci of rabies infection.

The experience of many countries convincingly proves the possibility of controlling urban epizootics by registering and immunizing dogs. However, for the complete elimination of rabies infection, it is necessary to improve its natural foci, and the extermination of wild carnivores gives only a temporary and local result and threatens the development of undesirable environmental consequences. Abroad, there is already a large positive experience of preventing rabies among wild animals (foxes, raccoons) by feeding them baits containing the vaccine. Oral anti-rabies vaccines are considered very promising in this regard: a live modified whole-virion vaccine from attenuated vaccine strains (SAD-Bern, Vnukovo-32) and a recombinant genetically engineered oral vaccine using the vaccinia virus as a vector, expressing the rabies virus G-protein gene.

In case of bites or drooling, it is necessary to thoroughly wash the wound or skin at the site of saliva contact with soapy water, cauterize the wound with an alcohol solution of iodine and begin specific prophylaxis with an anti-rabies vaccine and anti-rabies gamma globulin. Instead of the previously used highly reactogenic Fermi vaccine (from the brain tissue of sheep infected with a fixed virus), an anti-rabies inactivated culture vaccine against rabies is now recommended for disease prevention, which is made on a cell culture infected with an attenuated rabies virus (strain Vnukovo-32). Emergency therapeutic and prophylactic vaccination is carried out with a vaccine or a vaccine in combination with anti-rabies gamma globulin according to the schemes specified in the instructions for their use. The vaccination scheme is determined by the severity of the bite, its localization, the time elapsed since the bite, information about the biting animal and other circumstances.