Rabies virus (RABV)

According to data released by the World Health Organization, rabies is endemic in 150 countries around the world, and 59,000 people die from rabies every year, and about 1 person dies of rabies every 9 minutes in the world, and 99% of these deaths are caused by dog bites. Rabies is a rapidly progressive zoonotic disease caused by the rabies virus. It mainly violates the central nervous system (CNS) of humans and animals, and is divided into manic and paralytic types, with a fatality rate of nearly 100%.

What is rabies virus(RABV)?

RABV belongs to the Rhabdoviridae family. Rabies virus particles are bullet-shaped, 100-300 nm long and about 75 nm in diameter. Broadly speaking, rabies virus is often referred to as RABV. RABV is not the only cause of rabies, with the International Commission on Taxonomy of Viruses (ICTV) identifying 14 rabies viruses in 2014.

Structure of Rabies virus

Rabies virus particles are bullet-shaped, 100-300nm long and about 75nm in diameter. The length of the virus gene is about 12 kb, which is a single negative strand RNA with no segments and encodes five structural proteins from the 3 'to 5' end. Nucleoprotein (N), Phosphoprotein (P), Matrix protein (M), Glycoprotein (G) and RNA dependent RNA polymerase or Large protein (L). The virus particle is composed of Envelope and Nucleocapsid. The nucleocapsid is composed of genome RNA and tightly coiled N, P and L proteins, which have the functions of transcription and translation. The lipid membrane on the outer layer of the particle is inlaid with a Spike composed of trimers of G protein, which is the site where the virus neutralizes the antigen and binds to the host receptor. The M protein is located between the inner shell and the nucleocapsid, connecting the inner and outer parts.

Fig.1 The structure of rabies virus. (Barecha Chalchisa Buzayehu, et al., 2017)

How is rabies virus spread?

The rabies virus is mainly transmitted through animal bites, especially dogs. In areas with a high incidence of rabies, 99% of cases are caused by bites from infected dogs. In addition, the rabies virus can also be transmitted by wild animals such as bats, foxes, and raccoons. The virus enters the wounds of humans or animals through saliva, thus causing infection. The rabies virus has a wide range of hosts, including mammals and humans, and when infected, the virus spreads along the nerves and eventually attacks the central nervous system.

How does the rabies virus work?

The rabies virus has a strong affinity for nervous tissue, mainly through nerve retrograde, centripetal transmission to the center, and generally does not enter the bloodstream. The onset of rabies can be divided into the following three stages:

Extraneural small multiplication period: After the virus invades from the skin or mucous membrane at the bite site, it first multiplies in the striated muscle cells of the local wound, and invades the nearby peripheral nerves by binding to the acetylcholine receptor at the neuromuscular junction, and it is not less than 72 hours from the local wound to the invasion of peripheral nerves.

Invasion of the central nervous system from peripheral nerves: The rabies virus spreads centripetally along the axons of peripheral nerves, with a speed of about 5 cm/d, and begins to multiply in large numbers after reaching the dorsal root ganglia, and then invades the spinal cord, and then spreads to the entire central nervous system, mainly invading neurons in the brainstem and cerebellum, but can also terminate in a certain part during the diffusion process, forming special clinical manifestations.

Spread from the central nervous system to various organs: The rabies virus spreads centrifugally from the central nervous system to the peripheral nerves, invading various tissues and organs, especially the salivary glands, tongue taste buds, olfactory nerve epithelium, etc., due to the damage of the vagus nerve nucleus, swallowing nerve nucleus and hypoglossal nerve nucleus, spasm of respiratory muscles and swallowing muscles can occur, and clinical patients have symptoms such as hydrophobia, dyspnea, and dysphagia; Sympathetic nerve stimulation, increasing saliva secretion and sweating; Damage to the vagus ganglia, sympathetic ganglia, and cardiac ganglia can cause dysfunction of the patient's cardiovascular system and even sudden death.

Incubation period of rabies virus

The incubation period for the rabies virus is usually 2 to 3 months, but it can be as short as less than a week or as long as more than a year. The length of the incubation period after infection is influenced by a number of factors, including the dose of the virus, the site of infection, and the immune status of the individual. During the incubation period, infected people usually have no clinical symptoms until the virus has spread to the central nervous system, when typical symptoms of rabies appear. The time to onset of exposure varies from person to person and can vary widely.

Treatment of Rabies virus

Rabies is the most dangerous viral disease of all infectious diseases, and once it occurs, the prognosis is extremely poor. So far, there is no specific treatment, and a variety of new drugs such as interferon α, cytarabine adenosine, transfer factors and high-dose human anti-rabies globulin have been used in clinical treatment, all of which have failed. Therefore, it is emphasized that timely preventive treatment should be given to patients after the onset of the bite, and symptomatic comprehensive treatment should be the main treatment for patients after the onset of the disease.

Vaccine treatment

Prevention of rabies relies primarily on vaccination. In 1984, the World Health Organization recommended the use of modern cell culture and embryonated egg-based rabies vaccines (CCEEVs). Since the 60s of the 20th century, millions of people around the world have been vaccinated against CCEEVs. CCEEVs can be used for both pre-exposure prophylaxis and post-exposure prophylaxis. Vaccination as soon as possible after exposure, combined with rabies immunoglobulin, significantly reduces the risk of morbidity.

Treatment of inhibitors

While the main treatment for rabies is vaccine prevention, scientists are always exploring new chemotherapeutic approaches. Here are some of the chemotherapy drugs currently being studied:

GRP-60367: A first-in-class small molecule rabies virus entry inhibitor with nanomolar effect against certain rabies virus strains. By interfering with the pathway by which the virus enters cells, it is expected to be a new breakthrough in the treatment of rabies in the future.

Antiviral agent 15: A Clofazimine derivative with significant antiviral activity. Antiviral agent 15 has been shown to inhibit the replication of rabies virus and pseudotyped SARS-CoV-2 with EC₅₀ values of 1.45 μM and 14.6 μM, respectively. Its multi-target antiviral effect provides a new idea for the drug treatment of rabies.

Rottlerin: A natural product extracted from the plant Mallotus Philippinensis that inhibits the activity of PKCδ and has an inhibitory effect on rabies virus (RABV) infection. Rottlerin induces apoptosis by activating caspase 3 while stimulating autophagy by targeting the upstream mTORC1 signaling pathway, which opens up the possibility of treatment of rabies.

Summary

As a global public health problem, rabies continues to pose a serious threat to many countries. Although scientists have made great strides in the field of vaccines and chemical drugs, the fatality rate of rabies is still close to 100% once the disease occurs. Therefore, the focus should remain on prevention, especially for widespread vaccination of people and animals in high-risk areas. At the same time, with the deepening of chemotherapy research, there may be new drugs in the future to provide hope for the treatment of rabies.

References

• Davis, Benjamin M., et al., Everything you always wanted to know about rabies virus (but were afraid to ask). Annual review of virology 2.1 (2015): 451-471.
• Barecha, Chalchisa Buzayehu, et al., Epidemiology and public health significance of rabies. Perspect Clin Res 5.1 (2017): 55-67.

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