Rabies Virus- An Overview

Rabies virus is a member of the family Rhabdoviridae and the genus Lyssavirus. It is an enveloped, single-stranded RNA virus with a bullet-shaped or rod-shaped morphology . The virus measures approximately 75 x 180 nm and has a buoyant density in CsCl of about 1.19 g/cm3.

The virus has two major structural components: a helical ribonucleoprotein core (RNP) and a surrounding envelope. The RNP consists of the viral RNA genome tightly encased by the nucleoprotein (N) and associated with the phosphoprotein (P) and the large polymerase protein (L) . The envelope is a lipid-containing bilayer derived from the host cell membrane and covered with transmembrane glycoprotein spikes (G) . The matrix protein (M) forms a layer between the envelope and the RNP and plays a role in virus assembly and budding .

The viral genome is a linear, non-segmented, negative-sense RNA molecule of about 12 kb in length . It encodes five proteins: N, P, M, G, and L, in that order . The genome also has a leader sequence at the 3` end and a trailer sequence at the 5` end that are involved in transcription and replication.

The rabies virus genome is composed of single-stranded, negative-sense, non-segmented RNA of approximately 12 kb (kilobases) in length . The genome has a leader sequence of about 50 nucleotides at the 3` end, followed by five genes that encode the viral proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and large polymerase protein (L) . The order and relative size of the genes are shown in the figure below:

The viral ribonucleoprotein (RNP) core consists of the viral RNA encapsidated by N proteins and associated with the P and L proteins. The N protein binds to the RNA genome with a ratio of one N molecule per nine nucleotides. The P protein acts as a cofactor for the L protein, which is the viral RNA-dependent RNA polymerase that transcribes and replicates the viral genome. The other viral proteins, M and G, are involved in virion structure and attachment to cellular receptors, respectively. The M protein forms a layer on the inner side of the envelope, whereas the G protein is on the outer layer and forms the spikes that mediate virus entry.

The rabies virus genome has a high degree of conservation among different strains and variants, with an overall nucleotide identity of more than 90%. However, some regions of the genome show more variability than others, such as the G gene and the intergenic regions. These regions can be used for molecular epidemiology and phylogenetic analysis of rabies virus.

Rabies is a viral disease that affects the central nervous system of mammals, causing fatal encephalitis. It is transmitted through the bite or scratch of an infected animal, usually a dog or a bat. Rabies is a global public health problem that occurs in more than 150 countries and territories, causing tens of thousands of deaths every year, mainly in Asia and Africa . According to the World Health Organization (WHO), 40% of human rabies cases are children under 15 years of age.

The following table summarizes some key facts about the epidemiology of rabies virus :

Rabies is a preventable disease that can be eliminated by vaccinating dogs and preventing dog bites. However, many challenges remain in implementing effective rabies control programs, such as lack of awareness, resources, infrastructure, surveillance, and political commitment. Rabies is also a neglected tropical disease (NTD) that disproportionately affects poor and marginalized populations who have limited access to health care and PEP.

Rabies is a zoonotic disease that can affect both domestic and wild animals. The virus circulates in different reservoirs depending on the geographic region and ecological factors. The main reservoirs of rabies virus are:

• Dogs: responsible for most human rabies cases worldwide, especially in Asia and Africa. Dog-mediated rabies can be eliminated by mass vaccination of at least 70% of the dog population and responsible dog ownership.
• Bats: responsible for most human rabies cases in the Americas and some parts of Africa and Asia. Bat-mediated rabies can be prevented by avoiding contact with bats and their saliva, and seeking PEP after any potential exposure.
• Wildlife: responsible for some human rabies cases in Europe, North America, Australia and other regions. Wildlife-mediated rabies can be controlled by oral vaccination of wild carnivores such as foxes, raccoons, skunks and coyotes.

Rabies virus belongs to the genus Lyssavirus, which includes at least 16 different species that can cause rabies-like diseases in animals and humans. The genetic diversity of rabies virus influences its epidemiology, pathogenicity, host range, transmission dynamics and vaccine efficacy. Molecular methods such as reverse transcription-polymerase chain reaction (RT-PCR) and sequencing can be used to identify and characterize different rabies virus strains and monitor their evolution and spread .

Some possible sentences to conclude the point are:

• Understanding the epidemiology of rabies virus is essential for designing and implementing effective strategies for prevention, control and elimination of this deadly disease.
• Rabies virus is a dynamic and diverse pathogen that adapts to different hosts and environments. Continuous surveillance and research are needed to monitor its epidemiology and evolution.
• Rabies virus poses a serious threat to public health and animal welfare worldwide. Collaborative efforts among multiple sectors and stakeholders are required to achieve the global goal of zero human deaths from dog-mediated rabies by 2030.

Rabies virus is a zoonotic disease, which means it can spread from animals to humans. The most common way of transmission is through the bite of an infected animal, such as a dog, cat, raccoon, fox, bat, or skunk. The virus is present in the saliva of the rabid animal and can enter the human body through broken skin or mucous membranes in the eyes, nose, or mouth .

Another possible way of transmission is through contact of saliva or brain/nervous system tissue from an infected animal with open wounds or scratches on the human skin. This can happen when handling or skinning infected animals, or when cleaning or disposing of their carcasses. However, this mode of transmission is rare and has not been documented in humans.

Other types of contact with infected animals, such as petting, touching, or feeding them, are not considered to be risky for rabies transmission, as long as there is no exposure to saliva or nervous tissue. Similarly, contact with blood, urine, feces, or fur of infected animals does not pose a risk for infection.

There are some very uncommon ways of transmission that have been reported in rare cases. These include inhalation of aerosolized rabies virus in laboratory settings or in caves with large bat populations, corneal or organ transplants from donors who were unknowingly infected with rabies, and human-to-human transmission through bites or saliva contact from rabid patients. However, these modes of transmission are extremely rare and have not been documented in recent years.

Once the rabies virus enters the human body, it travels along the nerves to the brain, where it causes inflammation and damage. This process can take weeks to months, depending on the location and severity of the bite, the amount and strain of the virus, and the immune status of the person. During this incubation period, the person does not show any signs or symptoms of rabies and is not infectious to others. However, once the virus reaches the brain and causes clinical signs of rabies, such as fever, headache, anxiety, hydrophobia (fear of water), aggression, hallucinations, paralysis, and coma, the person becomes infectious and can transmit the virus through their saliva. At this stage, rabies is almost always fatal and there is no effective treatment available.

Therefore, it is very important to prevent rabies transmission by avoiding contact with potentially infected animals, especially wild animals or stray dogs and cats. If a person is bitten or scratched by an animal that may have rabies, they should wash the wound thoroughly with soap and water and seek medical attention immediately. They may need to receive post-exposure prophylaxis (PEP), which consists of a series of shots that can prevent the virus from reaching the brain and causing disease. PEP is most effective when given as soon as possible after exposure. Additionally, people who are at high risk of exposure to rabies, such as veterinarians, animal handlers, travelers to rabies-endemic areas, or people who live in areas where rabies is common, should consider getting vaccinated against rabies before exposure. Vaccination can provide protection against rabies infection and reduce the need for PEP after exposure.

The replication of rabies virus is believed to be similar to that of other negative-stranded RNA viruses. The virus attaches to the host cell membranes via the G protein, penetrates the cytoplasm by fusion or pinocytosis, and is uncoated to release the ribonucleoprotein (RNP) core. The RNP consists of the viral RNA genome encapsidated by the nucleoprotein (N) and associated with the phosphoprotein (P) and the large polymerase protein (L) .

The viral RNA-dependent RNA polymerase (L) transcribes the genomic strand of rabies RNA into five monocistronic mRNAs, which are capped and polyadenylated . These mRNAs code for the five viral proteins: N, P, M (matrix), G (glycoprotein) and L. The translation of these proteins occurs on free ribosomes in the cytoplasm, except for the G protein, which is synthesized and glycosylated in the endoplasmic reticulum and Golgi apparatus .

The genome RNP is also a template for complementary positive-sense RNA, which is responsible for the generation of negative-sense progeny RNA . During the assembly process, the N-P-L complex encapsulates negative-stranded genomic RNA to form the RNP core, and the M protein forms a capsule, or matrix, around the RNP . The RNP-M complex migrates to an area of the plasma membrane containing glycoprotein inserts, and the M-protein initiates coiling. The M-RNP complex binds with the glycoprotein, and the completed virus buds from the plasma membrane . The viral matrix protein forms a layer on the inner side of the envelope, whereas the viral glycoprotein is on the outer layer and forms the spikes.

Rabies virus is a neurotropic virus that causes fatal encephalitis in humans and animals. The pathogenesis of rabies virus involves several steps:

• Inoculation: Rabies virus is usually transmitted by the bite of an infected animal or the contact of saliva with broken skin or mucous membranes. The virus enters the muscle or connective tissue at the site of inoculation and replicates there .
• Neuroinvasion: Rabies virus then binds to specific receptors on the peripheral nerves, such as acetylcholine receptors, and travels along the axons to the central nervous system (CNS) by retrograde axonal transport . The incubation period of rabies depends on the distance between the site of inoculation and the CNS, as well as other factors such as age, immune status, viral strain and inoculum size.
• Neuroreplication: In the CNS, rabies virus multiplies in the neurons and glial cells, especially in the brain stem and limbic system . The virus causes neuronal dysfunction and apoptosis, as well as inflammatory responses and vascular damage . The virus also spreads to other parts of the CNS, such as the spinal cord and cranial nerves.
• Neurodissemination: From the CNS, rabies virus travels along the efferent nerves to various organs and tissues, such as salivary glands, eyes, skin, heart and kidneys . The virus is shed in saliva and other secretions, which can infect new hosts. The virus also reaches the endocrine and immune systems, causing hormonal and immunological disturbances .
• Clinical signs: The clinical signs of rabies usually appear after the virus has reached the brain and salivary glands. The signs can be divided into two phases: prodromal and neurological. The prodromal phase lasts for 2-10 days and is characterized by nonspecific symptoms such as fever, headache, malaise, anorexia, nausea, vomiting and sore throat . The neurological phase lasts for 2-7 days and is characterized by signs of CNS dysfunction such as anxiety, agitation, hallucinations, hydrophobia (fear of water), aerophobia (fear of air), hypersalivation, dysphagia (difficulty swallowing), paresis (weakness), paralysis, seizures and coma . Death usually occurs due to respiratory or cardiac arrest .

Rabies virus causes an acute and fatal encephalitis (inflammation of the brain) in all warm-blooded hosts, including humans and animals . The disease has a variable incubation period, depending on the location and severity of the bite, the amount and strain of the virus, and the immune status of the host. The incubation period may range from a few days to several months, but it is typically 1 to 3 months in humans .

The clinical spectrum of rabies can be divided into three phases: a prodromal phase, a neurologic phase, and a coma phase .

Prodromal phase

The prodromal phase lasts for 2 to 10 days and is characterized by nonspecific symptoms such as fever, headache, malaise, anorexia, nausea, vomiting, sore throat, and cough. Some patients may also experience pain, tingling, or itching at the site of the bite. This phase may be mistaken for a flu-like illness or other viral infections .

Neurologic phase

The neurologic phase lasts for 2 to 7 days and is marked by signs of nervous system dysfunction such as anxiety, confusion, agitation, hallucinations, delirium, and abnormal behavior. Patients may also exhibit signs of sympathetic overactivity such as pupillary dilation, lacrimation, salivation, perspiration, and tachycardia. A characteristic feature of rabies is hydrophobia (fear of water) or aerophobia (fear of air currents), which are triggered by attempts to drink or feel a breeze. These stimuli cause painful spasms of the throat and respiratory muscles. Patients may also have convulsions, paralysis, dysphagia (difficulty swallowing), dysarthria (difficulty speaking), and dyspnea (difficulty breathing) .

Coma phase

The coma phase is the final stage of rabies and usually leads to death within a few hours or days. Patients become unresponsive and develop cardiorespiratory arrest. The major causes of death are respiratory failure, arrhythmias, hypotension, and shock .

Rabies is a devastating disease that has no effective treatment once symptoms appear. Therefore, prevention through vaccination and post-exposure prophylaxis is crucial to avoid this fatal outcome. If you suspect that you or someone you know has been exposed to rabies virus, seek medical attention immediately .

Diagnosing rabies virus infection before the appearance of signs and symptoms is difficult, as the virus may not be detectable in blood, saliva, or cerebrospinal fluid during the incubation period. However, once the clinical manifestations of rabies develop, several tests can be performed to confirm the diagnosis and guide the treatment.

The most reliable and widely used test for rabies diagnosis in animals and humans is the direct fluorescent antibody (DFA) test. This test involves staining brain tissue samples with fluorescent antibodies that bind to rabies virus antigens. The presence of fluorescent signals under a microscope indicates a positive result. The DFA test can provide a rapid and accurate diagnosis within a few hours.

Another test that can be used to detect rabies virus antigens in brain tissue is the immunoperoxidase staining using antirabies monoclonal antibodies. This test is similar to the DFA test, but uses a different type of antibody and a chemical reaction that produces a colored product instead of fluorescence.

In humans, additional tests can be performed on samples of saliva, serum, spinal fluid, and skin biopsies of hair follicles at the nape of the neck. These tests include:

• Virus isolation by inoculating suckling mice or cell cultures with the sample and observing for signs of infection or cytopathic effects.
• Reverse transcription-polymerase chain reaction (RT-PCR) by amplifying parts of the rabies virus genome from the sample and detecting them by gel electrophoresis or sequencing.
• Antibody detection by using immunofluorescence or neutralization tests to measure the level of antibodies against rabies virus in the sample.

These tests may not be as sensitive or specific as the DFA test, and may require more time and resources to perform. Therefore, they are usually used as supplementary tests or when brain tissue samples are not available.

The diagnosis of rabies virus infection is crucial for timely administration of postexposure prophylaxis and prevention of further transmission. However, no effective treatment is available once the signs and symptoms of rabies develop. Therefore, prevention through vaccination and avoiding contact with potentially rabid animals is the best strategy to combat this deadly disease.

• There is no known effective treatment for rabies once the clinical symptoms appear.
• The disease usually causes death due to cardiorespiratory arrest.
• However, a small number of people have survived rabies with intensive medical care .
• The treatment of clinical rabies consists of the following components:
  • Medical support in an intensive care unit
  • Supportive care such as hydration, nutrition, and ventilation
  • Heavy sedation to reduce agitation and prevent self-injury
  • Analgesics to relieve pain and discomfort
  • Anticonvulsants to control seizures
  • Antivirals such as ribavirin and interferon-alpha, although their efficacy is uncertain
• The most important measure to prevent rabies is to seek immediate medical care after a potential exposure to a rabid animal.
• The post-exposure prophylaxis (PEP) consists of the following steps:
  • Wound cleansing with soap and water or iodine solution
  • Administration of rabies vaccine on days 0, 3, 7, and 14
  • Administration of rabies immune globulin (RIG) on day 0, preferably near the wound site
  • Observation of the animal that caused the exposure, if possible, for 10 days
  • Avoidance of further contact with the animal or its saliva
• The PEP is highly effective in preventing rabies if given promptly and correctly.
• The PEP may not be readily available or affordable in some areas where rabies is endemic.
• Therefore, it is also important to prevent exposureto rabid animals by taking the following precautions:
  • Vaccinating pets and livestock against rabies
  • Keeping pets under supervision and avoiding contact with stray or wild animals
  • Reporting any suspicious or aggressive animals to local authorities
  • Seeking advice from a health care provider before traveling to areas where rabies is common
  • Considering pre-exposure vaccination if traveling or working in high-risk areas or occupations

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