A Review Of Rabies Virus Biology Essay


Imagine a disease which had no treatment option once you felt its symptoms. Unless you had suspicion that you were potentially infected, you would get misdiagnosed and you would die in isolation, restrained, and heavily drugged (3). Unfortunately such a disease is a reality. Rabies virus results in nearly 100% fatality if not treated, and is responsible for over 55,000 human deaths every year, which is likely a conservative estimate due to under reporting and misdiagnosis (3). Rabies is caused by a Baltimore Class 5 virus in the order Mononegavirales. Rabies virus is in genus Lyssavirus, and its species designation is Lyssavirus rabies (4). Rabies virus is pathologically characteristic in its neuroinvasiveness and neurotropism, traveling up the nervous system from the wound site and into the brain where it causes severe neuropathology and death (1). This paper aims to explore the major components and mechanisms of Rabies virus, the disease caused by this virus, its treatments, and the public health impact of the disease.

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Rabies virus is characterized morphologically under an electron microscope by its “bullet” shaped dimensions, densely studded with glycoprotein projections in the membrane. The virus itself is fairly simple, being composed of only five proteins and its single-stranded, antisense, RNA genome 12 kb in length. The most important protein pathogenically is the glycoprotein encoded by the virus. This glycoprotein forms roughly 400 trimeric projections on the surface of the envelope, and is a major contributor in the virus' capability to spread cell-to-cell (1,4). The glycoprotein is also highly antigenic and may be responsible for the triggering of apoptosis in neural tissue. The apoptotic cells are thought to be very slowly cleared from the CNS, and result in the necrosis of the tissue in that area (1). Matrix protein is produced by Rabies virus and essentially holds the envelope containing glycoprotein to the core of the virus (3,4). It is also matrix protein that is responsible for bullet morphology of rabies virus and its budding capability from host cells (4,3). The core of the virus is composed of the (-) RNA genome bound by nucleoprotein which coils it into a helixed ribonucleoprotein core or RNPC. Phosphoprotein and polymerase associate with the RNPC and form the remainder of the virus core contained inside of the matrix protein capsid (4).

Rabies virus has a similar life cycle to typical Baltimore class 5 enveloped viruses. Replication takes place in the cytoplasm, in specialized compartments known as Negri bodies. These areas were previously the most effective characteristic in diagnosing rabies histologically. The cycle begins with the binding of the virus envelope to the host cell, most likely through the glycoprotein trimers found on the surface. Rabies virus shows a cellular tropism for nerve cells, but can also utilize muscle cells. The virus enters the cell by pinocytosis. The virus then fuses with the endosome due to the change in pH and injects the RNPC into the cytoplasm. The RNA dependent RNA polymerase that the virus brought with it goes to work, transcribing the antisense RNA into sense RNA for use by the host cells ribosomes. The viral polymerase attaches 5' caps and poly-adenylate tails to the RNA before translation into the five viral proteins. The glycoprotein made by the host ribosomes undergoes modification by the Golgi complex and endoplasmic reticulum before migrating to the plasma membrane of the cell. The concentration of nucleoprotein versus the concentration of leader RNA triggers the shift from protein production to genome replication. Genome replication occurs in the same manner as other Baltimore class 5 viruses. The replicated (-) RNA genome is bound by nucleoprotein which creates the helixed ribonucleoprotein core, after which phosphoprotein and polymerase bind and complete the core of the virus. Matrix proteins then bind around the RNPC and forms the bullet shaped capsid. The M-RNPC then travels through the cytoplasm and buds from areas of the plasma membrane that have high concentrations of glycoprotein. The complete rabies virus is then capable of infection (4).

Rabies is transmitted by an infected animal's saliva getting into the tissues of a healthy mammal. Rabies is unable to penetrate intact skin, therefore most cases of infection occur following a bite or scratch from an infected animal (3). The virus enters the body through the wound and travels from the wound site to the brain by using the host's nerves. Rabies virus is capable of this retrograde axonal transport because it can combine cell-to-cell spread and trans-synaptic spread, although we are unaware of how trans-synaptic spread is carried out (1). There is evidence that these methods of movement are made possible, and are controlled by, the glycoprotein that coats the Rabies virus membrane (1). The virus replicates within the nerves, slowly making its way to the brain and salivary glands at the rate of 15-100 mm per day (2). As the virus makes its way up the nerves, it causes no symptoms and is not transmissible through saliva. This period is known as the incubation period and can last from 3 weeks to 6 years (2,4). The rate of spread in the nervous system depends on the virus' uptake rate by the nerve cells, the speed of axonal transport, the rate of replication, and the strain's capacity for trans-synaptic spread (1). Rabies virus typically has a low replication rate, and experimentally this has been seen to have an inverse relationship with pathogenicity, possibly due to the evasion of the immune system through low viral load. The low replication rate could also be beneficial to pathogenicity by preserving the nerves used to travel into the CNS (1). Once in the CNS, the virus can follow the facial and glossopharyngeal cranial nerves to the salivary glands, which it infects and buds virus into the acinar lumen (5,4). The virus continues to travel up into the brainstem and brain where it causes the first of the clinical symptoms. There are several theories as to how rabies virus conducts its neuropathogenesis, the first being that the virus shuts down host maintenance genes and reduces protein production in neural tissue. The second theory proposes that the virus interferes with serotonin binding and release. The third theory is that glycoprotein pushes neurons into apoptotic pathways and the resulting dead cells do not get cleared from the CNS and cause necrosis of the surrounding cells. The remaining theories center on inactivation of voltage gated ion channels (1).

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The neuropathology of rabies results in quickly progressing and devastating symptoms. Upon experiencing the first clinical symptom, the individual typically has 1-7 days before death and has no chance of recovery. The first clinical symptom is neuropathic pain and tingling at the wound site after healing (4). This is caused by viral replication in the dorsal root ganglion of the afferent sensory nerve from the wound site causing action potential generation (2). The major clinical symptoms: fever, headache, fatigue, anxiety, agitation, confusion, hallucinations, and insomnia are not unique to rabies and cannot be used as a diagnostic tool. These symptoms are likely caused by an inflammation of the brain, spinal cord, and nerve roots (2,4). Clinical progression usually follows one of two routes: furious rabies in which there is extreme agitation and aggression, or dumb rabies in which there is early onset paralysis and decreased activity (3). Both eventually lead to paralysis, coma, and the shutdown of the respiratory system, resulting in death (3). The aggression caused by furious rabies as well as the heavily salivation, and saliva transmission all combine into a very effective transmission strategy for the virus (4).

Treatment of rabies virus infection must be done early and aggressively. Immune response to rabies virus is much lower than comparable diseases, which is surprising considering that glycoprotein is highly antigenic. In addition, compromised immunity had no effect on rabies pathogenesis, which means the pathology we see in healthy humans is as bad as the disease can get (1). Treatment must be carried out before clinical symptoms set in, as the treatment only acts to stop the virus from reaching the brain. Post-exposure prophylactic treatment regimens consist of cell-cultured vaccine administration, and in dire cases, administration of immunoglobulin upstream of the wound to stop disease progression and also at the local wound site to stop infiltration (3). Preventative treatment consists of a course of vaccines and the irrigation of potential infected wounds with a povidone-iodine solution (4). With early post-exposure prophylactic treatment, recovery is nearly 100%. However, if post-exposure prophylactic treatment is started after invasion of the CNS and presentation of clinical symptoms, treatment is usually ineffective (3). If clinical symptoms begin, treatment paradigms shift to a supportive role, usually consisting of isolation to prevent transmission, heavy sedation to avoid awareness and agitation, and IV morphine to alleviate clinical symptoms (2).

Rabies virus has caused disease on every continent except for Antarctica (3). The disease claims at least 55,000 human lives each year, with untold numbers of wild animals. The heaviest disease burden is in developing countries in Africa and Asia, with these two continents accounting for 95% of the total deaths recorded each year. It is therefore apparent that rabies case numbers are capable of being sizably reduced, but a lack in infrastructure will always be the biggest obstacle. There are several factors to consider when questioning why rabies is so prevalent in developing countries, the first of which is that rabies is under reported, and frequently misdiagnosed unless a post-mortem diagnosis is made, therefore the data concerning rabies health impact is lower than actual. The second cause of high rabies burden in developing countries is directly related to the last; low estimates of the disease cause a lack, or disproportionate level, of support and attention on a governmental level. The third cause is that rabies disease loads are not equally distributed across society. As we frequently see in disease of the developing world, the rural poor are most likely to get infected and die from this disease. In the case of rabies, rural children from poor families are at highest risk of the disease not only due to their lack of education about rabies and lack of money for full treatment, but also because children are more likely to play with stray dogs, the main carrier of rabies from animals to humans and seen as the source in 30-60% of rabies cases in children under 15 years old. Animal workers are also very likely to be exposed, as are those who spend a significant amount of time outdoors, whether for work or leisure (2).

While dogs are the most common source of rabies transmission to humans, the main reservoirs of the disease are wild animals. Raccoons, bats, wild foxes, skunks, and wolves are the largest reservoirs of disease and their transmission to dogs accounts for the resulting human infection. Therefore, the most cost effective rabies containment program is centered on dog vaccination, although it is still a heavy financial drain on society. The estimated cost in the United States for rabies prevention and treatment each year is $300 million (2). However, cost depends on many factors including the characteristics of post-exposure prophylactic treatment (PEP). The cost for PEP can vary depending on the vaccine used, the regimen of the vaccine administration, the type of immunoglobulin used, and the route by which all of this is administered. In Asia and Africa the estimated cost of PEP treatment annually was $583 million. The bulk of the cost was incurred by Asia due to its heavy use of PEP treatment. On African and Asian continents the annual estimated cost of lost livestock due to rabies was $12.3 million, while a 1985 estimate by Latin American countries estimated their annual lost cattle at 100,000 head, with a total cost of $30 million per year. On the local level, a course of PEP is roughly $40 in Asia and $49 in Africa. While this may not seem like much, when annual income is only a few hundred dollars per year per person, the cost becomes roughly 30-50 days of work per adult. Many infected people do not want to go to the hospital for treatment due to the amount of missed work, and some of the more archaic vaccines still used in some developing countries can cause side effects lasting up to six months. However, even with the high cost treatment still saves tens-of-thousands of lives each year. The estimated number of deaths if PEP treatment was not used is approximately 330,000 in Asia and Africa (2).

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Rabies virus causes tremendous, fatal disease in the developing world and its presence is far too common for the level of effective prevention and treatment available. Rabies still claims over 55,000 lives each year, largely in developing countries in Africa and Asia. This simple Baltimore Class 5 virus packs quite lethal punch in its ironically bullet shaped capsid, and shows incredible tenacity in its host (4). Although it is unlikely due to the heavy wild animal reservoirs, ridding the world of this disease would be a tremendous removal of burden from mankind and animals.


1) Dietzschold, Bernhard, Jianwei Li, Milosz Faber, and Matthias Schnell. "Concepts in the pathogenesis of rabies." Future virology. 3.5 (2008): 481-490. Print.

2) United Nations. WHO Expert Consultation on Rabies. Geneva: World Health Organization, 2005. Web. 30 March 2010.

3) United Nations. Human and Animal Rabies. Geneva: World Health Organization, 2010. Web. 31 March 2010. <http://www.who.int/rabies/en/>.

4) United States. Rabies. Atlanta: Centers for Disease Control and Prevention, 2010. Web. 31 March 2010. <http://www.cdc.gov/rabies/>.

5) Waxman, Stephen. Clinical Neuroanatomy. 25th ed. New York: Lange Medical Books/McGraw-Hill, 2003. 113,119. Print.