The neurological disease rabies is caused by the rabies virus (RABV) and can affect almost any mammal. The World Health Organization estimates that over 60,000 human deaths a year can be attributed to the rabies virus resulting from animal bites and the largest proportion of these infections being in Asia and Africa. In humans, rabies causes muscle weakness, dizziness, nausea, and other debilitating symptoms. After entering the body from an open wound or bite, the virus travels to the brain where it replicates. Treatment is begun immediately after a patient is exposed to an infected animal and includes post-exposure prophylaxis and vaccination as well as wound care. Rabies has a case fatality rate converging on 100% with roughly 60,000 reported deaths per year (Fooks et al., 2014). The number of rabies cases is likely larger due to the lack of reporting in many developing countries. According to the Mayo Clinic, the symptoms experienced by those effected by rabies have numerous physiological and behavioral repercussions (Diseases and Conditions: Rabies). Most individuals infected will experience muscle weakness and soreness, dizziness, fever, loss of appetite and fatigue. Other physiological symptoms include nausea, vomiting and muscle spasms. Rabies is unlike other acute viral infections of the central nervous system in that tissue necrosis and hemorrhages are not usually observed (Dietzschold, Li, Faber & Schnell 2008). The psychological symptoms from rabies can be severe, including delusions, irrational fear, and hallucinations (Diseases and Conditions: Rabies). An increase in aggression is common as well as an increase in irritability. Another well-known symptom of rabies, foaming at the mouth, does actually occur. An increase in saliva production is triggered which gives effected individuals the appearance of foaming at the mouth. The World Health Organization has classified the rabies virus into two forms, furious rabies and paralytic rabies (WHO Rabies, 2016).
Humans exhibiting furious rabies are hyperactive, hydrophobic and aerophobic before dying a few days later from cardiorespiratory arrest. Thirty percent of human rabies cases are paralytic, with the course of the rabies being less dramatic and a longer duration. The patient slowly becomes paralyzed before slipping into a coma and dying. Because this form is less severe, it is commonly misdiagnosed causing the statistics for rabies to be largely underestimated (WHO Rabies, 2016). There are certain risk factors that can increase an individual’s chance of contracting rabies relating to location and exposure to certain animals. Living in or near southeast Asia and Africa can greatly increase chances of contracting rabies because the rabies virus is more common in animals in these areas. Because the rabies virus must travel to an individual’s brain, any head or neck wounds can provide easier access, increasing chances of contracting rabies. The incubation period between the bite and the appearance of symptoms ranges between weeks and months (CDC: Rabies). The host cannot transfer the infection with a bite during the incubation period.
The RABV virus is in the genus Lyssavirus which is in the family Rhabdoviridae and order Mononegavirales (Zhu and Guo, 2016; Fooks et al., 2014). Encephalitis, or swelling of the brain, can occur in humans infected with any Lyssavirus but fatal cases in humans are rarely from any virus in the genus other than RABV (Fooks et al., 2014). The life cycle of the virus contains nine distinct steps. The first three steps, adsorption, penetration, and uncoating mediate entry into a host cell and the unpackaging of the contents in the bullet-shaped capsid.The entire proteome and genome of the virus are unpackaged simultaneously.
The genome of the RABV virus is a negative sense single-stranded RNA around 12 kb long, containing 5 genes that are all present in the capsid (Zhu and Guo, 2016). After cellular entry and uncoating, transcription of mRNA from the negative sense genome occurs by RNA-dependent RNA polymerase. Then translation of the viral mRNA into the viral proteome is mediated by host cell ribosomes.
This process forms nucleoprotein, phosphoprotein, matrix protein, glycoprotein, and RNA-dependent RNA polymerase. The G-proteins are glycosylated in the processing step and then the viral genome is replicated. Finally, assembly and budding eject the virion particles out of the host cell (Schnell et al., 2010). Glycoprotein, matrix protein, nucleoprotein and phosphoprotein all play structural roles of the bullet-shaped virus but they also play significant, if not essential, secondary roles in viral infection of a host cell (Zhu and Guo, 2016). RABV is capable of spreading from the CNS to the brain and back to peripheral neuron sites such as the oral cavity where the virus is capable of host transfer. At this stage the host begins to exhibit signs of the disease (CDC: Rabies). RABV is a zoonotic virus and the most important reservoirs that serve as a source of human disease are Canis familiaris, the domestic dog, and Desmodus rotundus, the common vampire bat (Hicks, 2012).
Rabies virus is well known for a high level of neuroinvasiveness and neurotropism (Dietzschold, Li, Faber & Schnell 2008).This virus avoids lysis and inflammation of infected neurons, but is able to kill T-cells sent to infection sites of the nervous system through apoptosis (Baloul, 2003). This allows the neuronal network to remain intact and allow the organism to spread the disease. The mechanism of infection includes adsorption, penetration and uncoating of the virus (Schnell et al., 2010). These are cellular processes which must work in conjunction with axonal transport of the virus from point of infection to the peripheral nervous system, central nervous system and ultimately the brain (Gluska, 2014). All of this is possible via the endosomal transport pathway. RABV uses fast axonal transport to travel to the brain from the peripheral nervous system of the host mammal while it continuously replicates (Fooks et al., 2014). Rabies virus enters the host’s body through a break in the skin, likely a bite, from an infected animal (Zhu and Guo, 2016). RABV is also known to spread to artic foxes through the consumption of infected carcasses or through contact with mucous membranes (Dietzschold, Li, Faber & Schnell 2008). Petting an infected animal or coming into contact with blood, urine, or feces is not generally considered a risk of infection (CDC: Rabies). The virus quickly spreads from peripheral bite sites to the central nervous system of the host’s body through the retrograde endosomal trafficking pathway via a p75NTR facilitated envelope in conjunction with retrograde axonal transport motile proteins that carry the virion envelope from synaptic terminal to cell body of neurons (Gluska, 2014). The rate of virus uptake, trans-synaptic spread, and virus replication are aided by several members of the RABV proteome, including the spike glycoprotein, a homotrimer. Multiple neuronal receptors exist through which the homotrimer is able to exploit (Dietzschold, Li, Faber & Schnell 2008).
The way in which the Rabies virus interacts with its host contributes largely to high mortality rate. Rabies has the unique ability to prevent cellular apoptosis (Ansari-Pour, 2016). It does so by forming an endosomal envelope through interaction between the glycoprotein of the virus with p75 and NCIM trans-membrane proteins of the host (Gluska, 2015). In doing so, the Rabies virus is able to maintain the life and health of the host’s cells, while it continues to produce new virions and transport itself about the CNS of its host simultaneously. Preventing cellular apoptosis through p75NTR and NCIM mediated envelope formation directly affects the subsequent immune response brought on by the host. Given the large amount of virions present within the host’s cells, the Rabies virus proceeds to infect the host nervous system. If the virus is able to proliferate without the presence of treatments or antibiotics, the host will experience death by encephalomyelitis. Encephalomyelitis causes the brain and spinal cord to swell. The swelling of these vital organs causes symptoms such as irregular heartbeats and breathing. The infection process is initiated with the fusion of the rabies virus envelope to the host cell membrane (CDC: Rabies).
Animals can be diagnosed with rabies using the direct fluorescent antibody test which examines the brain tissue for the rabies virus antigens but humans require several tests (CDC: Rabies). Around 120,000 animals are tested for rabies every year in the United States but less than 6% yield positive results. The World Health Organization organizes contact into three categories with corresponding risk (WHO Rabies, 2016). Category I is for general contact through feeding or touch animals with intact skin and does not require any treatments. Categories II and III are for exposures that are of higher risk: contact with skin not intact or bites from infected animals. Both category I and II require treatment of the wound site and vaccination (WHO Rabies, 2016). After a human has been exposed to the rabies virus, doctors administer the combination of human rabies immune globulin (HRIG) and rabies vaccination (CDC: Rabies). A person that has been vaccinated previous to the bite should receive only the vaccination. The details of treatment can be reviewed in the appendix under figure 1. The ribonucleoprotein complex made up of nucleoprotein, phosphorylated protein, RNA-dependent RNA polymerase, and genomic RNA may play a role in creating long-lasting immunity through the establishment of immunologic memory of the virus (Dietzschold, Li, Faber & Schnell 2008).
Rabies is a disease that is exceptionally geographically diverse. According to the World Health Organization, Rabies has affected someone in every single country on every single continent on earth, not including Antarctica (WHO Rabies, 2016). The highest risk of rabies can be found in almost the entire continents of Africa and Asia. This is most likely related to portions of these areas being underdeveloped, overcrowded, and having a large population of wild free-roaming small animals. People traveling to these areas are advised to seek medical attention and post-exposure prophylaxis if there is any bites, scratches, or exposure to any wild animals. Currently in the United States, more than 90% of the animal cases reported to the CDC are wildlife animals, compared to the majority of cases being domestic animals in 1960 (CDC Rabies, 2011). Almost all human fatalities associated with rabies in the United States are the result of failing to seek medical attention, generally because the patient is unaware of their exposure.
Rabies impacts the economy largely through the cost of infection, treatment, and death of patients as well prevention, research, and animal control programs. In the United States alone, over $300 million is spent annually on public health efforts to reduce the spread of rabies (CDC Rabies, 2011). There is a rabies pre-exposure vaccine that is available to the public, consisting of a series of three shots, each approximately $25. A post-exposure prophylaxis of 4 shots is available, at an approximate cost of $3000 (CDC Rabies, 2011). The CDC estimates that the cost per human life saved from rabies ranges from $10,000 to $100 million depending on the exposure and region. Rabies has the greatest impact on poor and vulnerable populations (WHO Rabies, 2016). In these communities, vaccines and immunoglobulin are not accessible and deaths go unreported. The most frequent victims are children aged 5-14 years old (WHO Rabies, 2016). The daily income in these populations is between US$1-$2 and a course of post-exposure prophylaxis is US$40 in Africa and US$49 in Asia, making the disease devastating (WHO Rabies, 2016).
As a society, laws have been constructed to aid in the prevention of rabies. All dogs in the United States are required to receive a rabies vaccination yearly, reducing the rabies sources for humans (WHO Rabies, 2016). Zoonotic diseases such as rabies require partnerships between health organizations for both humans and animals. In December of 2015, a pledge arose from WHO, World Organization for Animal Health, Food and Agriculture Organization of United Nations, and the Global Alliance for Rabies Control to achieve zero human rabies deaths by the year 2030 (WHO Rabies, 2016).
Rabies is a devastating neurological disease caused by the zoonotic RABV virus. Despite developments in vaccination and availability of post-exposure prophylaxis, there are still roughly 60,000 rabies deaths annually. Africa and Asia are the greatest affected regions in the world but even in the United States, over $300 million is spent annually on prevention efforts. Research in this field is incredibly important to better understand the virus and achieve the 2015 pledge of zero human deaths by 2030.
The RABV virus is in the genus Lyssavirus which is in the family Rhabdoviridae and order Mononegavirales (Zhu and Guo, 2016; Fooks et al., 2014). Encephalitis, or swelling of the brain, can occur in humans infected with any Lyssavirus but fatal cases in humans are rarely from any virus in the genus other than RABV (Fooks et al., 2014). The life cycle of the virus contains nine distinct steps. The first three steps, adsorption, penetration, and uncoating mediate entry into a host cell and the unpackaging of the contents in the bullet-shaped capsid.The entire proteome and genome of the virus are unpackaged simultaneously.
This process forms nucleoprotein, phosphoprotein, matrix protein, glycoprotein, and RNA-dependent RNA polymerase. The G-proteins are glycosylated in the processing step and then the viral genome is replicated. Finally, assembly and budding eject the virion particles out of the host cell (Schnell et al., 2010). Glycoprotein, matrix protein, nucleoprotein and phosphoprotein all play structural roles of the bullet-shaped virus but they also play significant, if not essential, secondary roles in viral infection of a host cell (Zhu and Guo, 2016). RABV is capable of spreading from the CNS to the brain and back to peripheral neuron sites such as the oral cavity where the virus is capable of host transfer. At this stage the host begins to exhibit signs of the disease (CDC: Rabies). RABV is a zoonotic virus and the most important reservoirs that serve as a source of human disease are Canis familiaris, the domestic dog, and Desmodus rotundus, the common vampire bat (Hicks, 2012).
Rabies virus is well known for a high level of neuroinvasiveness and neurotropism (Dietzschold, Li, Faber & Schnell 2008).This virus avoids lysis and inflammation of infected neurons, but is able to kill T-cells sent to infection sites of the nervous system through apoptosis (Baloul, 2003). This allows the neuronal network to remain intact and allow the organism to spread the disease. The mechanism of infection includes adsorption, penetration and uncoating of the virus (Schnell et al., 2010). These are cellular processes which must work in conjunction with axonal transport of the virus from point of infection to the peripheral nervous system, central nervous system and ultimately the brain (Gluska, 2014). All of this is possible via the endosomal transport pathway. RABV uses fast axonal transport to travel to the brain from the peripheral nervous system of the host mammal while it continuously replicates (Fooks et al., 2014). Rabies virus enters the host’s body through a break in the skin, likely a bite, from an infected animal (Zhu and Guo, 2016). RABV is also known to spread to artic foxes through the consumption of infected carcasses or through contact with mucous membranes (Dietzschold, Li, Faber & Schnell 2008). Petting an infected animal or coming into contact with blood, urine, or feces is not generally considered a risk of infection (CDC: Rabies). The virus quickly spreads from peripheral bite sites to the central nervous system of the host’s body through the retrograde endosomal trafficking pathway via a p75NTR facilitated envelope in conjunction with retrograde axonal transport motile proteins that carry the virion envelope from synaptic terminal to cell body of neurons (Gluska, 2014). The rate of virus uptake, trans-synaptic spread, and virus replication are aided by several members of the RABV proteome, including the spike glycoprotein, a homotrimer. Multiple neuronal receptors exist through which the homotrimer is able to exploit (Dietzschold, Li, Faber & Schnell 2008).
The way in which the Rabies virus interacts with its host contributes largely to high mortality rate. Rabies has the unique ability to prevent cellular apoptosis (Ansari-Pour, 2016). It does so by forming an endosomal envelope through interaction between the glycoprotein of the virus with p75 and NCIM trans-membrane proteins of the host (Gluska, 2015). In doing so, the Rabies virus is able to maintain the life and health of the host’s cells, while it continues to produce new virions and transport itself about the CNS of its host simultaneously. Preventing cellular apoptosis through p75NTR and NCIM mediated envelope formation directly affects the subsequent immune response brought on by the host. Given the large amount of virions present within the host’s cells, the Rabies virus proceeds to infect the host nervous system. If the virus is able to proliferate without the presence of treatments or antibiotics, the host will experience death by encephalomyelitis. Encephalomyelitis causes the brain and spinal cord to swell. The swelling of these vital organs causes symptoms such as irregular heartbeats and breathing. The infection process is initiated with the fusion of the rabies virus envelope to the host cell membrane (CDC: Rabies).
Animals can be diagnosed with rabies using the direct fluorescent antibody test which examines the brain tissue for the rabies virus antigens but humans require several tests (CDC: Rabies). Around 120,000 animals are tested for rabies every year in the United States but less than 6% yield positive results. The World Health Organization organizes contact into three categories with corresponding risk (WHO Rabies, 2016). Category I is for general contact through feeding or touch animals with intact skin and does not require any treatments. Categories II and III are for exposures that are of higher risk: contact with skin not intact or bites from infected animals. Both category I and II require treatment of the wound site and vaccination (WHO Rabies, 2016). After a human has been exposed to the rabies virus, doctors administer the combination of human rabies immune globulin (HRIG) and rabies vaccination (CDC: Rabies). A person that has been vaccinated previous to the bite should receive only the vaccination. The details of treatment can be reviewed in the appendix under figure 1. The ribonucleoprotein complex made up of nucleoprotein, phosphorylated protein, RNA-dependent RNA polymerase, and genomic RNA may play a role in creating long-lasting immunity through the establishment of immunologic memory of the virus (Dietzschold, Li, Faber & Schnell 2008).
Rabies is a disease that is exceptionally geographically diverse. According to the World Health Organization, Rabies has affected someone in every single country on every single continent on earth, not including Antarctica (WHO Rabies, 2016). The highest risk of rabies can be found in almost the entire continents of Africa and Asia. This is most likely related to portions of these areas being underdeveloped, overcrowded, and having a large population of wild free-roaming small animals. People traveling to these areas are advised to seek medical attention and post-exposure prophylaxis if there is any bites, scratches, or exposure to any wild animals. Currently in the United States, more than 90% of the animal cases reported to the CDC are wildlife animals, compared to the majority of cases being domestic animals in 1960 (CDC Rabies, 2011). Almost all human fatalities associated with rabies in the United States are the result of failing to seek medical attention, generally because the patient is unaware of their exposure.
Rabies impacts the economy largely through the cost of infection, treatment, and death of patients as well prevention, research, and animal control programs. In the United States alone, over $300 million is spent annually on public health efforts to reduce the spread of rabies (CDC Rabies, 2011). There is a rabies pre-exposure vaccine that is available to the public, consisting of a series of three shots, each approximately $25. A post-exposure prophylaxis of 4 shots is available, at an approximate cost of $3000 (CDC Rabies, 2011). The CDC estimates that the cost per human life saved from rabies ranges from $10,000 to $100 million depending on the exposure and region. Rabies has the greatest impact on poor and vulnerable populations (WHO Rabies, 2016). In these communities, vaccines and immunoglobulin are not accessible and deaths go unreported. The most frequent victims are children aged 5-14 years old (WHO Rabies, 2016). The daily income in these populations is between US$1-$2 and a course of post-exposure prophylaxis is US$40 in Africa and US$49 in Asia, making the disease devastating (WHO Rabies, 2016).
As a society, laws have been constructed to aid in the prevention of rabies. All dogs in the United States are required to receive a rabies vaccination yearly, reducing the rabies sources for humans (WHO Rabies, 2016). Zoonotic diseases such as rabies require partnerships between health organizations for both humans and animals. In December of 2015, a pledge arose from WHO, World Organization for Animal Health, Food and Agriculture Organization of United Nations, and the Global Alliance for Rabies Control to achieve zero human rabies deaths by the year 2030 (WHO Rabies, 2016).
Rabies is a devastating neurological disease caused by the zoonotic RABV virus. Despite developments in vaccination and availability of post-exposure prophylaxis, there are still roughly 60,000 rabies deaths annually. Africa and Asia are the greatest affected regions in the world but even in the United States, over $300 million is spent annually on prevention efforts. Research in this field is incredibly important to better understand the virus and achieve the 2015 pledge of zero human deaths by 2030.
Appendix
Figure 1: Rabies postexposure prophylaxis (PEP) schedule
Vaccination status
|
Intervention
|
Regimen*
|
Not previously vaccinated
|
Wound cleansing
|
All PEP should begin with immediate thorough cleansing of all wounds with soap and water. If available, a virucidal agent (e.g., povidine-iodine solution) should be used to irrigate the wounds.
|
Human rabies immune globulin (HRIG)
|
Administer 20 IU/kg body weight. If anatomically feasible, the full dose should be infiltrated around and into the wound(s), and any remaining volume should be administered at an anatomical site (intramuscular [IM]) distant from vaccine administration. Also, HRIG should not be administered in the same syringe as vaccine. Because RIG might partially suppress active production of rabies virus antibody, no more than the recommended dose should be administered.
| |
Vaccine
|
Human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) 1.0 mL, IM (deltoid area†), 1 each on days 0,§ 3, 7 and 14.
| |
Previously vaccinated**
|
Wound cleansing
|
All PEP should begin with immediate thorough cleansing of all wounds with soap and water. If available, a virucidal agent such as povidine-iodine solution should be used to irrigate the wounds.
|
HRIG
|
HRIG should not be administered.
| |
Vaccine
|
HDCV or PCECV 1.0 mL, IM (deltoid area†), 1 each on days 0§ and 3.
|
* These regimens are applicable for persons in all age groups, including children.
† The deltoid area is the only acceptable site of vaccination for adults and older children. For younger children, the outer aspect of the thigh may be used. Vaccine should never be administered in the gluteal area.
§ Day 0 is the day dose 1 of vaccine is administered.
¶ For persons with immunosuppression, rabies PEP should be administered using all 5 doses of vaccine on days 0, 3, 7, 14, and 28.
** Any person with a history of pre-exposure vaccination with HDCV, PCECV, or rabies vaccine adsorbed (RVA); prior PEP with HDCV, PCECV or RVA; or previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination.
Source: Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies: Recommendations of the Advisory Committee on Immunization Practices MMWR 2010:59(RR02);1-9.
Literature Cited
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Baloul L., Lafon M. (2003) Apoptosis and rabies virus neuroinvasion. Biochimie. Aug;85(8):777-88.
Dietzschold B., Li J., Faber M., & Schnell M. (2008). Concepts in the pathogenesis of rabies. Future Virol. Sep 3(5):481-490. Doi: 10.2217/174607460794.3.5.481.
Diseases and Conditions: Rabies. (2016, November 4). Retrieved November 10, 2016, fromhttp://www.mayoclinic.org/diseases-conditions/rabies/symptoms-causes/dxc-20263328
Fooks A. R., Banyard A. C., Horton D. L., et al. (2014). Current status of rabies and prospects for elimination. The Lancet, 384(9951), 1389-1399.
Gluska S., Finke S., Perlson E. (2015). Receptor-mediated increase in rabies virus axonal transport. Neural Regen Res;10:883-4
Gluska S., Zahavi E.E., Chein M., et al. (2014). Rabies Virus Hijacks and Accelerates the p75NTR Retrograde Axonal Transport Machinery. PLoS Pathog. Aug; 10(8): e1004348.
Hicks D. J., Fooks A. R., Johnson N. (2012). Developments in rabies vaccines. The Journal of Translational Immunology 169(3):199-204. Doi: 10.1111/j.1365-2249.2012.04592.x
Centers for Disease Control and Prevention: Rabies (2011, April 22). Retrieved November 26, 2016, fromhttp://www.cdc.gov/rabies/transmission/virus.html
Schnell M. J., McGettigan J. P., Wirblich C., Papaneri A. (2010). The cell biology of rabies virus: using stealth to reach the brain. Nat Rev Microbiol 2010 Jan;8(1):51-61 doi: 10.1038/nrmicro2260.
World Health Organization. (March 2016). Rabies Fact Sheet. Retrieved fromhttp://www.who.int/mediacentre/factsheets/fs099/en/
Zhu S., Guo C. (2016). Rabies Control and Treatment: From Prophylaxis to Strategies with Curative Potential. Viruses 8(11): 279. Doi: 10.3390/v8110279.
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