Knowing Neurons
Neurological and Psychiatric Disorders

Rabies: Taming the Beast

By Julia LaValley

For over 4000 years, rabies has been humanity’s companion. First described in 2300 BCE in the Mosaic Esmuna Code of Babylon, rabies is one of the oldest known diseases to date (Nayak et al., 2022). It has inspired fear and myth alike and may be the origin of myths such as vampirism, lycanthropy, and zombification (Rohde, 2019; Gryshyna, 2022). And fear of rabies is far from irrational; though we have known about the disease for thousands of years, we are still facing an almost 100% mortality rate and limited options for treatment (Koury & Warrington, 2023). It is present on every continent except Antarctica, and it kills around 59,000-70,000 people annually (Koury & Warrington, 2023; Willoughby et al., 2005).

There is no arguing against the idea that rabies, or the fear of it, has made an impact on humanity. It is apparent in everything from historical texts, like the Greek myth of King Lycaon who turned into a wolf with a foaming mouth, to modern works like Old Yeller or Cujo (Rohde, 2019). But despite how interwoven the disease has been and currently is with human society, many people don’t know the reality of this deadly disease.

The symptoms of rabies as depicted in media usually manifest as foaming at the mouth, fear of water, and extreme aggression. There is some accuracy to this but, as with many things, it also isn’t quite so simple.

What does rabies really look like?

The symptoms of rabies as depicted in media usually manifest as foaming at the mouth, fear of water, and extreme aggression. There is some accuracy to this but, as with many things, it also isn’t quite so simple.

There are 5 stages of a rabies infection: incubation, prodrome, acute neurologic illness, coma, and finally death. Incubation is simply the time between the exposure and the start of symptoms. This is when the virus is still traveling throughout the body. Prodrome is when more general, flu-like symptoms appear: GI-upset, fever, and muscle pain (Koury and Warrington, 2022). Other symptoms may include itching at the site of the bite wound, insomnia, and delirium and hallucinations as the patient progresses to stage 3 (Rohde, 2019). At this prodrome stage, the disease is already next to incurable and the progression of the infection is irreversible (Roy & Hooper, 2008).

Stage 3, acute neurologic illness, is where the stereotypical symptoms come into play, with patients beginning to experience symptoms affecting the nervous system (including the brain). However, despite the familiar profile of symptoms we see in media depictions, this stage can actually be different for different people. In most cases, patients experience the encephalitic form (also termed ‘furious’ rabies) with symptoms such as: fear of water (hydrophobia), agitation and personality changes, rigid neck, poor balance, odd postures of certain body parts, increased heart rate, increased breathing, and fever (Koury and Warrington, 2022). Additionally, although ‘frothing at the mouth’ may not be an entirely accurate description, rabies does cause increased salivation thought to be an evolutionary trick to improve transmission rates as the virus is carried in the host’s saliva. This is also why patients are thought to be hydrophobic; if the host drank water it would dilute the virus in their saliva, making it harder for the disease to spread. Interestingly, although the symptom is called hydrophobia, that term is a misnomer. The patient is not truly ‘afraid of water,’ but instead experiences spasms in their neck muscles when they attempt to swallow, making ingestion impossible (Warrell et al., 2017).

In about 20% of cases, patients will instead present primarily with weakness rather than the irritability and hydrophobia present in furious rabies (Gadre, 2010). Fever and altered personality may still be present, along with bladder dysfunction. This is termed paralytic or ‘dumb’ rabies. In extremely rare cases, there is also a third ‘non-classic’ category in which patients experience seizures and more extreme loss of motor and sensory control (Koury and Warrington, 2022).

In the fourth stage, patients fall into a coma. This typically occurs around 10 days from the onset of acute neurologic illness, and it may include periods where the patient stops breathing (apnea). Flaccid paralysis, characterized by limp (as opposed to rigid) musculature, can also occur. This coma ends in the patient’s death within 2-3 days of onset (Koury and Warrington, 2022).

In extremely rare cases, there is also a third ‘non-classic’ category in which patients experience seizures and more extreme loss of motor and sensory control

 

How can you get rabies?

Each species of animal that carries the virus generally has its own strain (Roy & Hooper, 2008). According to the World Health Organization, 99% of people who died from a rabies infection were infected by a rabid dog (WHO, n.d.). This is not to say that dogs are the only ones who carry rabies, but they are one of humanity’s most common companions, and this constant contact increases the likelihood of infection. If humanity went around petting racoons, we would probably see more cases of racoon-transmitted rabies as well. Interestingly, rabies transmitted by racoons is the most common transmission method on the East Coast of the United States (Figure 2), where dog rabies is quite rare (Ma et al., 2021). What this says about people’s petting habits is not clear. 

More generally, rabies is transmitted by direct contact with the saliva or nervous system tissue of an infected mammal. Direct contact in this case means through broken skin, or the mucous membranes of the eyes, nose, or mouth (CDC, 2019). The general way this happens is that an animal bites another animal or person, immediately introducing their saliva into the body. Another common pathway for transmission is a scratch followed by saliva dripping into the open wound. Getting saliva in your mouth, nose, or eyes, or ingesting infected nervous tissue also puts you at risk of infection.

Human-to-human transmission is rare but not unheard of. A human biting a human can infect the other person. Though never recorded, it is possible that mouth-to-mouth contact, or sexual intercourse with an infected person could lead to infection (Aguemon et al., 2016). Additionally, there has been at least one confirmed report of an organ donor infected with rabies transmitting the disease to the recipients of their organs. In this situation the recipients had received a kidney, a liver, or a segment of the donor’s artery. Previously there had been cases of corneal transplants leading to transmission, but this was the first reported case of transmission from internal organs (Srinivasan et al., 2005).

Though rabies is present on every inhabited continent, your risk of exposure is not the same everywhere. Parts of Asia and Africa where rabies has become endemic (occurring regularly in a population) experience the highest risk with regular reports of human rabies in many countries (WHO, 2021). This makes them relatively high-risk countries. While human rabies has not reached endemic status in South America, countries there do experience moderate risk from endemic dog rabies, although they often have control methods in place and are in the process of eradicating it. Finally, lower risk countries are in Europe or North America, where rabies infections in dogs or humans remain restricted to rare individual cases, and the bulk of infections occur mostly in wildlife (WHO, 2021). 

Figure 1: Map of the world with varying risk levels of rabies exposure by country from data collected in 2009 (Source: adapted from WHO, 2021)

In America and European countries the most common transmission route is not dog bites but wildlife exposure (Lippi & Cervellin, 2021). In these countries bites from a bat, skunk, raccoon, or fox should be treated as rabies exposure (Koury & Warrington, 2023). In the United States in 2019, the most reported rabid animals are: raccoons (32.9% [1,545]), bats (29.6% [1,387]), skunks (19.5% [915]), and foxes (7.7% [361]) (Ma et al., 2021). Additionally, in the cases of some island nations or states, rabies has been eradicated entirely.

Figure 2: Map of distribution of major rabies virus variants in the United states and Puerto Rico for 2015 through 2019. Darker shading indicates counties with confirmed animal rabies cases in the past 5 years. Because bats are unconstrained by geographic barriers, rabies is present in bats throughout the North American continent and not represented on the map. The different labels of skunk depict different variants of skunk rabies. RC = Racoon; SK = Skunk; FX = Fox; MG = Mongoose (Source: Ma et al., 2021)

Rabies and the nervous system:

After exposure occurs and the virus enters the body, it travels to the closest axons (the arm of a neuron that carries impulses to other cells) of sensory or motor nerves. It then travels along the peripheral nervous system (PNS) (the nervous system outside of the brain and spinal cord) by co-opting the body’s fast axonal transport system like a highway, traveling at a rate of 8-20 mm per day. The fast axonal transport system is the process of using the small bubbles that store material for transport, also known as vesicles, to move material within axons and potentially between cells. It may also be co-opting some of the neurons’ receptors and molecules to hasten its advance (Lippi & Cervellin, 2021). The virus’s ultimate target is the central nervous system (CNS) (the brain and spinal cord), but the time it takes to reach it is limited by its set travel speed and the distance it has to travel from the site of infection. This also means that the incubation period varies from individual to individual.

Once the virus makes contact with the CNS, it begins to replicate and spread throughout the brain and spinal cord with a particular appetite for the brainstem, thalamus, basal ganglia, and the spinal cord (Lippi & Cervellin, 2021). This is when the prodrome stage begins and treatment is all but ineffective. Symptoms seen in this stage generally depend on which neurons are infected with the replicating virus (Jackson, 2011). For example, infection of the limbic system results in some of the mood and behavioral symptoms rabies patients display. Finally, in the later stages of the disease, the virus travels back out into the PNS to increase salivation and facilitate transmission to a new host (Lippi & Cervellin, 2021).

One of the main reasons the rabies virus is so pernicious is its ability to evade the body’s immune response

One of the main reasons the rabies virus is so pernicious is its ability to evade the body’s immune response. By co-opting vesicles inside the body’s nerves, the virus largely circumvents the immune cells that circulate in our blood stream. This also lets the virus slip past an important brain defense: the blood-brain barrier (BBB) (Wang et al. 2013). The BBB is a thin layer of cells that guards between the blood in the body and the lining around the brain. It is selectively permeable, meaning it chooses to let some things through and keeps dangerous things out. Normally, infections in the brain  trigger inflammation, signaling the BBB to become more permeable and allow immune cells into the brain to clear out the infection (Daneman & Prat 2015). In the case of rabies, this process doesn’t occur, or at least occurs so late in the infection that the immune system has no hope of fending off the infection (Wang et al., 2013). During a rabies infection, the BBB remains intact and impermeable to immune cells, which could be due to a couple of reasons. First, it is possible that the rabies virus somehow prevents the BBB from becoming permeable by some sort of active interference, like a signal or damage to a certain type of cell. Second, the BBB may simply not receive the proper cues asking for immune cells. This explanation is compelling because rabies virus causes relatively little inflammation in the CNS until very late in infection, preventing the BBB from knowing there is a problem until it is too late (Roy et al., 2007).

Rabies in Research

Surprisingly, rabies is not all bad news. Recently, scientists have found ways to use the rabies virus for research purposes. Because of the fairly unique way the rabies virus co-opts our neurons as a transport mechanism, scientists have started utilizing it to map out the connections between neurons, using it as a neuroanatomical tracer (Jackson, 2011). Traditional neural tracers were materials that would flood an initial cell, cross the synapse to the next cell, and start to fill that one. The problem with this approach is that these tracers would lose steam, decreasing in concentration with each jump into another cell until they eventually fade. In using viral tracers like rabies virus, scientists leverage the virus’s natural tendencies: it travels up toward the brain exclusively (it doesn’t go backward), it replicates itself, making the concentration in each cell equal, and it keeps the cells completely functional without damaging their transmission capabilities (Ugolini, 2011).

Furthermore, the rabies virus can be modified with a fluorescent marker so that scientists can look under a fluorescent microscope and see the neurons that have been marked by the virus (Finke et al., 2004). Other options include using rabies virus antibodies to stain neurons that have been infected. This scientific development has allowed us to understand more about not only the rabies virus itself but also  the organization and operation of the nervous system (Ugolini, 2011).

In doing all of this research, scientists take care not to expose themselves to live rabies virus. The version of the virus they use is what we call a ‘fixed’ virus as opposed to the ‘street’ version. The fixed virus has gone through genetic manipulation to essentially disarm it of its ability to actually cause the disease, making it extremely safe for researchers to handle (Ugolini, 2011).

 

What to do if you get bitten.

If you are unfortunate enough to have a violent encounter with an animal, whether domestic or wildlife, go to the emergency room or closest medical facility immediately. If the animal’s vaccinations are up to date, you will most likely leave with a cleaned wound and some antibiotics. If the animal’s vaccination status is unknown or out of date, you may be treated for rabies exposure. For possible exposure to rabies, doctors will administer postexposure prophylaxis (PEP), which consists of the rabies vaccine (you will receive additional doses at days 3, 7, and 14) and a dose of ‘human rabies immune globulin’ (HRIG) (CDC – Rabies Postexposure Prophylaxis (PEP)—Medical Care—Rabies, 2022). HRIG is a material that is made up of rabies virus antibodies,  similar to what your body would naturally produce to try and fight the virus in your body. Administering it post-exposure acts as a sort of jump start to try and get ahead of the virus’s path. Your HRIG dose, which would be calculated based on your body size, would be delivered into various large muscles of your body and also directly under the bite wounds. It is important that HRIG is only ever given to never-before-rabies-vaccinated individuals, as giving it to vaccinated individuals can actually repress the body’s own production of antibodies and reduce patients’ ability to fight off the virus (CDC – Medical Care: Human Rabies Immune Globulin—Rabies, 2019). It is important to remember rabies infection is 100% preventable. If medical attention is sought directly after rabies exposure, the likelihood of developing illness is miniscule.

For possible exposure to rabies, doctors will administer postexposure prophylaxis (PEP), which consists of the rabies vaccine (you will receive additional doses at days 3, 7, and 14) and a dose of ‘human rabies immune globulin’ (HRIG)

But what if you don’t receive treatment immediately? Well, the statistics are not on your side; rabies is fatal in nearly 100% of cases (CDC – Rabies Postexposure Prophylaxis (PEP)—Medical Care—Rabies, 2022). However, that may not be the case for much longer. In 2004, doctors documented the first known case of an individual who recovered from a stage 3 rabies infection. She had no prior record of vaccination for rabies and did not seek treatment for the initial bite from a bat on her finger. It took one month for symptoms to present themselves and thus for her to seek medical care. Once she presented at the hospital, the virus had already entered her CNS, and she was showing symptoms including: fever, slurred speech, unsteady gait, muscular tremors, and unintentional eye movements. Despite this, after 76 days of treatment she recovered and was able to return home. She was left with some residual neurologic symptoms such as some balance and running issues and some difficulty speaking quickly. Otherwise she is now living a fairly normal life (Paoli, 2013). The treatment, now termed the Milwaukee protocol, was relatively simple and quite elegant: doctors induced a coma until the patient’s natural immune system built up enough of a response to fight off the virus itself. This immune support was encouraged with antivirals and some suppressors of neurotransmitters thought to aid in transmission of rabies from cell to cell. (Willoughby et al., 2005). Since this initial success there have been some other successes but also many failures (de Souza & Madhusudana, 2014). The Milwaukee protocol has been called into question and has mixed support (Zeiler & Jackson, 2016; de Souza & Madhusudana, 2014). But regardless of its level of continued efficacy, some hope for the future has come out of these success cases. And researchers believe this hope lies with the blood brain barrier.

As mentioned above, rabies has an unusual relationship with the BBB, preventing it from becoming permeable until it is too late. Still, it has recently been discovered that the timing and degree of permeability may depend on what strain you have. Patients with bat-originated rabies, like the girl above, seem to have more permeable BBB than those who were infected by other animals. This is supported by laboratory studies in which rabies antibodies were found in the brains of animals infected with bat-originating rabies virus. These antibodies originate outside of the brain and need to be transported through the BBB, meaning that if they are found within the brain the BBB had to have been permeable enough to let them through. This implies that if the body is supported through its weakened state and given antivirals, it may just be enough to fight off the infection. There have now been additional cases of people surviving similar infections (Wang et al., 2013). The success seen by these patients raises an interesting question: can we improve survival rates even more by helping rabies patients to permeabilize their BBB? Hopefully in the next few years science will deliver an answer.

At the moment, however, rabies is still extremely fatal. We are only in the very early years of developing a real fighting chance for those who develop an infection. But we are not where we were for our first 4000 years dealing with this disease. We have a vaccine, we have a real understanding of how the virus works, and we have even been able to utilize it to help us learn things about our own bodies. The best advice is still to vaccinate your animals, report any wild animals acting strangely, and seek medical attention if you are ever bitten or scratched by an animal. But rabies is now 100% preventable and hopefully we won’t have to fear it for much longer.

~~~

Written by Julia LaValley
Illustrated by Aishwaria Maxwell
Edited by Paige Nicklas, Liza Chartampila, and Shiri Spitz Siddiqi

~~~

Become a Patron!

References

Aguèmon, C. T., Tarantola, A., Zoumènou, E., Goyet, S., Assouto, P., Ly, S., Mewanou, S., Bourhy, H., Dodet, B., & Aguèmon, A.-R. (2016). Rabies transmission risks during peripartum – Two cases and a review of the literature. Vaccine, 34(15), 1752–1757. https://doi.org/10.1016/j.vaccine.2016.02.065

Belay, E. D., & Monroe, S. S. (2014). Low-Incidence, High-Consequence Pathogens. Emerging Infectious Diseases, 14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901478/

CDC – How is rabies transmitted? – Transmission. (2019). Centers for Disease Control and Prevention. https://www.cdc.gov/rabies/transmission/index.html

CDC – Medical Care: Human Rabies Immune Globulin—Rabies. (2019). Centers for Disease Control and Prevention. https://www.cdc.gov/rabies/medical_care/hrig.html

CDC – Rabies around the World—Rabies. (2020). Centers for Disease Control and Prevention. https://www.cdc.gov/rabies/location/world/index.html

CDC – Rabies Postexposure Prophylaxis (PEP)—Medical Care—Rabies. (2022). Centers for Disease Control and Prevention. https://www.cdc.gov/rabies/medical_care/index.html

Daneman, R., & Prat, A. (2015). The Blood–Brain Barrier. Cold Spring Harbor Perspectives in Biology, 7(1). https://doi.org/10.1101/cshperspect.a020412

de Souza, A., & Madhusudana, S. N. (2014). Survival from rabies encephalitis. Journal of the Neurological Sciences, 339(1), 8–14. https://doi.org/10.1016/j.jns.2014.02.013

Finke, S., Brzózka, K., & Conzelmann, K.-K. (2004). Tracking Fluorescence-Labeled Rabies Virus: Enhanced Green Fluorescent Protein-Tagged Phosphoprotein P Supports Virus Gene Expression and Formation of Infectious Particles. Journal of Virology, 78(22), 12333–12343. https://doi.org/10.1128/JVI.78.22.12333-12343.2004

Gadre, G., Satishchandra, P., Mahadevan, A., Suja, M. S., Madhusudana, S. N., Sundaram, C., & Shankar, S. K. (2010). Rabies viral encephalitis: Clinical determinants in diagnosis with special reference to paralytic form. Journal of Neurology, Neurosurgery & Psychiatry, 81(7), 812–820. https://doi.org/10.1136/jnnp.2009.185504

Gryshyna, A. (2022, October 31). An Eternal Search For a “Cure”: How Real-World Diseases May Have Led to the Modern Vampire. Knowing Neurons. https://knowingneurons.com/blog/2022/10/31/modern-vampire/

Jackson, A. C. (2011). Update on rabies. Research and Reports in Tropical Medicine, 2, 31–43. https://doi.org/10.2147/RRTM.S16013

Jackson, A. C. (2013). Chapter 1—History of Rabies Research. In Rabies (Third Edition) (pp. 1–15). Academic Press. https://doi.org/10.1016/B978-0-12-396547-9.00001-8

Koury, R., & Warrington, S. J. (2023). Rabies. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK448076/

Kusne, S., & Smilack, J. (2005). Transmission of rabies virus from an organ donor to four transplant recipients. Liver Transplantation, 11(10), 1295–1297. https://doi.org/10.1002/lt.20580

Lippi, G., & Cervellin, G. (2021). Updates on Rabies virus disease: Is evolution toward “Zombie virus” a tangible threat? Acta Bio Medica : Atenei Parmensis, 92(1), e2021045. https://doi.org/10.23750/abm.v92i1.9153

Ma, X., Monroe, B., Wallace, R., Orciari, L., Gigante, C., Kirby, J., Chipman, R., Fehlner-Gardiner, C., Gutierrez Cedillo, V., Peterson, B., Olson, V., & Bonwitt, J. (2021). Rabies surveillance in the United States during 2019 in: Journal of the American Veterinary Medical Association Volume 258 Issue 11 (2021). Journal of the American Vetrinary Medical Association, 258(11). https://avmajournals.avma.org/view/journals/javma/258/11/javma.258.11.1205.xml?rskey=ICrxXz&result=2

Nayak, J. B., Chaudhary, J. H., Bhavsar, P. P., Anjaria, P. A., Brahmbhatt, M. N., & Mistry, U. P. (2022). Rabies: Incurable Biological Threat. In Zoonosis of Public Health Interest. IntechOpen. https://doi.org/10.5772/intechopen.105079

Paoli, J. (2013). Is Rabies Really 100% Fatal? | Viruses101 | Learn Science at Scitable. https://www.nature.com/scitable/blog/viruses101/is_rabies_really_100_fatal/

Rohde, R. E. (2020). Common Myths and Legends of Rabies. Rabies, 69–78. https://doi.org/10.1016/B978-0-323-63979-8.00005-2

Roy, A., & Hooper, C. D. (2008). Immune evasion by rabies viruses through the maintenance of blood-brain barrier integrity. Journal of NauroVirology, 14(5), 401–411. https://www.tandfonline.com/doi/abs/10.1080/13550280802235924

Roy, A., Phares, T. W., Koprowski, H., & Hooper, D. C. (2007). Failure To Open the Blood-Brain Barrier and Deliver Immune Effectors to Central Nervous System Tissues Leads to the Lethal Outcome of Silver-Haired Bat Rabies Virus Infection. Journal of Virology, 81(3), 1110–1118. https://doi.org/10.1128/jvi.01964-06

Tarantola, A. (2017). Four Thousand Years of Concepts Relating to Rabies in Animals and Humans, Its Prevention and Its Cure. Tropical Medicine and Infectious Disease, 2(2), 5. https://doi.org/10.3390/tropicalmed2020005

Thomas, L. (2021, October 11). Why is the Rabies CFR So High? News-Medical Life Sciences. https://www.news-medical.net/health/Why-is-the-Rabies-CFR-So-High.aspx

Ugolini, G. (2011). Chapter 10—Rabies Virus as a Transneuronal Tracer of Neuronal Connections. In A. C. Jackson (Ed.), Advances in Virus Research (Vol. 79, pp. 165–202). Academic Press. https://doi.org/10.1016/B978-0-12-387040-7.00010-X

Wang, L., Cao, Y., Tang, Q., & Liang, G. (2013). Role of the blood-brain barrier in rabies virus infection and protection. Protein & Cell, 4(12), 901–903. https://doi.org/10.1007/s13238-013-3918-8

Warrell, M., Warrell, D., & Tarantola, A. (2017). The Imperative of Palliation in the Management of Rabies Encephalomyelitis. Tropical Medicine and Infectious Disease, 4(2). https://www.mdpi.com/2414-6366/2/4/52

WHO – Rabies. (n.d.). WHO | World Health Organization. Retrieved October 31, 2023, from https://www.who.int/health-topics/rabies

WHO – Rabies—Presence of dog-transmitted human rabies. (2021). WHO | World Health Organization. https://apps.who.int/neglected_diseases/ntddata/rabies/rabies.html

Willoughby, R. E., Tieves, K. S., Hoffman, G., Ghanayem, N., Amile-Lefond, C., Schwabe, M., Chusid, M., & Ruppercht, C. (2005). Survival after Treatment of Rabies with Induction of Coma. The New England Journal of Medicine, 352. https://www.nejm.org/doi/full/10.1056/NEJMoa050382

Wilson, P., & Rohde, R. (2021, September 27). The One Health of Rabies: It’s Not Just for Animals. American Society for Microbiology. https://asm.org/Articles/2021/September/The-One-Health-of-Rabies-It-s-Not-Just-for-Animals

Zeiler, F. A., & Jackson, A. C. (2016). Critical Appraisal of the Milwaukee Protocol for Rabies: This Failed Approach Should Be Abandoned. Canadian Journal of Neurological Sciences, 43(1), 44–51. https://doi.org/10.1017/cjn.2015.331

Author

  • Julia LaValley

    Julia is a PhD student in the Neuroscience and Behavior program at UMass Amherst. Her research involves using florescent imaging paired with immunohistochemistry and in situ hybridization to investigate the neural centers responsible for sensory processing and motor control in invertebrate mollusks. In addition to her research, she is also active in the science policy and science communication fields. Outside of work, Julia enjoys going for hikes with her dogs, reading sci-fi, and trying new recipes. For more information, please visit her profile. (https://www.linkedin.com/in/julia-lavalley/)

Julia LaValley

Julia is a PhD student in the Neuroscience and Behavior program at UMass Amherst. Her research involves using florescent imaging paired with immunohistochemistry and in situ hybridization to investigate the neural centers responsible for sensory processing and motor control in invertebrate mollusks. In addition to her research, she is also active in the science policy and science communication fields. Outside of work, Julia enjoys going for hikes with her dogs, reading sci-fi, and trying new recipes. For more information, please visit her profile. (https://www.linkedin.com/in/julia-lavalley/)