Facing the Mythical Fury: The Calamitous Path of Lyssavirus Rabies

Anna Conway

Illustrations by Emily Holtz

It is an unseasonably pleasant afternoon in August when Jane Doe and her partner decide to take a weekend camping trip. They pack their minivan with sleeping bags and sandwiches and set off toward their campsite on a congested Florida highway. Friday and Saturday go off without a hitch. They have lots of fun, but Jane becomes weary from two nights of sleeping on the harsh ground. She decides to pitch a hammock between two tall trees while the early afternoon sun is still high in the sky. Jane then notices a little brown bat flying haphazardly a few yards away, low to the ground. She thinks nothing of the creature as it is minding its own business. Suddenly, she feels a pinch near her knee, by the lower end of her hamstring. She hurriedly leans down to inspect the source of the pain. The bat had bitten her. The wound is shallow and hardly draws any blood at all. Viewing it as an annoyance more than anything else, Jane — an otherwise healthy thirty-year-old woman— hops into her hammock and enjoys a nap in the sun. However, this is a fatal mistake. A horrifying predator by the name of Lyssavirus rabies has found its way beneath her skin, ready to claim her as its next victim.

Lyssavirus rabies derives its name from Lyssa, the Greek goddess of rage and fury, known for turning dogs mad and against their owners [1]. Lyssavirus rabies, colloquially known as the rabies virus, is responsible for approximately 59,000 deaths per year, with 95% of cases occurring in Asia and Africa [2, 3]. Most frightening of all, the virus is almost always fatal once symptoms have begun. This stage is often referred to as the ‘point of no return,’ where the virus attacks the nervous system, ultimately leaving people as mere shells of their former selves [4, 5, 6]. Let’s turn back to Jane Doe on her camping trip, and examine what exactly happens when a human is infected with the rabies virus.

What is the Rabies Virus?

Composed of a short chain of five proteins, the rabies virus is a considerably simple structure with only two goals: infect and replicate [7, 8, 9]. Completely dependent on its host’s metabolic processes to survive, the rabies virus is a cellular intruder — sapping energy and hijacking cell functioning to transform those cells into centers for replication [9]. Beginning its journey from the bite in Jane Doe’s hamstring, the rabies virus silently replicates and infects neighboring cells: a slow yet widespread invasion entirely unbeknownst to Jane [4, 10]. Anxious to return to work on Monday morning, Jane places a band-aid over the inconspicuous wound and resumes her daily life, gradually forgetting about that humid afternoon and the bite on her leg. For a little while, it seemed as though nothing would come of that distant memory. On average, rabies has an incubation period of 15 to 90 days, during which those infected are asymptomatic and remain unaware of the vast internal spread of the virus [3, 10, 11, 12]. Since Jane was bitten on a lower extremity — further from the spinal cord — her incubation period will likely fall closer to 90 days, which is more than enough time for the wound to heal and for the memory of the bite to fade [10, 13].

A Patient Predator

Under the skin, however, the rabies virus is furiously carrying out the instructions encoded in its genome: replicate and move toward the central nervous system, where it can continue to replicate at an accelerated rate [6, 14]. From its original infection point in Jane Doe’s hamstring, the virus leaps into her peripheral nervous system — that is, all of the nerves outside the brain and spinal cord — via the neuromuscular junction [12, 14, 15]. The neuromuscular junction (NMJ) is a synapse, or bridge for communication, between a neuron and a muscle [16]. The NMJ is vital for movement, relaying signals from the nervous and muscular systems to prompt muscle contractions [16]. Once the virus invades Jane’s peripheral nervous system, it moves toward the next target: the spinal cord [14]. If the rabies virus behaved like other molecules in the body, such as proteins, it would be passed along in the ‘forward’ direction: from the dendrites — the receiving end of the neuron — to the cell body and down the axon toward the axon terminal — the transmitting end of the neuron [17]. While less frequent, molecules can move ‘backward’ via the reverse process, referred to as retrograde transport: moving from the axon terminal, up the axon, and toward the cell body and dendrites. As transport must be quick and efficient no matter the direction, retrograde transport is aided by other protein players, primarily a motor protein called dynein [17].

The rabies virus is distinct because it takes advantage of retrograde transport by hijacking dynein proteins [14, 18]. The virus acts as a stowaway, ‘hitching a ride’ on dynein to be transported up the axon via microtubules — a cellular highway — progressing closer to the central nervous system with each neuron it travels on [14, 18]. Eventually, the rabies virus progresses toward Jane Doe’s spinal cord, all the while replicating and taking over more cells on the path to total destruction [12, 14].

You might be asking yourself: what is Jane’s immune system doing to fight off the virus? Unfortunately, the answer is very little [8, 19]. Ordinarily, when the body is infected with a foreign pathogen, the immune system acts quickly to destroy the infection and protect healthy cells [19]. The immune response is kickstarted by interferons that act as alarm bells when released by infected cells [20]. Interferons cause both the infected and neighboring cells to produce antiviral proteins, which prevents further viral replication in every cell involved [20, 21]. Interferons can also summon specialized immune cells to the infection site and compound the antiviral effort [21]. However, the rabies virus works to inhibit interferon signaling pathways [19, 22]. Despite the infected cells’ attempt to initiate an antiviral effort via interferons, the virus ensures that cells are rendered unable to produce and deliver interferons outward [19]. Thus, neighboring cells do not erect their antiviral defenses, and are easily invaded by the rabies virus, which can then replicate unchecked within them [3, 19, 23]. Throughout a typical viral invasion, the infected cells produce a substantial amount of chemokines, another type of molecule that acts as an alarm system [24]. Chemokines prompt your immune cells to rush toward the infection site and fight off the virus [19]. However, the rabies virus causes cells to produce only a moderate amount of chemokines. As such, a full-scale immune response is not actualized, and the virus flies under the immune system’s radar [19]. All the while, Jane Doe remains none the wiser. She goes to work, hangs out with her friends, and feels completely healthy while the rabies virus tirelessly progresses toward her central nervous system — specifically the spinal cord. Jane is entirely unaware that soon, it will be too late to alter her fate.

A Neurological Nightmare

On a cold Tuesday morning, Jane Doe wakes up with a fever. She twists and turns in bed, feeling uncomfortable. She remains oblivious to the fact that the rabies virus has reached its first major destination— the central nervous system [3]. Jane is unaware that her run-of-the-mill fever indicates something far more sinister: that the virus has reached the point of no return, where no current treatment regimen is capable of reversing the inevitable [6, 8, 25]. While there is still a degree of uncertainty regarding exactly what happens once the rabies virus reaches the spinal cord, it is believed that the virus’s introduction to the central nervous system prompts a devastating cascade of neuronal dysfunction, ultimately leading to death [3, 12, 25, 26]. Though the virus has previously evaded the immune system, it is the virus’s introduction to the central nervous system that finally triggers a full-scale immune response [8]. Jane lies on her bed, feeling feverish and fatigued, alternating between curling up into her blankets and kicking them off [25, 27]. Jane has entered the early phase of the disease, where she begins displaying non-specific symptoms as a result of her immune system’s early fight against the rabies virus [4, 8]. Unfortunately, the immune system is far too late. The rabies virus has succeeded in infiltrating the central nervous system and now blocks immune cells from clearing the virus by preventing the enhancement of blood-brain barrier permeability [28, 29]. The blood-brain barrier is composed of a tight layer of specialized cells located around the blood vessels in the central nervous system [30]. The blood-brain barrier works to prevent toxins, pathogens, and potentially harmful chemicals from gaining access to the central nervous system [30]. Even though Jane’s immune system has been alerted to the presence of a viral infection, most immune cells are unable to access her brain and spinal cord [29, 31, 32]. Not only are immune cells barred from entry into the central nervous system, but they are also ordered to perform apoptosis: programmed cell death [31]. The immune system is once again hindered as the virus begins to infect Jane’s brain, wreaking fatal havoc in the process [31].

Brain activity is due to action potentials, which are electrical signals sent down the axon that allow for communication between neurons [33]. The successful propagation of neural signals is highly dependent on ion channels within the neuron’s membrane: namely, sodium and potassium channels [34]. The malfunctioning of these channels is closely related to many neurological disorders, such as epilepsy [35]. The rabies virus causes dysfunction in sodium and potassium channels; as a result, action potentials cannot be properly sent down the axon, and communication between neurons is impaired [25, 36]. Once the virus spreads throughout the brain, the neural areas responsible for controlling impulses and aggression become dysfunctional [36]. As a result, Jane begins to yell and punch her bedroom walls in two-minute spells [4]. Her partner — frightened for Jane’s safety — begs and pleads for an explanation for her aggression. Unfortunately, Jane is also experiencing confusion, accompanied by the disorienting effects of a fever [4, 25]. She is unable to properly articulate what is wrong as the virus overtakes her brain, in preparation to fatally ravage the rest of her body [25].

The rabies virus then spreads outward from the central nervous system, descending back into the peripheral nervous system in a process called centrifugal spread [25, 37]. The virus’s next destinations are Jane’s internal organs. Jane’s throat begins to ache, and the previously bitten leg develops a tremor [4, 25, 38]. Her partner offers her a glass of water, hoping to aid in her fever. Jane, however, is beginning to experience a classic symptom of rabies: hydrophobia [4]. It is believed that hydrophobia is caused by infection in the areas of the brainstem that control neurons involved in swallowing. While ordinarily protective, the rabies virus causes our body’s natural choking instinct to become wildly overactive, sometimes occurring anytime water is ingested at all. As the water washes down Jane’s throat, her diaphragm painfully contracts in a horrific spasm that lasts about ten seconds. She vomits the water back up and begins to convulse, refusing any further offers of water. She even trembles in fear at the mere sight of it [4]. However, her self-imposed dehydration does not prevent the ‘foaming of the mouth’ that we commonly associate with rabies, which occurs as the virus infiltrates the salivary glands to provide its host with a method of transmitting the virus to others, via biting [39]. At this point in the virus’s assault, Jane Doe is in pain, thirsty, and deeply confused as to what is happening to her. Just under two weeks after the initial onset of clinical symptoms, the introduction of the virus into the heart causes a defect in the electrical conduction of cardiac impulses [40]. As a complication of the rabies virus, Jane goes into heart failure from myocarditis — or inflammation of the heart — which is listed as her cause of death [40].

Hope in Rabies Treatment

While Jane’s story is harrowing, researchers and policymakers are striving to ensure that rabies is someday eradicated, so that no more stories have to end like Jane’s. Since a common method of rabies transmission is through dog bites, many countries in the Western Hemisphere have rolled out massive vaccination campaigns for domestic dogs and created more stringent guidelines for responsible pet ownership [41]. The goal is herd immunity: maintaining widespread rabies resistance in a large percentage of the canine population. As a result of these measures, strains of the rabies virus are becoming progressively rarer. Cases of human rabies in North America have plummeted to near zero, and have been steadily decreasing throughout the Caribbean and South America [41]. Moreover, extremely efficacious protocols have been implemented for when an individual believes that they have been infected with rabies, which aim to address the virus before it reaches the point of no return [42]. An individual would receive a series of purely preventative injections referred to as post-exposure prophylaxis, or PEP. PEP, at its core, relates to the function of antibodies against antigens [42]. Antibodies are proteins produced by immune cells that are specialized to fight against antigens: which are any substances the immune system can respond to [43, 44]. Antigens that are recognized as foreign are subsequently attacked by the immune system, using antibodies [44]. PEP protocol takes a three-pronged approach: carefully washing any wounds potentially involved in rabies transmission, administering a rabies vaccination, and providing rabies immunoglobulin (RIG) [42]. RIG is composed of antibodies from humans that have received the rabies vaccine [45]. Since it often takes upwards of eight days for the average person to begin producing their own rabies-fighting antibodies in response to the vaccination alone, RIG is administered so the body can begin fighting off the virus as soon as possible. Once administered, the virus is unable to hide from the now-enhanced immune system [45]. The World Health Organization estimates that current PEP regimens are nearly 100% effective, and there are very few recorded deaths due to rabies after someone with confirmed rabies exposure undergoes the PEP regimen prior to the onset of clinical symptoms [42].

So, what can be done if someone is experiencing symptoms of a rabies infection? In such cases, doctors have often attempted a regimen called the Milwaukee Protocol. Through this protocol, people are placed into a medically induced coma and are provided with a cocktail of drugs that have antiviral properties in an attempt to slow the neurological destruction caused by the rabies virus [46, 47]. The combination of therapies in the Milwaukee Protocol was inspired by discovered treatments for other diseases, such as cancers and HIV, which respond well to multiple drugs administered simultaneously [46]. In a famous 2004 case study, a fifteen-year-old girl survived the rabies virus with only mild neurological deficits after undergoing the Milwaukee Protocol [48, 49]. However, it is unclear whether the Milwaukee Protocol truly made a difference when it came to her survival [4, 46]. Sadly, there have been numerous documented failures of the Milwaukee Protocol since the case study was published [46, 47, 50]. Due to the Milwaukee protocol’s lack of efficacy, many experts have recommended that the protocol be discontinued as a treatment for rabies [4]. Instead, most medical attention has been placed on preventing the spread of the virus and treating it in its early stages to ensure that the rabies infection does not reach the point of no return in infected individuals [46].

While the protocol’s lack of success is discouraging, further research is being conducted to create an effective regimen to treat rabies in its symptomatic stage so that there is a chance of recovery from what is typically the point of no return. Monoclonal antibodies, which are lab-made proteins that are meant to be a clone of one specific antibody, seem to be the key [51, 52]. Once monoclonal antibodies stick to their corresponding antigen, they can assist in destroying other cells that also contain a harmful antigen by marking those infected cells for later immune destruction [51, 52]. When treated with a combination of two monoclonal antibodies, rabid mice who were already in a symptomatic stage were completely cured of the virus [53]. While research on humans has yielded less conclusive results, current research is steadily moving toward a cure for symptomatic rabies — an innovation that would save countless lives, Jane’s included [54].

Quelling Lyssa’s Fury: A Path to Rabies Eradication

While the rabies virus still occupies many people’s worst nightmares, progress is on the horizon [55, 56, 57]. The World Health Organization maintains its goal of eradicating canine-born rabies from 155 countries by 2030 [58]. While nearly 60% of current human rabies cases originate in Asia, many countries such as Thailand and Vietnam are seeing rapid decreases due to increased canine vaccination [55, 56]. Singapore has even been declared rabies-free [55, 56]. A growing focus on community-based public health programs has shown to be majorly effective at both contributing to the eradication of rabies and the maintenance of rabies-free areas, which are becoming progressively wider [56]. Furthermore, the global disease burden — often measured together as both years spent disabled by disease and years lost due to disease-related premature death — caused by rabies has shrunk over the last thirty years. [57, 59]. While improvement is significant and deserves celebration, disease burden due to rabies is still highly correlated to socioeconomic index, with those from middle and low-income countries bearing the vast majority of that burden [57].

Greater global attention must be focused on guaranteeing equal access to the PEP regimen across all populations, as well as providing education to ensure that those exposed to the rabies virus seek treatment [60]. Jane’s story might have ended in tragedy, but there is a great deal of hope for a future entirely rid of the rabies virus, sending Lyssa’s wrath back to the myths where it belongs.

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