The Quest to Beat Rabies at Its Own Neuro-Destructive Game

Despite being arguably the oldest disease known to humans, rabies remains a terrifying mystery. Allowed to progress to the neuro-symptomatic stage, the infection is universally fatal. It's a nightmare death: psychosis, terror, convulsions, coma.

Research out this week from a team based at Tel Aviv University, published in the journal PLOS Pathogens, offers a rare glimpse into the mechanics of the virus. In particular, it describes how the virus is able to enter the central nervous system so quickly and with such apparent determination. Essentially, the virus perpetrates a series of neurological hijackings, latching on to nervous system's intercellular transport mechanisms and piloting them right into the spinal column and then on into the brain.

Rabies doesn't kill many people in the United States anymore, taking just one or two lives in a given year. This is largely thanks to one of the most successful disease eradication programs in human history, the result of a combination consisting of scrupulous reporting of infected animals, mandatory dog and cat vaccinations, and the development of a human rabies vaccine that can be administered after a bite has occurred (but before symptoms), an approach known as post-exposure prophylaxis.

For the vast majority of infections, the virus is introduced with a bite. In the US, this is usually courtesy of a bat, but in other parts of the world with less rigorous vaccination programs, a dog is most likely to be the cause. Saliva containing the virus is delivered via the bite into the victim's local muscular tissue. Like any smart virus, it immediately begins taking over human cells, injecting its genetic material deep within and effectively turning the "captured" muscle cells into virus factories.

This is the prodromal stage, characterized by nonspecific symptoms that might resemble the flu or some other mild illness. The virus gradually builds up its army and, eventually, it takes note of neighboring neuromuscular junctions. These junctions are just what they sound like: the synapses where nerves connect with muscle fibers. And rabies has a unique affinity for nervous tissue, quickly spreading from the body's outlying peripheral nerves to the spinal cord and, soon enough, the brain itself.

The quickness with which rabies travels through the nervous system is startling, and it's here that the current study offers some answers.

The Tel Aviv researchers started by growing mouse nervous tissue in an observation chamber. Using live cell imaging, a technique akin to time-lapse microscopy, they were able to trace out the whole hijacking process.

"We suggest that RABV [rabies] hijacks a specific mechanism that enables the neuron to transport cargos over long distances," the study explains. Basically, the rabies virus binds itself to a nerve growth factor (NGF) known as p75, which would just be some typical cargo within the body's neuro-transport system.

For transport, p75 is internalized into a compartment of sorts, like a cellular shipping container. Since it's bound to the NGF, the rabies virus gets to go along with it.

This ability is clever and fascinating, but it gets better (or worse). The virus isn't just a passive stowaway; it pushes the transport mechanism "train" to move even faster than it would had its cargo been a regular NGF. It's as if the virus has a gun to the head of the neurological transport medium, growling, "get to the spinal column, now."

"Rabies not only hijacks the nervous system's machinery, it also manipulates that machinery to move faster," explains Eran Perlson, the current study's lead investigator, in a statement provided by Tel Aviv University. "We have shown that rabies enters a neuron in the peripheral nervous system by binding to a nerve growth factor receptor, responsible for the health of neurons, called p75. The difference is that its transport is very fast, even faster than that of its endogenous ligand, the small molecules that travel regularly along the neuron and keep the neuron healthy."

How it manipulates this machinery is still a mystery. We now know that the virus has some way (the gun) of directing its hijacked neural vehicle toward a final central nervous system destination, but the exact nature is for future study. Understanding this mechanism might mean exploiting or perhaps even blocking it, which could potentially slow the virus's progression dramatically.

As it stands, there's really not much that can be done once the virus is on its way to the brain. Once it's there it's there, and that's the start of some ghastly pathogenic brutality. A 2012 study exploring the re-emergence of the virus in Bali during the late-'00s summarizes the neurological features of the disease well enough:

The acute neurological signs were either furious (79.8%) or paralytic (20.2%). In the furious cases, 89.2% of patients showed intermittent agitation and confusion. Signs of autonomic dysfunction were hydrophobia (93.1%), hypersalivation (88.2%), aerophobia (73.1%), dyspnea (74.5%), photophobia (29.8%) and piloerection (4.8%). Other signs included fever (18.2%), muscle fasciculation (3.8%), and convulsions (15.4%). Cranial nerve involvement and ophthalmoplegia, facial weakness and dysphagia were reported in 2.9% of patients. In the paralytic rabies cases, signs of flaccid paralysis were recorded in 21% of patients, urinary incontinence in 27.5%, and abdominal discomfort in 10.8%. The acute signs ended with abrupt death or progression into coma before death.

So, that's it: uncontrollable rage, delirium, psychosis, excruciating pain, coma, death. Treatments are mostly supportive and the fatality rate is near 100 percent, no matter what. Contrast this with the fatality rate for Ebola, which ranges dramatically among countries with differing health care systems and, thus, abilities to provide basic support to patients. Figure that you're a whole lot less likely to die of Ebola in a well-equipped hospital than elsewhere. Rabies? Not so much.

For a brief moment, there was some hope in what's known as the Milwaukee protocol. This is a an extreme last-ditch effort consisting of an induced coma along with batteries of antiviral drugs, ketamine, and anticonvulsants. It worked successfully once in a patient named Jeanna Giese, along with a small handful of others later on.

The disease leaves its mark even on those few that've been cured. "I had to learn how to stand and then to walk, turn around, move my toes," Giese told Radiolab in 2013. "I was really, after rabies, a new born baby who couldn't do anything. I had to relearn that all…mentally I knew how to do stuff but my body wouldn't cooperate with what I wanted it to do. It definitely took a toll on me psychologically. You know I'm still recovering. I'm not completely back. Stuff like balance and, um, I can't run normally."

A 2013 paper published in the journal Antiviral Research wrote the Milwaukee protocol off entirely. "Although the positive outcome in [the Jeanna Giese] case has been attributed to the treatment regimen, it more likely reflects the patient's own brisk immune response, as anti-rabies virus antibodies were detected at the time of hospital admission, even though she had not been vaccinated," the report's author, Alan C. Jackson, wrote. "This is supported by the failure of the 'Milwaukee Protocol' to prevent death in numerous subsequent cases."

"Use of this protocol should therefore be discontinued," Jackson concluded.

In a paper earlier this year, Jackson expanded on the difficulties in using antiviral drugs in treating the rabies virus. Mainly, it's an issue of delivery. "There are many important issues for consideration for drug delivery to the central nervous system in rabies, which are in part related to the presence of the blood-brain barrier and also the blood-spinal cord barrier," Jackson wrote. "New approaches are needed and an improved understanding of basic mechanisms responsible for the clinical disease in rabies may prove to be useful for the development of novel therapeutic approaches."

This is hopefully where current study can shed some light. If a virus can exploit the nervous system's transport system, perhaps doctors can too.

"Understanding how an organism such as rabies manipulates this machinery may help us in the future to either restore the process or even to manipulate it to our own therapeutic needs," Perlson said. "A tempting premise is to use this same machinery to introduce drugs or genes into the nervous system."

It would then be a treatment based on "hijacking the hijacker," using whatever sinister means the rabies virus uses to drive itself into the central nervous system to drive an antiviral agent in right after it.