Rabies is so good at penetrating the central nervous system it could help treat Parkinson’s
Transmitted by animal bites, rabies is a terrifying disease. Virtually every person who contracts the virus and shows symptoms dies…
Transmitted by animal bites, rabies is a terrifying disease. Virtually every person who contracts the virus and shows symptoms dies horribly. Victims suffer from severe physical and psychological effects. While it starts out with flu-like symptoms, it progresses to hallucinations, fear, paralysis, aggression, difficulty swallowing, and ultimately coma and death.
What makes it so terrible is its insidious ability to penetrate the central nervous system, seek out neurons, and attack them. Yet, it is precisely this ability that may make it an effective treatment vehicle for disorders of the central nervous system, the most common of which is Parkinson’s disease.
Parkinson’s is a progressive disorder of the central nervous system that affects millions worldwide with up to 2% contracting the disease, typically after age 65. A number of celebrities have been diagnosed, the most well-known being Michael J. Fox. Others include Billy Graham, who suffered with it for nearly 30 years until his death at age 99, George H. W. Bush, Muhammed Ali, and Alan Alda. Although it does not reduce life expectancy significantly, it presents unique challenges in mobility, speech, and may include psychological symptoms such as dementia. Some sufferers in the latest stages are completely bedridden.
There is no cure for Parkinson’s and, while drugs and treatments can manage symptoms, the loss of motor function as well as non-motor symptoms cannot be stopped or reversed.
The connection between rabies and Parkinson’s as well as diseases like it is in the virus that causes rabies, which, despite being a well-known virus, has many unique and poorly understood properties.
The first is its unusual method of infection. The virus typically starts in the muscle where the bite or scratch occurs, but, rather than traveling through the blood stream as many viruses do, it seeks out nerves through a neuro-muscular junction in the peripheral nervous system. It then infects the nerves sequentially making its way into the central nervous system, the spine and brain.
A variety of mechanisms protect the brain from invasions, the best known of which is the blood-brain barrier. For a long time, scientists believed that the brain was “immune privileged” in that it did not experience immune responses at all. We now know that is not true, but the way the immune system works in the brain is fundamentally different from the rest of the body. Thus, the brain is like a heavily defended fort or city, designed to keep things out (including life saving medicines) but internally it is not as well defended.
By traveling in reverse along nerves emanating from the brain, the rabies virus avoids the blood brain barrier. It can also invade the nerves devoted to our sense of smell to get at the brain directly because these are the only nerves that are part of the central nervous system but exposed to the outside. Once inside the brain it infects neurons using the very mechanism that the brain uses to function — its interconnections, hopping from neuron to neuron along the axons and even speeding them up to spread faster.
One of the other strange features of the rabies virus is its tendency to attack neurons only. It does not attack the surrounding brain tissue. This ability requires a unique mechanism to identify neurons versus other types of cells in a region that is jam packed with not only neurons but glial cells as well. Rabies viruses appears to use multiple mechanisms to bind to neurons since editing one mechanism out of its genetic code doesn’t remove the ability. The virus also typically attacks the emotional centers of the brain resulting in the aggression that leads to its being transmitted through bites. It isn’t clear how it targets this area of the brain.
The virus not only avoids the immune system by invading a part of the body that has reduced immunity, the nervous system, but it also disrupts the signaling the body uses to call for help when the virus is detected.
The virus is skilled at blocking entry of killer T and B cells into the brain. Vaccination against rabies stimulates these cells, and they are critical to surviving the infection (also important for COVID-19).
In order to infect others, rabies travels outward from the brain into the sense organs by the opposite route it took to infect the brain, along the nerves themselves, making its way into the saliva as well as the hair. In some species, such as bats, the infection takes a long time and the animals may even recover.
Oddly enough, although it has a near 100% fatality rate once symptoms show, scientists don’t know how rabies kills people. The actual damage rabies does to the brain turns out to be minimal, partly because it is so good at avoiding the immune system and therefore spares the brain from the devastating havoc that an inflammatory response could create. The psychological symptoms are likely a result of the virus itself rather than any immune response to it. One theory put forward was that excitotoxicity caused death. Essentially, neurons become so excited that they destroy themselves. But No evidence of excitotoxicity has been found in rabies infected animals. All we know for now is that rabies somehow disrupts the brain’s ability to regulate the heart, lungs, and circulatory system, ultimately causing those organs to fail. Indeed, rabies can infect the neurons in the heart directly, suggesting a potential cause of death outside the brain.
Human responses to rabies are typically either the “furious” or “paralytic” variety. The furious kind is classic rabies involving severe agitation and hydrophobia (inability to take water). As the symptoms progress, agitation gives way to paralysis and then coma. Death occurs with cardiac arrest or respiratory failure. In the paralytic variety, paralysis occurs without the agitation and then the same awful demise occurs.
Famed poet and author of such classics as The Raven and The Cask of Amontillado, Edgar Allen Poe, is thought to have perished of rabies — not alcohol poisoning as legend suggests. An alcoholic in his younger days, Poe had sworn off alcohol for the most part because of a terrible sensitivity to it. Rather than dying drunk in a gutter in Baltimore as his detractors claim, he was admitted to a hospital suffering from delirium. He experienced hallucinations and extreme agitation for four days, appearing to get better briefly, before slipping into a coma and dying in 1849 at age 40.
Because rabies is a master of deception and disguise, penetrating the nervous system in ways that life saving medicines cannot, it may be a perfect delivery mechanism for medicines to treat central nervous system disorders. In a 2018 study, Chinese researchers did just that, using the virus’s tricky mechanism to treat iron overload in the brain, caused by Parkinson’s.
The study, done on mice, involved designing a delivery system using rabies virus proteins to deliver deferoxamine to the brain.
Deferoxamine or DFO is drug used for iron chelation therapy to reduce the overload of iron in the brain, but it has a very short time between being put into the body before it disintegrates (about 20 minutes). It does not penetrate the blood-brain barrier well at all. The treatment cannot be given orally and requires 5–7 overnight subcutaneous infusions per week. It also has to be administered in high doses and has some serious side effects.
Attaching the drug to a rabies virus protein called glycoprotein-29, the researchers were able to deliver the drug to the brain and significantly reduce iron stress with small doses. The reduction in iron reduced neural damage and behavioral problems as a result.
While this process did not use the rabies virus itself, it did take some tricks out of the viruses book to develop a hugely beneficial treatment (at least in mice). Such nanotechnologies are making enormous progress towards treatments of disorders of the central nervous system where the blood brain barrier is a factor.
Rabies used to kill many more people like Poe but, thanks to Louis Pasteur who also invented the process named for him: pasteurization, there is a treatment. Rabies has such a slow incubation period, from a week to a couple of months, that, unlike many viruses, you can receive an inoculation against it after you’ve already been exposed. The inoculation lacks many of the virus’s immune system avoiding abilities because it is a weakened virus. It instead stimulates the system to destroy the real virus before it can cause symptoms.
Pasteur administered the first vaccine in 1885 to a 9 year old boy whose mother insisted Pasteur attempt the experimental procedure. The boy made a full recovery. Nowadays treatment typically involves both the vaccine as well as human immunoglobulin injections which provide a direct infusion of antibodies against the virus. This procedure, called post-exposure prophylaxis, should follow any bite by a strange animal or even waking up to find a bat in your bedroom. (Bats have such tiny teeth you can’t know if you’ve been bitten.)
About 30 million people a year receive this treatment, yet 60,000 people still die of the disease. In the US, however, only 25 cases have been reported in the past decade. Pasteur’s achievement, it turns out, has led to rabies becoming a neglected disease, unfortunately, because, as with many diseases, it is confined mainly to resource-poor regions. This neglect is unconscionable on its own, yet, it may also have caused us to miss a potential boon of information about how to manipulate the nervous system. Understanding rabies could make all the different to Parkinson’s sufferers and perhaps sufferers of other diseases as well.
You, Linhao, et al. “Targeted brain delivery of rabies virus glycoprotein 29-modified deferoxamine-loaded nanoparticles reverses functional deficits in parkinsonian mice.” Acs Nano 12.5 (2018): 4123–4139.
Gluska, Shani, et al. “Rabies virus hijacks and accelerates the p75NTR retrograde axonal transport machinery.” PLoS pathogens 10.8 (2014): e1004348.