Most people have heard of rabies, either from a movie or perhaps in the news. Rabies is an ancient
disease, at least 4,000 years old, which has been mentioned in the writings of doctors, pharmacists,
veterinarians, poets, philosophers, and surgeons in various forms over the years. The earliest
records were written on tablets, and as far back as 1900-1600 BCE, these writings hinted
at the possibility that rabies transmission was somehow related to the saliva of an afflicted
animal. The greatest minds in nearly every era since then had sought to understand how to prevent
and treat rabies, and speculated about what caused it. Some remedies involved herbs or incantations,
while others involved amputation or burning the bite wound with religious relics. It wasn’t until
Louis Pasteur developed the killed-rabies vaccine in the 1880s that a bite from a so-called
“mad” dog didn’t mean certain death. So let’s dive into what makes this
virus so deadly. The rabies virus belongs to the genus Lyssavirus, in the Rhabdoviridae family,
which includes a few other pathogens, but nothing quite as terrifying as rabies.
Rhabdoviruses are surprisingly simple viruses that encode only five proteins, and they appear as
bullet-shaped, enveloped virions with glycoprotein spikes on the surface. These virions have a
helical nucleocapsid within the envelope that’s symmetrically coiled into a cylindrical structure.
The nucleocapsid is composed of one molecule of negative sense, single-stranded RNA that’s
about 12,000 bases long. Even with only five proteins encoded, the virus has the ability
to protect itself from ribonuclease digestion and retain a shape that is ideal for transcription.
The way that it replicates is as follows. First, the glycoprotein spikes of the virus attach to the
host cell. This attachment triggers endocytosis, where the plasma membrane of the host cell folds
inward and forms a membrane-bound vesicle, called an endosome, around the virus,
essentially trapping the virion in a plasma membrane bubble within the host cell. Once there,
the viral envelope fuses with the membrane of the endosome, which uncoats the virion and sends the
nucleocapsid into the cytoplasm for replication. Within the cytoplasm, the virus uses a combination
of its nucleocapsid-encoded enzymes and host cell machinery to transcribe viral RNA.
Five mRNAs, one for each encoded protein, are produced. The virion then assembles in two phases.
First, the nucleocapsid is assembled in the cytoplasm. Then the virion is pushed out through
the cell plasma membrane in a process called budding, taking part of that membrane with it,
which gives the virion its envelope. And the new virion is now ready to infect another host cell.
Now that we know what’s happening on a cellular level, let’s zoom out and think about what happens
in the body of someone who’s been infected. The rabies virus can be introduced either from
the bite of an infected animal, by inhaling aerosolized virus in places like bat caves,
from an organ transplant with infected tissue, or by some other sort of inoculation through the
mucosal membranes, like a scratch. Bites are the most common transmission method though,
and it’s specifically the saliva of the infected animal that transmits the virus.
First, the virus replicates in the muscle tissue at the bite site, which is part of
the incubation phase, but there are typically no symptoms at all during this phase. Here’s
what makes this virus so scary. The incubation period can last anywhere from days to months,
or even a year. It depends on the location of the wound and the viral load. Once symptoms set in,
the disease is fatal. There are very few known cases of survival once clinical disease kicks in,
which is why vaccination is incredibly important.
After the initial replication in the muscle tissue, or incubation phase,
the virus infects the central nervous system, traveling to the spinal cord and finally,
the brain, which is the prodrome phase. The prodrome phase can last between two and ten days,
and symptoms typically include fever, headache, itching at the site of the bite, malaise,
gastrointestinal symptoms, fatigue, or anorexia. Within the brain, the brain stem, hippocampus,
and critically important nerve cells then become infected, which cause the classic symptoms, coma,
and death. This is the neurologic phase. These classic symptoms are typically neurological
in nature, and the most common symptom, which happens in 20-50% of cases, is a fear of water,
or hydrophobia. That may sound strange, but what’s really happening there is it becomes
very painful to swallow water. At the same time, many patients experience seizures, disorientation,
and hallucinations, and anywhere from 15-60% of people infected experience paralysis, which can
lead to respiratory failure. The virus spreads to the skin of the head and neck, including the eyes,
nose, and salivary glands, the latter of which can transmit the virus to someone else.
After the neurologic phase, which lasts two to ten days, patients typically become comatose.
Rabies is considered a classic zoonotic infection, spreading from animals to humans. The rabies virus
is endemic, meaning regularly found, all over the world, with the exception of Australia. In
urban settings, dogs are the main transmitter, but many species of wildlife can transmit the virus.
In the United States in particular, we have a robust vaccination program for dogs,
so it turns out that rabies is actually more prevalent in cats,
because they are not unvaccinated. Other than that, in the US, wild raccoons, skunks, bats,
foxes, and farm animals can pass the virus to unvaccinated cats or dogs. However, in Latin
America and Asia, where stray, unvaccinated dogs are more common, there are thousands
of rabies cases in dogs each year. Worldwide, about 59,000 people die from rabies each year.
When it comes to diagnosis, any of the symptoms we just discussed are typically enough.
What’s really unfortunate, though, is that any kind of diagnosis, either by antibody test or
through symptoms, can’t happen until it’s too late to intervene. Post-exposure prophylaxis,
meaning a vaccine administered after the moment of infection, is the only way to prevent rabies
infection. That’s why doctors recommend that if you have any suspicions whatsoever that
you’ve been in contact with rabies, it’s best to get the vaccine to be on the safe side.