For the first time, Israeli scientists have watched and tracked exactly how the rabies virus gets into the central nervous system, where it causes a deadly explosion of symptoms.
The virus has long been known to travel along neurons, the cells that transmit the electrical and chemical signals enabling movement, feeling, and thought. Until now, though, nobody had been able to figure out how.
Using powerful live cell imaging, the scientists found that the virus hijacks the “train” that transports cell components along a neuron, and drives it full throttle into the spinal cord. From there, the virus likely takes other trains to the brain and then throughout the peripheral nervous system, they say – shutting down the body as it goes along.
“The rabies virus is transported through railway-like machinery in the neurons,” said Shani Gluska, a doctoral student at Tel Aviv University, who led the study along with Prof. Eran Perlson, a physiologist at the university. “With very high-end microscopy, we saw for ourselves how the virus not only hijacks the transport machinery, but also makes it go faster.”
The scientists say their findings, published in the journal PLOS Pathogens in August, could one day enable scientists to take control of the neuron train system to treat rabies, as well as other neurodegenerative diseases.
Seeing is believing
Rabies is infamous for its dramatic symptoms, like aggression, psychosis, wild movements, and “foaming at the mouth.” Without treatment in time by vaccination, rabies severely inflames the brain, ultimately leading to paralysis of the heart and lungs and, with a few recent exceptions, to death. More than 55,000 people die every year from rabies, mostly in Africa and Asia, according to the World Health Organization.
To see how the rabies virus travels through the nervous system, the Israeli scientists grew mouse sensory neurons in the lab and infected them with the virus. They tagged the virus with a fluorescent marker, then watched and recorded its movements in real time with a high-power microscope.
‘If we can learn how rabies manipulates the system, we can maybe try to manipulate it ourselves’
The scientists saw that the virus takes a route normally reserved for nerve growth factors, proteins that are responsible for development and health of neurons. The virus enters a neuron in the peripheral nervous system by binding to a nerve growth factor receptor called p75.
Once inside, the virus boards a “train car,” a bubble-like vesicle, and departs from the cell membrane. “Engines” – nano-sized motor proteins that typically chug up and down neurons to keep them alive – then hitch themselves to the car and pull it along “tracks,” microtubules. The ride continues through the neuron’s tail-like axon, which can stretch up to a meter in length, and on to its cell body, which is located in the spinal cord.
In the spinal cord, the scientists believe the virus catches the first available train to the brain, where it wreaks havoc before embarking on a tour of the body – though the study did not include the kinds of neurons that run directly to or from the brain. Compared to the growth factors that take the same p75 route, the virus travels much more quickly.
The scientists say the virus may speed up the train by pushing the engines harder, by dumping more “fuel,” or ATP, into the engines, or by demanding more engines or a better track. A minority of the rabies viruses in the study took other, slower routes along the neurons.
Putting the brakes on nerve disease
The results reveal what is likely a major mechanism the rabies virus uses to enter the peripheral nervous system, usually from the muscles, and to travel rapidly to the central nervous system, the scientists say.
Based on previous research, they say the virus probably travels in a similar way elsewhere in the nervous system: along motor neurons to the spinal cord, along interneurons in the spinal cord to the brain, and along motor neurons from the brain back to the peripheral nervous system.
Improved understanding of how the neuron train works could lead to new disease treatments, they say.
“If we can learn how rabies manipulates the system, we can maybe try to manipulate it ourselves,” said Perlson, who oversaw the study in his lab, which focuses on neuron signaling and transport. When it comes to rabies, interfering with the virus’ travel plans could extend the window of time for treatment, the scientists say.
The rabies vaccine is only effective until the virus reaches the central nervous system and begins causing symptoms, which usually takes one to three months. On the other hand, disruptions of the neuron train system contribute to neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).
The scientists say getting the train back on track could treat and possibly even cure such diseases.