For the first time, researchers have managed to successfully trace how the deadly rabies virus traverses considerable distances through nerve cells before ending up in the central nervous system (CNS), where it begins to exert its fatal effects. They found that the virus not only hijacks transport machinery that serves to keep the cell healthy and functional, but it actually manipulates this system in such a way that it cranks up its speed, thus facilitating its own efficient delivery to the CNS. The work has been published in PLOS Pathogens.
Rabies is a vaccine-preventable disease that affects over 150 countries and territories worldwide, resulting in some 55,000 deaths each year. It’s caused by a virus that can be transmitted to humans through the saliva of a rabid animal, which is a dog in the majority of cases.
After an individual is infected, the virus rapidly spreads from the peripheral nervous system (PNS) to the CNS where it causes encephalitis, or inflammation of the brain. After this, a variety of symptoms ensue such as paralysis, hallucination, excess salivation and aggression. Once a patient starts to show symptoms, treatment is essentially completely ineffective and the patient almost always dies.
Arriving at the CNS involves a considerable journey through nerves in the PNS. These cells consist of a long stringy protrusion known as an axon that extends from the cell body, or soma, to another cell. To traverse these cells, the virus must hijack existing cellular transport machinery, but until now the details of this event were unknown.
To find out more, researchers from Tel Aviv University used live cell imaging to track the virus as it made its way through the axon after entering the cell at nerve tips. They discovered that the virus gained cell entry by sticking to a receptor known as p75. This receptor is responsible for assisting the transport of a family of molecules known as neurotrophins. These are proteins produced by cells of the nervous system that promote the survival, differentiation and growth of neurons.
After the virus-bound receptor is internalized by cellular mechanisms, it is transported along the axon in tiny compartments, or vesicles, in a similar manner to the neurotrophins. Essentially, the virus hitches a ride on existing transport systems that exist to ensure the health and survival of the cell. Interestingly, they found that the interaction between the virus and p75 actually manipulates the velocity of this transport machinery, triggering it dramatically to speed up. This means that the virus can very efficiently reach the cell body, which is a pre-requisite for entry into the CNS.
As pointed out by lead researcher Dr. Eran Perlson, disruption of this delicate transport system can lead to neurodegenerative diseases. “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,” he added.
According to Perlson, one day it might even be possible to use this machinery to introduce drugs or even genes into the nervous system. If this could be achieved, then this may open up new ways to treat certain diseases that affect the CNS, including rabies.
