A terrifying feature of the deadly rabies virus is how fast it moves along the body's nervous system toward the brain, at speeds approaching half a meter per day. Its speed has been a medical mystery – but now researchers have a promising new lead that could explain how rabies spreads.
Above: An electron micrograph of the rabies virus, with virions appearing as dark-grey rods | Photo Credit: CDC/Dr. Fred Murphy
Observations made by Tel Aviv University's Shani Gluski suggest the rabies virus hijacks the central nervous system by means of a growth factor receptor named p75NTR. The describe their findings in detail in the latest issue of PLOS Pathogens.
p75NTR belongs to a family of receptors that, in a healthy body, is responsible for binding neurological factors on the surface of neurons and ushering them inside the cell. There, they are packaged and carried swiftly along the length of the cell in the direction of the cell body. This process is called retrograde axonal transport. Lots of pathogens exploit the retrograde axonal transport system to invade the central nervous system, including herpes, polio, and, of course, rabies. That p75NTR has been shown to transport neurological factors at a speed comparable to rabies' spread made it an ideal target of investigation for Gluski's team.
In the lab, the researchers took neurological tissue from embryonic mice and placed them into small microfluidic chambers. Once the cultures were established, a modified version of the rabies virus capable of producing the visible green fluorescent protein was added to see the virus as it moves. To ensure any observations were due to interaction with p75NTR, some of the cultures were given a piece of small hairpin RNA (shRNA) known to inhibit production of receptor. They then watched and waited to see what would happen next.
In the cells expressing p75NTR receptor, the virus was readily internalized. In contrast, when p75NTR was present in lower amounts thanks to the shRNA, there was significantly less infection. This revealed the importance of the receptor in virus infection. But while this was expected, what was seen after infection occurred was stunning.
In cells expressing p75NTR, the virus was compartmentalized in an acidic vesicle coated in this receptor. At this point, the virus moved at an incredible pace towards the cell body. In comparison to other molecules normally transported via this mechanism, such as nerve growth factor, the speed was significantly faster. The authors were not able to fully explain how this might have happened but the result was conclusive – rabies knew how to put the pedal to the metal.
In other words, not only did the rabies virus hijack the axonal transport system, it somehow hacked it into running faster than it normally does. Gluski's team is not clear on how the virus does this, but it's a compelling lead, and a much needed one, at that; the rabies virus may not be intelligent, but its clever enough with our biology to claim over 50,000 lives a year.