Rabies – selectivity unequaled

Rabies – selectivity unequalied

Before continuing, it is important to note a number of implications regarding this extreme selectivity of the target for rabies infection.  First, it is the scarcity of the rabies receptor outside the CNS that accounts for the long, often extremely long, time period between exposure and infection.  The virus must chance across one of these rare receptors to gain access to the CNS. 

On the other hand, it is known that neurons within the CNS express the rabies receptor in very great numbers.  So, once the virus does infect the CNS it is rapidly transported to almost all areas of the spinal cord and brain.  Even here, however, infection of additional neurons only takes place at specialized connections between neurons.  These specialized junctions are known as synapses.  Just like the neuromuscular junction (synapse) where the rabies virus first enters the CNS, synapses are where neurons communicate with each other.  Binding to these communication sites, these receptors, the rabies virus can alter, most likely inhibits, certain avenues of communication in the brain.  Importantly, rabies does not exit from the host cell at any point except via synapses (the communications portals).  Nor does rabies induce the host neuron to burst – thus releasing a large number of viral particles, but killing the host – as many viruses do.  Rabies does not appear to structurally damage the CNS at all, only altering it functionally.  There are some reports of damage associated with injection of rabies virus.  Given the extensive use of rabies as a neuroanatomical tracer without reports of damage, I believe that reports of damage are the result of additional material contained in a preparation from an infected animal that has been injected along with the virus.

Some authors have suggested that the rabies virus infects some, particularly skeletal muscle cells, during the time between exposure and infection.  I have not seen a direct demonstration that this occurs, and certainly there is no evidence of replication in, or release of new viral particles from, these hypothetical cells. What has been observed is a high concentration of virus within skeletal muscle tissue; not necessarily within muscle cells themselves. Of course, the neuromuscular junctions are located in muscles and these contain the receptor by which rabies normally first infects the CNS.

 In reality, rabies virus is just pushed along around through the body until by chance it encounters the appropriate receptor, or, if the victim is extremely lucky, it may be excreted before producing infection.  It is certainly possible that the areas near the appropriate receptor may have special properties that make them reservoirs for the virus.  It may even be that the virus becomes attached to the receptor, but the conditions needed to internalize the receptor have not yet occurred.  In either scenario, this indicates the virus is sitting outside of all cells waiting for whatever stimulus induces its internalization into skeletal motorneurons.  If this were not the case Pasteur’s world-changing vaccine would be of little value.  The antibodies evoked by the vaccine are themselves too large to enter the CNS.  Their only chance of stopping rabies infection is to capture it, all of it, before any viral particles enter the CNS.  The vaccine does this very, very well, fully confirming that the virus remains outside of cells, most certainly outside of the nervous system, for a fairly long time.  We know this because the vaccine can be administered post-exposure (but pre-infection) and be completely effective.

In the laboratory, one can get rabies to infect a number of cells.  This does not imply any lack of specificity by the rabies virus.  Cells internalize (by a process called endocytosis) many external substances and membrane components (e.g. receptors) via large vesicles (sacs).  Given a high enough concentration of rabies virus in the solution cells are living in, it is highly likely virus will be accidently internalized.  There may also be receptors with very low affinity for the virus that, coupled with the high laboratory concentrations of virus, may allow internalization.  In the body however, the specific neuronal receptor is critical.  

A report of infection via inhalation of aerosolized virus has been made.  The conditions for this – millions of bats within a small cave – were certainly extreme.  This, possibly single, report does not imply a lack of specificity either; some neurons of our smell (olfactory) system, part of the CNS, are directly apposed to the external world.  In this case, infection most likely occurred via the unique neuronal rabies receptor that is well-known to be highly expressed within the CNS. 

Given that laboratory infection of cells is probably mainly non-physiological – does not represent natural infection – why don’t investigators use cultured neurons to study rabies infection in the laboratory?  Unfortunately, it is difficult to grow neurons in the laboratory.  While numerous reports and examples exist, these neurons were overwhelmingly gathered from embryonic tissue, long before the nervous system fully grew and developed.  Even when harvested from (early) post-birth tissue, the neurons are immature and do not express many of the receptors seen in adult neurons, at least not in their adult form, and also do not have many of the between-cell attachments standard in the native CNS.  Our understanding of how the rabies virus moves through the nervous system strongly suggests that specialized connections between neurons must be in place in order for it to infect most areas of the brain.  The study of rabies infection of neurons in vitro is difficult and simply has not been carried out very often.  And, it is actually the receptor, whose activity is changed by viral attachment and not the virus per se, that holds the promise for us understanding lyssants.  The virus is just there to survive and reproduce itself.  The virus is, in its characteristically horrifying way, goading us to find the receptor.