Rabies – infection, furious vs. paralytic forms, bats vs. wolves, motorneurons

Rabies – infection, furious vs. paralytic forms, bats vs. wolves, motorneurons

Rabies first infects a motorneuron, a neuron whose function is to tell skeletal muscles to contract to make our bodies move.  Inside the axon of the neuron it travels back (formally: in a retrograde manner) to the main cell body of the motorneuron that is situated inside the central nervous system (CNS) proper.  The cell body is where the protein- and the RNA-making machinery are located.  It is here that the virus finally begins to multiply and then spreads out to other neurons. 

Axons of motorneurons heading back into the CNS are clustered together in bundles.  These bundles are known as nerves.  Thus, once taken up by the presynaptic ending of a motor neuron, the virus travels inside nerves, that is, inside axons, to the CNS.  Because the viral particle is inside a neuron it is fully protected (unfortunately) from any antibodies the immune system might have made that could capture the viral particles.  This trip to the CNS takes some time, and that time will depend on the length of the axon/nerve that has been infected.  Infection that began in the toe will take longer to enter the CNS proper than a bite on the neck.  However, this length of time only accounts for a small part of the time between infection and symptoms, and does not at all account for the wide variability in time from exposure to symptoms.  That variability – up to a couple of years at least – is completely a function of the time it takes a viral particle to find and be internalized by the receptor that will take it into the CNS.  In the meantime, the virus is simply floating around in the body.  To emphasize again, if this were not true, Pasteur’s vaccine would be useless.

Yet, infection does occur more rapidly following some bites than others.  Moreover, some infections result in furious rabies while others produce paralytic rabies.  Both of these differences need to be explained. 

Bat bites, or possibly bat rabies, are more frequently associated with the paralytic form of rabies, while dog and wolf bites are more often associated with induction of furious rabies.  It is possible that this is due to differences in the virus itself, yet bat bites clearly can induce furious rabies in dogs and other animals.  It is certainly true that one can determine which animal a particular rabies viral particle came from.  However, this is a result of the virus using cellular components from the particular animal it has infected in order to make its outer shell, e.g., Hardy plank vs. aluminum siding.  It is not the result of any known difference in the viral RNA or the receptor recognition motif.  There are not different types of rabies virus that could possibly account for differences in the time to infection nor in inducing furious versus paralytic rabies.

A more plausible explanation might be because a bat’s bite is likely to introduce less virus-laden saliva into the victim than most dog or wolf bites.  It seems very reasonable that being exposed to more viral particles would shorten the time before one find its way into the central nervous system, that is, shortens the period between exposure and infection.  Perhaps the difference between furious and paralytic rabies is also largely a function of the amount of viral particles the victim is exposed to, leading to a greater number of axons, of neurons, infected.  But, infected at the same time?  That strains credulity. 

The site of initial exposure does appear to play a role, at least in the period of time between exposure and infection.  “Closer to the CNS” is often used to describe this observation.  As the time from initial infection to the onset of symptoms is not hugely different when traversing the axons from the toes or the neck, I propose that it is something else, something about the density and/or location of the rabies receptor that accounts for the difference.  A bat bite penetrates the skin, but probably does not often enter muscles directly, certainly not very deeply into them.  On the other hand, a wolf’s bite will almost certainly penetrate and gore muscle, breaking the various membranes that cover muscle tissue.  The dog’s bite has a much greater chance of directly exposing neuromuscular junctions to the virus.  This seems reasonable to explain why wolf bites might induce rabies infection more quickly, but still doesn't explain the two types of rabies, nor that wolf bites seem more likely to result in furious rabies.

It is possible that the rabies virus can enter the axons of both types of skeletal motorneurons, alpha and gamma, although I’m not aware of data on this point.  And, perhaps gamma-motorneurons have more, or stronger affinity, receptors for rabies than alpha-motorneurons.  Muscles of the neck, for example, have a high density of gamma-motorneurons and therefore infection via gamma-motorneurons could occur more rapidly.  Being closer to the CNS may simply mean a muscle being responsible for more types of controlled movements -- those required to let our eyes, ears, and nose have the best chance of picking up information about the world around us -- and therefore having more gamma-motorneurons.  Gamma-motorneuron endings are encased in an additional membrane, a joint capsule, which would also have to be penetrated in order to access the gamma-motorneuron terminals.  In this way, as well, a wolf’s bite, designed to rip and tear flesh, that is, muscle, would be more likely to rip open those joint capsules, exposing the nerve terminals to the virus.  Moreover, as the neuronal pathways from alpha- and gamma-motorneurons into the brain are different, at least for the first few steps, I further propose that infection of gamma-motorneurons primarily leads to furious rabies, while infection via alpha-motorneurons primarily induces paralytic rabies.  This is speculation, but testable.