What is the pathophysiology of rabies?

Updated: Jun 21, 2019
  • Author: Sandra G Gompf, MD, FACP, FIDSA; Chief Editor: Michael Stuart Bronze, MD  more...
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Rabies virus infection is remarkable for the lack of evident pathology in the face of dramatic neurological symptoms. Minimal inflammation and neuronal cytopathy may be observed even postmortem. Similarly, viremia does not occur or play a role in spread to the CNS.

Pathophysiology has been best characterized in canine rabies variants. Canine rabies in humans requires deep-muscle inoculation. Endogenous muscle micro-RNA bind to viral transcripts and limit both replication and viral protein production, such that the virus is able to evade detection by antigen-presenting cells. Once enough virus replicates (or with a high-level inoculum or direct nerve injury), it binds motor neuron junctions at postsynaptic nicotinic acetylcholine receptors, which initiates uptake into the motor endplate. From here, the virus rapidly propagates across motor axons and chemical synapses in retrograde fashion toward the ganglia and nerve roots, at which point the prodromal symptoms of neuralgia and hypoesthesia may begin, in addition to fever and flulike illness.

Once reaching the CNS, it spreads throughout via the more ubiquitous nicotinic acetylcholine receptors of the brain. Of note, anterograde spread of rabies virus may then occur via sensory and autonomic pathways from the CNS to viscera, explaining many of the symptoms of progressive disease. Throughout propagation of the virus along motor pathways, the virus elicits little inflammation, and the motor neurons continue their otherwise normal functions of neurotransmission. Increasing signs of inflammation develop as CNS and visceral spread occurs, although a significant paucity of findings remains, other than mild nonspecific MRI T2 enhancements. Spinal fluid remains largely acellular, even in the presence of detectable rabies virus.

Propagation to the CNS via peripheral sensory or autonomic synapses does not seem to occur with canine variants, and only about 30% of cases result in peripheral sensory neuralgia. However, 70% of cases with bat variants result in neuropathic pain in the region of inoculation, as well as Horner syndrome and other findings; thus, these alternate pathways may occur in bat rabies variants. [20, 21]

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