Title : Rabies: Challenges in taming the beast
Abstract:
Rabies has occurred in humans and animals since antiquity and remains an important public health problem with about 60,000 human deaths per year, particularly in Asia and Africa. The disease is virtually always fatal, although at least 34 survivors have been documented; unfortunately, many have severe neurological sequelae. Louis Pasteur developed a rabies vaccine and successfully immunized Joseph Meister in 1885, which was an important development for post-exposure prophylaxis of rabies. Rabies can be effectively prevented after recognized exposures with wound cleansing and administration of rabies immune globulin and rabies vaccine. Endemic dog rabies is the main threat to humans, although transmission also occurs to humans and companion animals from wildlife. Bat exposures from small bats may not be recognized and transmission from bats is the main cause of human rabies in the USA and Canada. Our understanding of rabies pathogenesis remains incomplete. Rabies virus spreads from neuron-to-neuron via axonal transport to and within the central nervous system and causes an encephalomyelitis with mild inflammatory changes and without prominent degenerative neuronal changes. Studies performed in models of experimental rabies have recently shown degenerative changes involving axons and dendrites due to oxidative stress, which is caused by mitochondrial dysfunction. One rabies virus protein, the rabies virus phosphoprotein (P), interacts with mitochondrial Complex I, resulting in increased Complex I activity and the production of reactive oxygen species (ROS), which preferentially damage neuronal processes. Mutational analysis suggested the importance of the 157-169 region of the P and serine residues at 162 and 166 are important. Two rabies virus recombinants with serine to alanine mutations at positions 162 and 166 did not increase Complex I activity and result in ROS generation. The treatment of human rabies has not yet demonstrated any efficacious therapies beyond critical care. The Milwaukee protocol, which includes therapeutic coma as the key component, has been aggressively promoted. Numerous repeated failures over the past 20 years, a lack of published successes, and the lack of a sound scientific rationale have led this protocol to be considered ineffective therapy and its use is not recommended. For aggressive care, a critical care unit is essential. Combination therapy is reasonable and effective in other diseases. Antiviral therapy is important, but new antiviral drugs are needed because currently available drugs have not shown efficacy. Immunotherapies, including new rabies vaccines and neutralizing rabies virus antibodies, require careful consideration. Antibodies have shown some efficacy in a mouse model. There are important delivery issues for drugs and antibodies as a result of blood-brain and blood-spinal cord barriers. Neuroprotective therapies that antagonize injurious biochemical and molecular events are lacking for common acute neurological diseases. Efficacy has been shown for hypothermia for brain injury after cardiac arrest. Selective cerebral hypothermia could be considered a potential therapy for rabies because it is associated with many beneficial effects and has less systemic adverse effects than whole body cooling. The development of novel therapies for rabies in the future will likely depend on an improved understanding of rabies pathogenesis.
