Concepts in the pathogenesis of rabies

Rabies is a zoonotic disease that remains an important public health problem worldwide and causes more than 70,000 human deaths each year. The causative agent of rabies is rabies virus (RV), a negative-stranded RNA virus of the rhabdovirus family. Neuroinvasiveness and neurotropism are the main features that define the pathogenesis of rabies. Although RV pathogenicity is a multigenic trait involving several elements of the RV genome, the RV glycoprotein plays a major role in RV pathogenesis by controlling the rate of virus uptake and trans-synaptic virus spread, and by regulating the rate of virus replication. Pathogenic street RV strains differ significantly from tissue culture-adapted RV strains in their neuroinvasiveness. Whereas street RV strains are highly neuroinvasive, most tissue culture-adapted RV strains have either no or only limited ability to invade the CNS from a peripheral site. The high neuroinvasiveness of pathogenic street RVs is, at least in part, due to their ability to evade immune responses and to conserve the structures of neurons. The finding that tissue culture-adapted RV strains replicate very fast and induce strong innate and adaptive immune responses opens new avenues for therapeutic intervention against rabies.