The cell biology of rabies virus: using stealth to reach the brain

Key Points Rabies is a devastating infectious disease, known to mankind since the 23rd century B.C. , that is distributed almost worldwide. Effective control mechanisms in the developed world overshadow the fact that rabies is still an enormous threat to human health in developing countries, with an annual death toll of more than 55,000 people. Therefore, rabies is considered a neglected infectious disease. New methods to genetically manipulate the rabies virus genome fostered a new era in the study of the rabies virus life cycle, rabies pathogenicity and the development of vaccines and therapeutics. Replication and transcription of rabies virus in vitro is now well understood; however, many other steps of the viral replication cycle, such as the entry of rabies virus into its target cells, remain poorly explored. Others, such as the intracellular transport of rabies virus, have only recently become targets of intense study. Also, the nature of the rabies virus receptor and its importance for the neurotropism of rabies virus are still matters of debate. Apoptosis was previously suggested as a mechanism in rabies virus pathogenesis. However, recent research strongly suggests that pathogenic rabies virus probably prevents apoptosis rather than induce it. Great progress has been made in understanding the interaction of rabies virus with the innate immune system. Rabies virus interferes with the host cell's ability to block early steps in viral replication through the type I interferon response by its multifunctional phosphoprotein. Although considerable progress has been made in the past 10 years in elucidating the interaction of rabies virus with its host cell, we suggest that a standardized use of viral strains will simplify the combination and comparison of research results, thus facilitating further understanding of this important viral pathogen and the prevention and treatment of the devastating disease it causes. Rabies virus is a neurotropic virus that travels between neurons to reach the brain. Schnell and colleagues describe the viral life cycle, from entry into the cell to budding of new virions and spread to neighbouring cells, and explain how it interferes with the host immune response. Rabies virus, the prototypical neurotropic virus, causes one of the most lethal zoonotic diseases. According to official estimates, over 55,000 people die of the disease annually, but this is probably a severe underestimation. A combination of virulence factors ena