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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.

Abstract

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 enables the virus to enter neurons at peripheral sites and travel through the spinal cord to the brain of the infected host, where it often induces aggression that facilitates the transfer of the virus to a new host. This Review summarizes the current knowledge of the replication cycle of rabies virus and virus– host cell interactions, both of which are fundamental elements in our quest to understand the life cycle of rabies virus and the pathogenesis of rabies.

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Figure 1: Rabies worldwide.
Figure 2: The rabies virus virion.
Figure 3: Aspects of the rabies virus life cycle.
Figure 4: Rabies virus entry into neurons and intra-neuronal transport.
Figure 5: Rabies virus inhibition of the innate immune response.

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Acknowledgements

We thank Gene Tan for assistance in designing figure 2 and Paul Schiffmacher for assistance in designing figures 3–5. This work was supported in part by a Center for Neuroanatomy and Neurotropic Viruses grant to Peter Strick, Center for Neuroscience, University of Pittsburgh (USPHS-NCRR P40RR028604, subcontract to M.J.S.) and internal funds of Thomas Jefferson University, Medical College, Jefferson Vaccine Center, Philadelphia, USA.

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Correspondence to Matthias J. Schnell.

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Matthias J. Schnell, James P. McGettigan, Christoph Wirblich and Amy Papaneri

The cell biology of rabies virus: using stealth to reach the brain. Nature Reviews Microbiology 30 Nov 2009, [doi:nrmicro2260].

J. P. McGettigan and M. J. Schnell have patents and/or patent applications for rabies virus-based vaccines and vectors, grants from companies as well as personal financial interests.

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Trans-complemented

Complemented by expression of missing components in the host cell.

Postsynaptic

Positioned after the synapse.

Presynaptic

Positioned before the synapse.

Aggresome

An inclusion body in which proteins accumulate when the cells degradation machinery is not functioning properly or is overwhelmed.

Toll-like receptor

A receptor that recognizes viral, bacterial or fungal material and signals to induce an immune response.

Internal ribosome entry site

RNA sequence that allows ribosomes to bind to an mRNA at a position other than the 5′ end.

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Schnell, M., McGettigan, J., Wirblich, C. et al. The cell biology of rabies virus: using stealth to reach the brain. Nat Rev Microbiol 8, 51–61 (2010). https://doi.org/10.1038/nrmicro2260

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