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The spread and evolution of rabies virus: conquering new frontiers

Key Points

  • With much of the molecular virology characterized, we are now gaining an appreciation of how nuanced rabies virus infection dynamics are and how immune status relates to transmission.

  • The growing number of recognized rabies virus-related lyssaviruses highlights shortcomings in our discriminatory diagnostics and raises questions about their impact on human health. The lack of therapeutics for some of these lyssaviruses is a major concern.

  • Enzootic maintenance of rabies virus within a population depends on transmission within narrow windows. The virus avoids extinction by both general and reservoir host-specific mechanisms with remarkable epidemiological plasticity.

  • Features of rabies virus biology, ecology and evolution have made the virus a model pathogen for disease ecology and evolution. Recent work using mathematical models and phylodynamic analyses have enabled reconstruction and forecasting of epizootic spread of the virus at the landscape level.

  • At an evolutionary level, there is evidence that strong barriers prevent rabies virus from establishing in new host species, and both ecological opportunities and viral adaptation are needed to overcome these barriers. Studies of rabies virus molecular evolutionary dynamics have revealed the role of purifying selection and the importance of viral and host genetic backgrounds in host shifts. Further study of contemporary host shifts will likely shed light on the unknown origin of rabies.

  • We suggest that efforts be focused on developing strategies and technologies to manage rabies viruses within bat reservoirs as previously done with carnivores, integrating diagnostics that can rapidly differentiate strains into surveillance efforts, honing our predictive power to detect outbreaks and coordinating local resources to halt the spread of this lethal zoonosis.


Rabies is a lethal zoonotic disease that is caused by lyssaviruses, most often rabies virus. Despite control efforts, sporadic outbreaks in wildlife populations are largely unpredictable, underscoring our incomplete knowledge of what governs viral transmission and spread in reservoir hosts. Furthermore, the evolutionary history of rabies virus and related lyssaviruses remains largely unclear. Robust surveillance efforts combined with diagnostics and disease modelling are now providing insights into the epidemiology and evolution of rabies virus. The immune status of the host, the nature of exposure and strain differences all clearly influence infection and transmission dynamics. In this Review, we focus on rabies virus infections in the wildlife and synthesize current knowledge in the rapidly advancing fields of rabies virus epidemiology and evolution, and advocate for multidisciplinary approaches to advance our understanding of this disease.

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Figure 1: The rabies virus life cycle and cell entry.
Figure 2: Lyssavirus transmission dynamics in bats and terrestrial animals.
Figure 3: Current continental distribution of bat lyssaviruses and terrestrial mammalian lyssavirus reservoirs.
Figure 4: The influence of reservoir host ecology on the epidemiology of rabies.


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The authors thank J. Wilson (Thomas Jefferson University, Philadelphia, PA, USA) for her critical reading and editing of the manuscript. M.J.S. is supported in part by National Institutes of Health grants 1R01AI127823, 1R21AI128175 and 5P40OD010996-12 (P. Strick, University of Pittsburgh, subcontract M.J.S.) and the Jefferson Vaccine Center. D.G.S. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (102507/Z/13/Z).

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C.R.F. and D.G.S. researched data for the article. C.R.F., D.G.S. and M.J.S. made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Matthias J. Schnell.

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PowerPoint slides



Animal species that perpetuate the long-term transmission of a rabies virus strain and can transmit the virus to other species. Sometimes called a reservoir host or maintenance host.


Viral strains with small genetic differences that may or may not be detectable by antigenic characterization.

RABV-related lyssaviruses

Viruses of the Lyssavirus genus of RNA viruses other than the prototypical member, rabies virus.


Viral populations maintained within a particular reservoir, often in a geographically defined area that can be genetically distinguished from other sympatric viral populations.


Infectious particles, complete with the viral genome and viral proteins, capable of transmission to a new cell or host.


Viral samples that have been obtained from an infected individual or animal host.


The proportion of animals or individuals presenting virus-specific antibodies in their serum, indicative of exposure to either the virus or vaccine.

Spillover infections

Transmission events in which a lyssavirus strain successfully infects an animal of a non-reservoir species.


Subgeneric classification of lyssavirus species grouped by genetic and immunological characteristics.

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Fisher, C., Streicker, D. & Schnell, M. The spread and evolution of rabies virus: conquering new frontiers. Nat Rev Microbiol 16, 241–255 (2018).

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