Rabies: Virus and Disease


This article summarises the current literature on rabies and the aetiological agents responsible for this disease, which includes all members of the genus, of which rabies virus (RABV) is the prototype species. Members of the orders Chiroptera and Carnivora serve as maintenance reservoirs for all recognised lyssavirus species and knowledge of the diversity, evolution and geographical range of these viruses is continually improving. Many mammalian species, including humans, are susceptible to spill‐over infections from the maintenance hosts. Despite the availability of efficacious prophylactics, once clinical signs develop, the disease is almost invariably fatal. Effective rabies control requires elimination of the disease from animal reservoirs. In developed countries, parenteral dog vaccination and oral vaccination of wildlife have effectively controlled rabies in many regions but socioeconomic factors limit the application of similar measures in many developing countries where the vast majority of human cases are reported. Better understanding of disease pathogenesis and host immune responses is sought in efforts to develop effective therapeutic interventions.

Key Concepts

  • Rabies is a neurological disease that can affect almost all mammals and is almost invariably fatal once clinical signs develop.
  • Rabies is caused by all members of the Lyssavirus genus, bullet‐shaped neurotropic viruses with small RNA genomes, which are normally transmitted in virus‐laden saliva through bites.
  • The vast majority of human rabies cases are the result of exposure to rabid animals.
  • Prevention of human disease is undertaken by a regimen of timely post‐exposure prophylaxis.
  • Distinct Lyssavirus species and variants thereof are maintained in dogs in many developing countries and by several wildlife species including foxes, skunks, raccoons, raccoon dogs, mongooses, jackals and many species of bats throughout much of the world.
  • Through a series of viral–host interactions, rabies virus (RABV) has evolved mechanisms that maintain the neural network required for its propagation and spread within the infected host while avoiding clearance by the host's immune system.
  • Knowledge of the diversity of the Lyssavirus genus is steadily expanding with increased surveillance and development of molecular tools to enable rapid characterisation of new isolates.
  • Current vaccines and biologicals are ineffective against the more diverse members of the genus, thereby indicating that novel reagents with broader efficacy may be required for future disease control.
  • Ultimately, control and eradication of rabies will require elimination of the disease from animal reservoirs through the application of efficacious and cost‐effective methods of animal vaccination.

Keywords: hydrophobia; Lyssavirus; mad dog; encephalitis; zoonosis; animal reservoirs; prophylaxis; virus–host interactions; pathogenesis; disease surveillance

Figure 1. Rabies virions are bullet‐shaped and measure approximately 180 nm in length and 75 nm in diameter. The outer surface is covered by 10‐nm spike‐like glycoprotein peplomers. The basic structure and composition is depicted in the longitudinal diagram. The internal construction of the virion is portrayed in the cross‐sectional diagram.
Figure 2. The cycle of replication and infection in lyssaviruses involves (1) adsorption, (2) penetration, (3) uncoating, (4) transcription, (5) translation, (6) processing, (7) replication, (8) assembly and (9) budding.
Figure 3. A schematic showing the organisation of the rabies virus genome [Pasteur Virus (PV) strain (Genbank accession number M13215)], which is a single‐stranded, antisense, non‐segmented RNA of approximately 12 kb. A leader (Le) sequence of 58 nucleotides at the 3′‐terminus is followed by N, P, M, G and L genes, which code for the 5 structural proteins and a 70‐nucleotide trailer (Tr) sequence at the 5′‐terminus. The intergenic non translated regions (NC) vary in length and sequence considerably. The numbers below each gene are the length, in nucleotides, of the mRNA transcripts for each gene. Amino acid lengths of the proteins are N (450), P (297), M (202), G (524, 505 after processing) and L (2142). Minor length variations are observed in some other lyssaviruses. The arrow at bottom indicates the direction of transcription with the transcription gradient represented in colour from black (high) to grey (low).
Figure 4. A coalescent analysis illustrating lyssavirus phylogeny. An alignment of the first 800 bases of the N gene open reading frame of 91 viral isolates representative of the genus was produced using the CLUSTALX package (available from http://www.clustal.org/). This alignment was analysed by the BEAST package (v1.7.5) (available from http://beast.bio.ed.ac.uk/) in which the BEAUTi software generated an input file using the GTR + G substitution model and a relaxed molecular clock; BEAST was run for 50 million iterations with 10% burn‐in and the output was examined by the Tracer programme (available from http://tree.bio.ed.ac.uk/software/tracer/) to confirm all ESS (estimated sample size) values were >200. Convergence was established by performance of duplicate runs. The multiple trees generated by the BEAST analysis were converted to a single maximum clade credibility tree using the TreeAnnotator programme of the BEAST package and Figtree v1.4 (available from http://tree.bio.ed.ac.uk/software/figtree) was used for final tree visualisation. The scale at bottom indicates the predicted time frame of lyssavirus emergence (estimated at 2256 years) from a single progenitor; the time in years since the emergence of the most recent common ancestor for each clade is shown either above or to the right of all major nodes; posterior probability values >0.7, which are considered to provide significant support for the illustrated branch patterns, are also shown in brackets. The text at the right of the tree identifies the clades representing each species; phylogroup (PG) I members are outlined in black, PG II in blue and the proposed PG III in red. The sub‐division of RABV into seven established viral clades is also indicated thus: Africa 2 and 3, American indigenous, Arctic/Arctic‐like Asia, Cosmopolitan and Sri Lanka. To the left of each clade name, the countries affected and the main reservoir species are indicated. Each isolate is identified using the following format: a prefix comprising a two‐digit numeral representing the year of isolation, a unique identifier and a two‐ or three‐letter suffix indicating the country of origin thus, AFS, Republic of South Africa; ARS, Republic of Saudi Arabia; AUS, Australia; BIR, Myanmar; BRZ, Brazil; CAM, Cameroon; CAN, Canada; CBG, Cambodia; CH, Chile; CHI, China; COL, Columbia; ESP, Spain; EST, Estonia; ETH, Ethiopia; FIN, Finland; FRA, France; GER, Germany; GUI, Guinea; GUY, French Guyana; HAV, Burkina Faso; IN, India; IND, Indonesia; IRN, Iran; ISL, Israel; KYA, Kenya; KYR, Kyrgizstan; MAR, Morocco; MEX, Mexico; MOZ, Mozambique; NAM, Namibia; NEP, Nepal; NGA, Nigeria; NTH, The Netherlands; PAK, Pakistan; POL, Poland; RUS, Russia; SEN, Senegal; SER, Serbia; SKR, South Korea; SRL, Sri Lanka; TAJ, Tajikistan; TAN, Tanzania; TD, Trinidad; THA, Thailand; TKY, Turkey; TW, Taiwan; US, United States of America (preceded by state); YOU, former Republic of Yugoslavia and ZIM, Zimbabwe.


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Further Reading

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Nadin‐Davis, Susan A(Jan 2015) Rabies: Virus and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002244.pub3]