Rabies: Virus and Disease

Abstract

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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References

Bakker AB, Python C, Kissling CJ, et al. (2008) First administration to humans of a monoclonal antibody cocktail against rabies virus: safety, tolerability, and neutralizing activity. Vaccine 26: 5922–5927.

Banyard AC, Hayman DTS, Freuling CM, et al. (2013) Bat rabies. In: Jackson AC, (ed.) Rabies, 3rd edn., pp. 215–267. Oxford, UK: Academic Press.

Borucki MK, Chen‐Harris H, Lao V, et al. (2013) Ultra‐deep sequencing of intra‐host rabies virus populations during cross‐species transmission. PloS Neglected Tropical Diseases 7: e2555.

Bourhy H, Reynes J‐M, Dunham EJ, et al. (2008) The origin and phylogeography of dog rabies virus. Journal of General Virology 89: 2673–2681.

Briggs DJ, Nagarajan T and Rupprecht CE (2013) Rabies vaccines. In: Jackson AC, (ed.) Rabies, 3rd edn., pp. 497–526. Oxford, UK: Academic Press.

Ceballos NA, Morón SV, Berciano JM, et al. (2013) Novel Lyssavirus in bat, Spain. Emerging Infectious Diseases 19: 793–795.

Centers for Disease Control and Prevention (2010) Use of a Reduced (4‐Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report 59 (RR‐2): 1–9.

Coetzer A, Nel LH and Rupprecht C (2014) Demonstration of lyssavirus antigens by a direct rapid immunohistochemical test. In: Rupprecht C and Nagarajan T, (eds). Current Laboratory Techniques in Rabies Diagnosis, Research and Prevention, vol. 1, pp. 27–36. San Diego, CA: Academic Press.

Dacheux L, Reynes JM, Buchy P, et al. (2008) A reliable diagnosis of human rabies based on analysis of skin biopsy specimens. Clinical Infectious Diseases 47: 1410–1417.

De Serres G, Dallaire F, Côte M, et al. (2008) Bat rabies in the United States and Canada from 1950 through 2007: human cases with and without bat contact. Clinical Infectious Diseases 46: 1329–1337.

Dietzschold B, Li J, Faber M, et al. (2008) Concepts in the pathogenesis of rabies. Future Virology 3: 481–490.

Evans JS, Horton DL, Easton AJ, Fooks AR and Banyard AC (2012) Rabies virus vaccines: Is there a need for a pan‐lyssavirus vaccine? Vaccine 30: 7447–7454.

Freuling CM, Hampson K, Selhorst T, et al. (2013) The elimination of fox rabies from Europe: determinants of success and lessons for the future. Philosophical transactions of the Royal Society B 368: 20120142.

Freuling CM, Hoffmann B, Fischer M, et al. (2014) Real‐time quantitative polymerase chain reaction for the demonstration of lyssavirus nucleic acid. In: Rupprecht C and Nagarajan T, (eds). Current laboratory techniques in rabies diagnosis, research and prevention, vol. 1, pp. 75–84. San Diego, CA: Academic Press.

Hanlon CA (2013) Rabies in terrestrial animals. In: Jackson AC, (ed.) Rabies, 3rd edn., pp. 179–213. Oxford, UK: Academic Press.

Hanlon CA and Nadin‐Davis SA (2013) Laboratory diagnosis of rabies. In: Jackson AC, (ed.) 3rd edn., Rabies, pp. 409–459. Oxford, UK: Academic Press.

International Committee on Taxonomy of Viruses (2013) ICTV Files and Discussions. ICTV Master Species List 2013 – Version 2. Available at http://talk.ictvonline.org/files/ictv_documents/m/msl/1231.aspx. Accessed on August 7, 2014.

Jackson AC (2013a) History of rabies research. In: Jackson AC, (ed.) Rabies, 3rd edn., pp. 1–15. Oxford, UK: Academic Press.

Jackson AC (2013b) Human disease. In: Jackson AC, (ed.) Rabies, 3rd edn., pp. 269–298. Oxford, UK: Academic Press.

Jackson AC (2013c) Therapy of human rabies. In: Jackson AC, (ed.) Rabies, 3rd edn., pp. 575–589. Oxford, UK: Academic Press.

Jackson AC and Fu ZF (2013) Pathogenesis. In: Jackson AC, (ed.) Rabies, 3rd edn., pp. 299–349. Oxford, UK: Academic Press.

Kuzmin IV, Hughes GJ, Botvinkin AD, Orciari LA and Rupprecht CE (2005) Phylogenetic relationships of Irkut and West Caucasian bat viruses within the Lyssavirus genus and suggested quantitative criteria based on the N gene sequence for lyssavirus genotype definition. Virus Research 111: 28–43.

Kuzmin IV, Mayer AE, Niezgoda M, et al. (2010) Shimoni bat virus, a new representative of the Lyssavirus genus. Virus Research 149: 197–210.

Kuzmin IV, Niezgoda M, Franka R, et al. (2008a) Lagos bat virus in Kenya. Journal of Clinical Microbiology 46: 1451–1461.

Kuzmin IV, Niezgoda M, Franka R, et al. (2008b) Possible emergence of West Caucasian bat virus in Africa. Emerging Infectious Diseases 14: 1887–1889.

Kuzmin IV, Wu X, Tordo N, et al. (2008c) Complete genomes of Aravan, Khujand, Irkut and West Caucasian bat viruses, with special attention to the polymerase gene and non‐coding regions. Virus Research 136: 81–90.

Kuzmin IV, Shi M, Orciari LA, et al. (2012) Molecular inferences suggest multiple host shifts of rabies virus from bats to mesocarnivores in Arizona during 2001–2009. PLoS Pathogens 8: e1002786.

Kuzmina NA, Lemey P, Kuzmin IV, et al. (2013) The phylogeography and spatiotemporal spread of south‐central skunk rabies virus. PLoS One 8: e82348.

Larrous F, Gholami A, Mouhamad S, Estaquier J and Bourhy H (2010) Two overlapping domains of a Lyssavirus matrix protein that acts on different cell death pathways. Journal of Virology 84: 9897–9906.

Liu Y, Zhang S, Zhao J, Zhang F and Hu R (2013) Isolation of Irkut virus from a Murina leucogaster bat in China. PloS Neglected Tropical Diseases 7: e2097.

Marston DA, Ellis RJ, Horton DL, et al. (2012) Complete genome sequence of Ikoma Lyssavirus. Journal of Virology 86: 10242–10243.

Nadin‐Davis SA (2013) Molecular epidemiology. In: Jackson AC, (ed.) Rabies, 3rd edn., pp. 123–177. Oxford, UK: Academic Press.

Nadin‐Davis SA and Real LA (2011) Molecular phylogenetics of the lyssaviruses—insights from a coalescent approach. In: Jackson AC, (ed.) Advances in Virus Research, vol. 79, pp. 203–238. Burlington, VT: Academic Press.

Nadin‐Davis SA, Feng Y, Mousse D, Wandeler AI and Aris‐Brosou S (2010) Spatial and temporal dynamics of rabies virus variants in big brown bat populations across Canada: footprints of an emerging zoonosis. Molecular Ecology 19: 2120–2136.

Nolden T, Banyard AC, Finke S, et al. (2014) Comparative studies on the genetic, antigenic and pathogenic characteristics of Bokeloh bat lyssavirus. Journal of General Virology 95: 1647–1653.

Oksayan S, Wiltzer L, Rowe CL, et al. (2012) A novel nuclear trafficking module regulates the nucleocytoplasmic localization of the rabies virus interferon antagonist, P protein. Journal of Biological Chemistry 287: 28112–28121.

Préhaud C, Wolff N, Terrien E, et al. (2010) Attenuation of rabies virulence: takeover by the cytoplasmic domain of its envelope protein. Science Signalling 3 (105): ra5.

Rosatte RC (2013) Rabies control in wild carnivores. In: Jackson AC, (ed.) Rabies, 3rd edn., pp. 617–670. Oxford, UK: Academic Press.

Rupprecht C and Nagarajan T (2014) Current Laboratory techniques in rabies diagnosis, research, and prevention, vol. 1. San Diego, CA: Academic Press.

Rupprecht CE, Hanlon CA and Slate D (2006) Control and prevention of rabies in animals: paradigm shifts. Developments in Biologicals (Basel) Rabies in Europe 125: 103–111.

Schnell MJ, McGettigan JP, Wirblich C, et al. (2010) The cell biology of rabies virus: using stealth to reach the brain. Nature Reviews. Microbiology 8: 51–61.

Scott TP, Fischer M, Khaiseb S, et al. (2013) Complete genome and molecular epidemiological data infer the maintenance of rabies among kudu (Tragelaphus strepsiceros) in Namibia. PloS ONE 8: e58739.

Streicker DG, Turmelle AS, Vonhof MJ, et al. (2010) Host phylogeny constrains cross‐species emergence and establishment of rabies virus in bats. Science 329: 676–679.

Talbi C, Lemey P, Suchard MA, et al. (2010) Phylodynamics and human‐mediated dispersal of a zoonotic virus. PLoS Pathogens 6 (10): e1001166.

Van Eeden C, Markotter W and Nel LH (2011) Molecular phylogeny of Duvenhage virus. South African Journal of Science 107: article # 177.

Vigilato MAN, Clavijo A, Knobl T, et al. (2013) Progress towards eliminating canine rabies: policies and perspective from Latin America and the Caribbean. Philosophical Transactions of the Royal Society B 368: 20120143.

Warshawsky B and Desai S (2010) Exposure to bats: updated recommendations. Canadian Medical Association Journal 182: 60.

Willoughby RE, Tieves KS, Hoffman GM, et al. (2005) Survival after treatment of rabies with induction of coma. New England Journal of Medicine 352: 2508–2514.

World Health Organization (2013) WHO Expert Consultation on Rabies, Second Report, 2013. WHO Technical Report Series No. 982. Geneva, Switzerland: WHO.

Wunner WH and Conzelmann K‐K (2013) Rabies virus. In: Jackson AC, (ed.) Rabies, 3rd edn., pp. 17–60. San Diego, CA: Academic Press.

Further Reading

King AA, Fooks AR, Aubert M, et al. (2004) Historical Perspective of Rabies in Europe and the Mediterranean Basin. Paris, France: OIE.

Lembo T, Attlan M, Bourhy H, et al. (2011) Renewed global partnerships and redesigned roadmaps for rabies prevention and control. Veterinary Medicine International ID # 923149.

Lafon M (2008) Immune evasion, a critical strategy for rabies virus. Developments in Biologicals (Basel) 131: 413–419.

Meslin FX, Kaplan MM and Koprowski H (1996) Laboratory Techniques in Rabies, 4th edn. Geneva, Switzerland: WHO.

Mollentze N, Biek R and Streicker DG (2014) The role of viral evolution in rabies hosts shifts and emergence. Current Opinion in Virology 8: 68–72.

Nadin‐Davis SA and Fehlner‐Gardiner C (2008) Lyssaviruses –Current trends. Advances in Virus Research 71: 207–250.

Nel LH and Markotter W (2007) Lyssaviruses. Critical Reviews in Microbiology 33: 301–324.

Rupprecht CE, Willoughby R and Slate D (2006) Current and future trends in the prevention, treatment and control of rabies. Expert Review of Anti‐Infective Therapy 4: 1021–1038.

Schnell MJ, Tan GS and Dietzschold B (2005) The application of reverse genetics technology in the study of rabies virus (RV) pathogenesis and for the development of novel RV vaccines. Journal of Neurovirology 11: 76–81.

Smith DL, Lucey B, Waller LA, Childs JE and Real LA (2002) Predicting the spatial dynamics of rabies epidemics on heterogeneous landscapes. Proceedings of the National Academy of Sciences of the United States of America 99: 3668–3672.

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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]