Archives of Virology

, Volume 159, Issue 7, pp 1593–1601 | Cite as

Comparison of complete genome sequences of dog rabies viruses isolated from China and Mexico reveals key amino acid changes that may be associated with virus replication and virulence

  • Fulai Yu
  • Guoqing Zhang
  • Xiangfu Zhong
  • Na Han
  • Yunfeng Song
  • Ling Zhao
  • Min Cui
  • Simon RaynerEmail author
  • Zhen F. FuEmail author
Original Article


Rabies is a global problem, but its impact and prevalence vary across different regions. In some areas, such as parts of Africa and Asia, the virus is prevalent in the domestic dog population, leading to epidemic waves and large numbers of human fatalities. In other regions, such as the Americas, the virus predominates in wildlife and bat populations, with sporadic spillover into domestic animals. In this work, we attempted to investigate whether these distinct environments led to selective pressures that result in measurable changes within the genome at the amino acid level. To this end, we collected and sequenced the full genome of two isolates from divergent environments. The first isolate (DRV-AH08) was from China, where the virus is present in the dog population and the country is experiencing a serious epidemic. The second isolate (DRV-Mexico) was taken from Mexico, where the virus is present in both wildlife and domestic dog populations, but at low levels as a consequence of an effective vaccination program. We then combined and compared these with other full genome sequences to identify distinct amino acid changes that might be associated with environment. Phylogenetic analysis identified strain DRV-AH08 as belonging to the China-I lineage, which has emerged to become the dominant lineage in the current epidemic. The Mexico strain was placed in the D11 Mexico lineage, associated with the West USA-Mexico border clade. Amino acid sequence analysis identified only 17 amino acid differences in the N, G and L proteins. These differences may be associated with virus replication and virulence–for example, the short incubation period observed in the current epidemic in China.


Rabies Rabies Virus Amino Acid Difference Short Incubation Period RABV Strain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported partially by Public Health Service grant AI-051560 from the National Institute of Allergy and Infectious Diseases, USA, and a grant from the Natural Science Foundation of China (30928020).

Supplementary material

705_2013_1966_MOESM1_ESM.docx (32 kb)
Supplementary material 1 (DOCX 31 kb)


  1. 1.
    Anilionis A, Wunner WH, Curtis PJ (1981) Structure of the glycoprotein gene in rabies virus. Nature 294:275–278PubMedCrossRefGoogle Scholar
  2. 2.
    Badrane H, Bahloul C, Perrin P, Tordo N (2001) Evidence of two Lyssavirus phylogroups with distinct pathogenicity and immunogenicity. J Virol 75:3268–3276PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Badrane H, Tordo N (2001) Host switching in Lyssavirus history from the Chiroptera to the Carnivora orders. J Virol 75:8096–8104PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Bourhy H, Kissi B, Audry L, Smreczak M, Sadkowska-Todys M, Kulonen K, Tordo N, Zmudzinski JF, Holmes EC (1999) Ecology and evolution of rabies virus in Europe. J Gen Virol 80(Pt 10):2545–2557PubMedGoogle Scholar
  5. 5.
    Bourhy H, Reynes JM, Dunham EJ, Dacheux L, Larrous F, Huong VT, Xu G, Yan J, Miranda ME, Holmes EC (2008) The origin and phylogeography of dog rabies virus. J Gen Virol 89:2673–2681PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Bourhy H, Dautry-Varsat A, Hotez PJ, Salomon J (2010) Rabies, still neglected after 125 years of vaccination. PLoS Negl Trop Dis 4:e839PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Davis PL, Bourhy H, Holmes EC (2006) The evolutionary history and dynamics of bat rabies virus. Infect Genet Evol 6:464–473PubMedCrossRefGoogle Scholar
  8. 8.
    Dietzschold B, Morimoto K, Hooper DC, Smith JS, Rupprecht CE, Koprowski H (2000) Genotypic and phenotypic diversity of rabies virus variants involved in human rabies: implications for postexposure prophylaxis. J Hum Virol 3:50–57PubMedGoogle Scholar
  9. 9.
    Fu ZF (1997) Rabies and rabies research: past, present and future. Vaccine 15(Suppl):S20–S24PubMedCrossRefGoogle Scholar
  10. 10.
    Henderson JC, Biek R, Hanlon CA, O’Dee S, Real LA (2008) Rabies virus in raccoons, Ohio, 2004. Emerg Infect Dis 14:650–652PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Hirano S, Itou T, Shibuya H, Kashiwazaki Y, Sakai T (2005) Molecular epidemiology of rabies virus isolates in Uganda. Virus Res 147:135–138CrossRefGoogle Scholar
  12. 12.
    Holmes EC, Woelk CH, Kassis R, Bourhy H (2002) Genetic constraints and the adaptive evolution of rabies virus in nature. Virology 292:247–257PubMedCrossRefGoogle Scholar
  13. 13.
    Hughes GJ, Orciari LA, Rupprecht CE (2005) Evolutionary timescale of rabies virus adaptation to North American bats inferred from the substitution rate of the nucleoprotein gene. J Gen Virol 86:1467–1474PubMedCrossRefGoogle Scholar
  14. 14.
    Ito N, Takayama M, Yamada K, Sugiyama M, Minamoto N (2001) Rescue of rabies virus from cloned cDNA and identification of the pathogenicity-related gene: glycoprotein gene is associated with virulence for adult mice. J Virol 75:9121–9128PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Ito N, Takayama-Ito M, Yamada K, Hosokawa J, Sugiyama M, Minamoto N (2003) Improved recovery of rabies virus from cloned cDNA using a vaccinia virus-free reverse genetics system. Microbiol Immunol 47:613–617PubMedCrossRefGoogle Scholar
  16. 16.
    Kakkar M, Venkataramanan V, Krishnan S, Chauhan RS, Abbas SS (2012) Moving from rabies research to rabies control: lessons from India. PLoS Negl Trop Dis 6:e1748PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Kissi B, Tordo N, Bourhy H (1995) Genetic polymorphism in the rabies virus nucleoprotein gene. Virology 209:526–537PubMedCrossRefGoogle Scholar
  18. 18.
    Knobel DL, Cleaveland S, Coleman PG, Fevre EM, Meltzer MI, Miranda ME, Shaw A, Zinsstag J, Meslin FX (2005) Re-evaluating the burden of rabies in Africa and Asia. Bull World Health Organ 83:360–368PubMedCentralPubMedGoogle Scholar
  19. 19.
    Kuzmin IV, Orciari LA, Arai YT, Smith JS, Hanlon CA, Kameoka Y, Rupprecht CE (2003) Bat lyssaviruses (Aravan and Khujand) from Central Asia: phylogenetic relationships according to N, P and G gene sequences. Virus Res 97:65–79PubMedCrossRefGoogle Scholar
  20. 20.
    Kuzmin IV, Shi M, Orciari LA, Yager PA, Velasco-Villa A, Kuzmina NA, Streicker DG, Bergman DL, Rupprecht CE (2012) Molecular inferences suggest multiple host shifts of rabies viruses from bats to mesocarnivores in Arizona during 2001–2009. PLoS Pathog 8:e1002786PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Meng SL, Yan JX, Xu GL, Nadin-Davis SA, Ming PG, Liu SY, Wu J, Ming HT, Zhu FC, Zhou DJ, Xiao QY, Dong GM, Yang XM (2007) A molecular epidemiological study targeting the glycoprotein gene of rabies virus isolates from China. Virus Res 124:125–138PubMedCrossRefGoogle Scholar
  22. 22.
    Morimoto K, Foley HD, McGettigan JP, Schnell MJ, Dietzschold B (2000) Reinvestigation of the role of the rabies virus glycoprotein in viral pathogenesis using a reverse genetics approach. J Neurovirol 6:373–381PubMedCrossRefGoogle Scholar
  23. 23.
    Nadin-Davis SA, Sampath MI, Casey GA, Tinline RR, Wandeler AI (1999) Phylogeographic patterns exhibited by Ontario rabies virus variants. Epidemiol Infect 123:325–336PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Posada D (2003) Using MODELTEST and PAUP* to select a model of nucleotide substitution. Curr Protoc Bioinformatics Chapter 6: Unit 6 5Google Scholar
  25. 25.
    Takayama-Ito M, Ito N, Yamada K, Sugiyama M, Minamoto N (2006) Multiple amino acids in the glycoprotein of rabies virus are responsible for pathogenicity in adult mice. Virus Res 115:169–175PubMedCrossRefGoogle Scholar
  26. 26.
    Tao X, Han N, Guo Z, Tang Q, Rayner S, Liang G (2013) Molecular characterization of China human rabies vaccine strains. Virol Sin 28(2):116–123PubMedCrossRefGoogle Scholar
  27. 27.
    Velasco-Villa A, Orciari LA, Souza V, Juarez-Islas V, Gomez-Sierra M, Castillo A, Flisser A, Rupprecht CE (2005) Molecular epizootiology of rabies associated with terrestrial carnivores in Mexico. Virus Res 111:13–27PubMedCrossRefGoogle Scholar
  28. 28.
    Velasco-Villa A, Orciari LA, Juarez-Islas V, Gomez-Sierra M, Padilla-Medina I, Flisser A, Souza V, Castillo A, Franka R, Escalante-Mane M, Sauri-Gonzalez I, Rupprecht CE (2006) Molecular diversity of rabies viruses associated with bats in Mexico and other countries of the Americas. J Clin Microbiol 44:1697–1710PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Velasco-Villa A, Reeder SA, Orciari LA, Yager PA, Franka R, Blanton JD, Zuckero L, Hunt P, Oertli EH, Robinson LE, Rupprecht CE (2008) Enzootic rabies elimination from dogs and reemergence in wild terrestrial carnivores, United States. Emerg Infect Dis 14:1849–1854PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Wunner WH, Larson JK, Dietzschold B, Smith CL (1988) The molecular biology of rabies viruses. Rev Infect Dis 10(Suppl 4):S771–S784PubMedCrossRefGoogle Scholar
  31. 31.
    Xue X, Zheng X, Gai W, Liang H, Ma J, Li L, Wang T, Feng N, Huang G, Zhao Y, Yang S, Xia X (2010) Sequencing the complete genome of rabies virus CVS-11 strain and constructing its full-length infectious cDNA clone. Wei Sheng Wu Xue Bao 53:409–415Google Scholar
  32. 32.
    Yin CP, Zhou H, Wu H, Tao XY, Rayner S, Wang SM, Tang Q, Liang GD (2012) Analysis on factors related to rabies epidemic in China from 2007–2011. Virol Sin 27:132–143PubMedCrossRefGoogle Scholar
  33. 33.
    Yu F, Zhang G, Xiao S, Fang L, Xu G, Yan J, Chen H, Fu ZF (2012) Complete genome sequence of a street rabies virus isolated from a rabid dog in China. J Virol 86:10890–10891PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Yu J, Li H, Tang Q, Rayner S, Han N, Guo Z, Liu H, Adams J, Fang W, Tao X, Wang S, Liang G (2012) The spatial and temporal dynamics of rabies in China. PLoS Negl Trop Dis 6:e1640PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Zhang G, Fu ZF (2012) Complete genome sequence of a street rabies virus from Mexico. J Virol 86:10892–10893PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Zhang YZ, Xiong CL, Xiao DL, Jiang RJ, Wang ZX, Zhang LZ, Fu ZF (2005) Human rabies in China. Emerg Infect Dis 11:1983–1984PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Zhang YZ, Xiong CL, Zou Y, Wang DM, Jiang RJ, Xiao QY, Hao ZY, Zhang LZ, Yu YX, Fu ZF (2006) Molecular characterization of rabies virus isolates in China during 2004. Virus Res 121:179–188PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Fulai Yu
    • 1
  • Guoqing Zhang
    • 1
    • 2
  • Xiangfu Zhong
    • 3
  • Na Han
    • 3
  • Yunfeng Song
    • 1
  • Ling Zhao
    • 1
  • Min Cui
    • 1
  • Simon Rayner
    • 3
    Email author
  • Zhen F. Fu
    • 1
    • 2
    Email author
  1. 1.State-key Laboratory of Agricultural Microbiology, College of Veterinary MedicineHuazhong Agricultural UniversityWuhanChina
  2. 2.Department of Pathology, College of Veterinary MedicineUniversity of GeorgiaAthensUSA
  3. 3.Key Laboratory of Agricultural and Environmental MicrobiologyWuhan Institute of Virology, Chinese Academy of SciencesWuhanChina

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