Molecular Mechanisms of Raccoon Rabies Virus Progression in Its Natural Host

Abstract

Rabies virus presents a global public health problem. Our current understanding of the molecular determinants of rabies virulence stems from rodent models and laboratory strains of the virus, however, it is unclear how well rodent models represent viral response in natural reservoirs. Here, we examined interactions between the raccoon variant of rabies virus (RRV) and its natural host, raccoons, to gain a better understanding of molecular determinants of virulence in this system. We found expression patterns of RRV genes under tight control until the virus reached the central nervous system where replication increased significantly. Further, our examination of viral variants within an individual revealed that variant diversity may have an effect on virulence. We found that a mutation at a region of a T helper cell epitope on the nucleoprotein was associated with viral challenge outcomes and could be associated with RRV pathogenicity.

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Srithayakumar, V. , Sribalachandran, H. , Rosatte, R. and Kyle, C. (2014) Molecular Mechanisms of Raccoon Rabies Virus Progression in Its Natural Host. Advances in Microbiology, 4, 1222-1236. doi: 10.4236/aim.2014.416132.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Bouhy, H., Sureau, P. and Tordo, N. (1990) From Rabies to Rabies-Related Viruses. Veterinary Microbiology, 23, 115-128. http://dx.doi.org/10.1016/0378-1135(90)90141-H
[2] Tordo, N., Poch, O., Ermine, A., Keith, G. and Rougeon, F. (1988) Completion of the Rabies Virus Genome Sequence Determination: Highly Conserved Domains among the L (Polymerase) Proteins of Unsegmented Negative-Strand RNA Viruses. Virology, 165, 565-576.
http://dx.doi.org/10.1016/0042-6822(88)90600-9
[3] Rosatte, R.C. (2011) Evolution of Wildlife Rabies Control Tactics. Advances in Viral Research, 79, 397-419.
[4] Rosatte, R.C. (2013) Rabies Control in Wild Carnivores. In: Jackson, A., Ed., Rabies: Scientific Basis of the Disease and Its Management, Academic Press, Oxford, 617-670.
http://dx.doi.org/10.1016/B978-0-12-396547-9.00018-3
[5] World Health Organization (2005) Press Release 2005.
[6] Jackson, A.C. (2013) Rabies: Scientific Basis of the Disease and Its Management. Academic Press, Oxford.
[7] Tsiang, H., La Porte, S., Derer, M., Koenig, J. and Ambroise, D.J. (1986) Infection of Cultured Rat Myotubes and Neurons from the Spinal Cord by Rabies Virus. Journal of Neuropathology & Experimental Neurology, 45, 28-42. http://dx.doi.org/10.1097/00005072-198601000-00003
[8] Shankar, V., Dietzschold, B. and Koprowski, H. (1991) Direct Entry of Rabies Virus into the Central Nervous System without Prior Local Replication. Journal of Virology, 65, 2736-2738.
[9] Prosniak, M., Dietzschold, B., Koprowski, H. and Hooper, D.C. (2001) Effect of Rabies Virus Infection on Gene Expression in Mouse Brain. Proceedings of the National Academy of Sciences of the United States of America, 98, 2758-2763. http://dx.doi.org/10.1073/pnas.051630298
[10] Jackson, A.C. and Reimer, D.L. (1989) Pathogenesis of Experimental Rabies in Mice: An Immunohistochemical Study. Acta Neuropathologica, 78, 159-165.
http://dx.doi.org/10.1007/BF00688204
[11] Johnson, N., McKimmie, C.S., Mansfield, K.L., Wakeley, P.R., Brookes, S.M., Fazakerley, J.K. and Fooks, A.R. (2006) Lyssavirus Infection Activates Interferon Gene Expression in the Brain. Journal of General Virology, 87, 2663-2667. http://dx.doi.org/10.1099/vir.0.82024-0
[12] Mansfield, K.L., Johnson, N., Nuñez, A., Hicks, D., Jackson, A.C. and Fooks, A.R. (2008) Up-Regulation of Chemokine Gene Transcripts and T-Cell Infiltration into the Central Nervous System and Dorsal Root Ganglia Are Characteristics of Experimental European Bat Lyssavirus Type 2 Infection of Mice. Journal of NeuroVirology, 14, 218-228. http://dx.doi.org/10.1080/13550280802008297
[13] Zhao, P., Zhao, L., Zhang, T., Qi, Y., Wang, T., Liu, K., Wang, H., Feng, H., Jin, H., et al. (2011) Innate Immune Response Gene Expression Profiles in Central Nervous System of Mice Infected with Rabies Virus. Comparative Immunology, Microbiology and Infectious Diseases, 34, 503-512.
http://dx.doi.org/10.1016/j.cimid.2011.09.003
[14] Srithayakumar, V., Sribalachandran, H., Rosatte, R., Nadin-Davis, S. and Kyle, C.J. (2014) Innate Immune Responses in Raccoons after Raccoon Rabies Virus Infection. Journal of General Virology, 95, 16-25. http://dx.doi.org/10.1099/vir.0.053942-0
[15] Dietzschold, B., Wunner, W.H., Wiktor, T.J., Lopes, A.D., Lafon, M., Smith, C.L. and Koprowski, H. (1983) Characterization of an Antigenic Determinant of the Glycoprotein that Correlates with Pathogenicity of Rabies Virus. Proceedings of the National Academy of Sciences of the United States of America, 80, 70-74. http://dx.doi.org/10.1073/pnas.80.1.70
[16] Seif, I., Coulon, P., Rollin, P.E. and Flamand, A. (1985) Rabies Virulence: Effect on Pathogenicity and Sequence Characterization of Rabies Virus Mutations Affecting Antigenic Site-III of the Glycoprotein. Journal of Virology, 53, 926-934.
[17] Morimoto, K., Foley, H.D., McGettigan, J.P., Schnell, M.J. and Dietzschold, B. (2000) Reinvestigation of the Role of the Rabies Virus Glycoprotein in Viral Pathogenesis Using a Reverse Genetics Approach. Journal of Neurovirology, 6, 373-381. http://dx.doi.org/10.3109/13550280009018301
[18] Morimoto, K., Hooper, D.C., Spitsin, S., Koprowski, H. and Dietzschold, B. (1999) Pathogenicity of Different Rabies Virus Variants Inversely Correlates with Apoptosis and Rabies Virus Glycoprotein Expression in Infected Primary Neuron Cultures. Journal of Virology, 73, 510-518.
[19] Ito, N., Takayama, M., Yamada, K., Sugiyama, M. and 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. Journal of Virology, 75, 9121-9128.
http://dx.doi.org/10.1128/JVI.75.19.9121-9128.2001
[20] Prehaud, C., Lay, S., Dietzschold, B. and Lafon, M. (2003) Glycoprotein of Nonpathogenic Rabies Viruses Is a Key Determinant of Human Cell Apoptosis. Journal of Virology, 77, 10537-10547.
http://dx.doi.org/10.1128/JVI.77.19.10537-10547.2003
[21] Takayama-Ito, M., Ito, N., Yamada, K., Sugiyama, M. and Minamoto, N. (2006) Multiple Amino Acids in the Glycoprotein of Rabies Virus Are Responsible for Pathogenicity in Adult Mice. Virus Research, 115, 169-175. http://dx.doi.org/10.1016/j.virusres.2005.08.004
[22] Shimizu, K., Ito, N., Mita, T., Yamada, K., Hosokawa-Muto, J., Sugiyama, M. and Minamoto, N. (2007) Involvement of Nucleoprotein, Phosphoprotein, and Matrix Protein Genes of Rabies Virus in Virulence for Adult Mice. Virus Research, 123, 154-160. http://dx.doi.org/10.1016/j.virusres.2006.08.011
[23] Masatani, T., Ito, N., Shimizu, K., Ito, Y., Nakagawa, K., Abe, M., Yamaoka, S. and Sugiyama, M. (2011) Amino Acids at Positions 273 and 394 in Rabies Virus Nucleoprotein Are Important for both Evasion of Host RIG-I-Mediated Antiviral Response and Pathogenicity. Virus Research, 155, 168-174. http://dx.doi.org/10.1016/j.virusres.2010.09.016
[24] Ito, N., Mita, T., Shimizu, K., Ito, Y., Masatani, T., Nakagawa, K., Yamaoka, S., Abe, M., Okadera, K., Minamoto, N. and Sugiyama, M. (2011) Amino Acid Substitution at Position 95 in Rabies Virus Matrix Protein Affects Viral Pathogenicity. Journal of Veterinary Medical Science, 73, 1363-1366.
http://dx.doi.org/10.1292/jvms.11-0151
[25] Jackson, A.C. and Wunner, W.H. (2007) Rabies. 2nd Edition, Academic Press, San Diego.
[26] Coulon, P., Ternaux, J.P., Flamand, A. and Tuffereau, C. (1998) An Avirulent Mutant of Rabies Virus Is Unable to Infect Motoneurons in Vivo and in Vitro. Journal of Virology, 72, 273-278.
[27] Biek, R., Henderson, J.C., Waller, L.A., Rupprecht, C.E. and Real, L.A. (2007) A High-Resolution Genetic Signature of Demographic and Spatial Expansion in Epizootic Rabies Virus. Proceedings of the National Academy of Sciences of the United States of America, 104, 7993-7998.
http://dx.doi.org/10.1073/pnas.0700741104
[28] Totton, S., Tinline, R., Rosatte, R. and Bigler, L. (2002) Contact Rates of Raccoons (Procyon lotor) at a Communal Feeding Site in Rural Eastern Ontario. Journal of Wildlife Diseases, 38, 313-319. http://dx.doi.org/10.7589/0090-3558-38.2.313
[29] Hadidian, J., Prange, S., Rosatte, R., Riley, S. and Gehrt, S. (2010) Raccoons (Procyon lotor). In: Gehrt, S., Riley, S. and Cypher, B., Eds., Urban Carnivores, Ecology, Conflict and Conservation, The Johns Hopkins University Press, Baltimore, 35-48.
[30] Rosatte, R., Sobey, K., Donovan, D., Bruce, L., Allan, M., Silver, A., et al. (2006) Behaviour, Movements, and Demographics of Rabid Raccoons in Ontario, Canada: Management Implications. Journal of Wildlife Diseases, 42, 589-605. http://dx.doi.org/10.7589/0090-3558-42.3.589
[31] Carey, A. and McLean, R. (1983) The Ecology of Rabies: Evidence of Co-Adaptation. Journal of Applied Ecology, 20, 777-800. http://dx.doi.org/10.2307/2403126
[32] Szanto, A. (2009) Molecular Genetics of the Raccoon Rabies Virus. Doctoral Dissertation, Trent University, Peterborough.
[33] Knowles, Personal Communication.
[34] Rupprecht, C.E., Koprowski, H., Hamir, A.N. and Johnston, D.H. (1988) Efficacy of a Vaccinia-Rabies Glycoprotein Recombinant Virus Vaccine in Raccoons (Procyon lotor). Clinical Infectious Diseases, 10, S803-S809. http://dx.doi.org/10.1093/clinids/10.Supplement_4.S803
[35] Brown, L., Rosatte, R., Fehlner-Gardiner, C., Taylor, S., Davies, J. and Donovan, D. (2012) Immune Response and Protection in Raccoons (Procyon lotor) Following Consumption of Baits Containing ONRAB, a Human Adenovirus Rabies Glycoprotein Recombinant Vaccine. Journal of Wildlife Diseases, 48, 1010-1020. http://dx.doi.org/10.7589/2012-01-023
[36] Schmittgen, T. and Livak, K. (2008) Analyzing Real-Time PCR Data by the Comparative CT Method. Nature Protocols, 3, 1101-1108. http://dx.doi.org/10.1038/nprot.2008.73
[37] Tamura, K., Dudley, J., Nei, M. and Kumar, S. (2007) MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) Software Version 4.0. Molecular Biology and Evolution, 24, 1596-1599.
http://dx.doi.org/10.1093/molbev/msm092
[38] Arnold, K., Bordoli, L., Kopp, J. and Schwede, T. (2006) The SWISS-MODEL Workspace: A Web-Based Environment for Protein Structure Homology Modelling. Bioinformatics, 22, 195-201.
http://dx.doi.org/10.1093/bioinformatics/bti770
[39] Kiefer, F., Arnold, K., Kuenzli, M., Bordoli, L. and Schwede, T. (2009) The SWISS-MODEL Repository and Associated Resources. Nucleic Acids Research, 37, D387-D392.
http://dx.doi.org/10.1093/nar/gkn750
[40] Worth, C.L., Preissner, R. and Blundell, T.L. (2011) SDM—A Server for Predicting Effects of Mutations on Protein Stability and Malfunction. Nucleic Acids Research, 39, W215-W222.
http://dx.doi.org/10.1093/nar/gkr363
[41] Rupprecht, C.E., Smith, J.S., Fekadu, M. and Childs, J.E. (1995) The Ascension of Wildlife Rabies—A Cause for Public-Health Concern or Intervention. Emerging Infectious Diseases, 1, 107-114.
[42] Brzozka, K., Finke, S. and Conzelmann, K. (2006) Inhibition of Interferon Signaling by Rabies Virus Phosphoprotein P: Activation-Dependent Binding of STAT1 and STAT2. Journal of Virology, 80, 2675-2683. http://dx.doi.org/10.1128/JVI.80.6.2675-2683.2006
[43] ChelbiAlix, M., Vidy, A., El Bougrini, J. and Blondel, D. (2006) Rabies Viral Mechanisms to Escape the IFN System: The Viral Protein P Interferes with IRF-3, Stat1, and PML Nuclear Bodies. Journal of Interferon & Cytokine Research, 26, 271-280. http://dx.doi.org/10.1089/jir.2006.26.271
[44] Wirblich, C. and Schnell, M.J. (2011) Rabies Virus (RV) Glycoprotein Expression Levels Are Not Critical for Pathogenicity of RV. Journal of Virology, 85, 697-704. http://dx.doi.org/10.1128/JVI.01309-10
[45] Faber, M., Pulmanausahakul, R., Hodawadekar, S.S., Spitsin, S., McGettigan, J.P., Schnell, M.J. and Dietzschold, B. (2002) Overexpression of the Rabies Virus Glycoprotein Results in Enhancement of Apoptosis and Antiviral Immune Response. Journal of Virology, 76, 3374-3381.
http://dx.doi.org/10.1128/JVI.76.7.3374-3381.2002
[46] Faber, M., Pulmanausahakul, R., Nagao, K., Prosniak, M., Rice, A.B., Koprowski, H., Schnell, M.J. and Dietzschold, B. (2004) Identification of Viral Genomic Elements Responsible for Rabies Virus Neuroinvasiveness. Proceedings of the National Academy of Sciences of the United States of America, 101, 16328-16332. http://dx.doi.org/10.1073/pnas.0407289101
[47] Wang, Z.W., Sarmento, L., Wang, Y., Li, X., Dhingra, V., Tseggai, T., Jiang, B. and Fu, Z.F. (2005) Attenuated Rabies Virus Activates, While Pathogenic Rabies Virus Evades, the Host Innate Immune Responses in the Central Nervous System. Journal of Virology, 79, 12554-12565.
http://dx.doi.org/10.1128/JVI.79.19.12554-12565.2005
[48] Holland, J.J., Delatorre, J.C. and Steinhauer, D.A. (1992) RNA Virus Populations as Quasi-Species. Current Topics in Microbiology and Immunology, 176, 1-20.
http://dx.doi.org/10.1007/978-3-642-77011-1_1
[49] Domingo, E. and Holland, J.J. (1997) RNA Virus Mutations and Fitness for Survival. Annual Review of Microbiology, 51, 151-178. http://dx.doi.org/10.1146/annurev.micro.51.1.151
[50] Smith, D.B., McAllister, J., Casino, C. and Simmonds, P. (1997) Virus “Quasispecies”: Making a Mountain out of a Molehill? Journal of General Virology, 78, 1511-1519.
[51] Khawplod, P., Shoji, Y., Ubol, S., Mitmoonpitak, C., Wilde, H., Nishizono, A., Kurane, I. and Morimoto, K. (2006) Genetic Analysis of Dog Rabies Viruses Circulating in Bangkok. Infection, Genetics and Evolution, 6, 235-240. http://dx.doi.org/10.1016/j.meegid.2005.06.002
[52] Vignuzzi, M., Stone, J.K., Arnold, J.J., Cameron, C.E. and Andino, R. (2006) Quasispecies Diversity Determines Pathogenesis through Cooperative Interactions in a Viral Population. Nature, 439, 344-348. http://dx.doi.org/10.1038/nature04388
[53] Crotty, S., Cameron, C.E. and Andino, R. (2001) RNA Virus Error Catastrophe: Direct Molecular Test by Using Ribavirin. Proceedings of the National Academy of Sciences of the United States of America, 98, 6895-6900. http://dx.doi.org/10.1073/pnas.111085598
[54] Fu, Z.F., Wunner, W.H. and Dietzschold, B. (1994) Immunoprotection by Rabies Virus Nucleoprotein. Current Topics in Microbiology and Immunology, 187, 161-172.
http://dx.doi.org/10.1007/978-3-642-78490-3_9
[55] Minamoto, N., Tanaka, H., Hishida, M., Goto, H., Ito, H., Naruse, S., Yamamoto, K., Sugiyama, M., Kinjo, T., Mannen, K. and Mifune, K. (1994) Linear and Conformation-Dependent Antigenic Sites on the Nucleoprotein of Rabies Virus. Microbiology and Immunology, 38, 449-455.
http://dx.doi.org/10.1111/j.1348-0421.1994.tb01806.x
[56] Goto, H., Minamoto, N., Ito, H., Ito, N., Sugiyama, M., Kinjo, T. and Kawai, A. (2000) Mapping of Epitopes and Structural Analysis of Antigenic Sites in the Nucleoprotein of Rabies Virus. Journal of General Virology, 81, 119-127.
[57] Betts, M.J. and Russell, R.B. (2003) Amino Acid Properties and Consequences of Substitutions. In: Barnes, M.R., Ed., Bioinformatics for Geneticists, Ch. 14, John Wiley & Sons Ltd., West Sussex, 289-316.

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