1887

Abstract

Zoonotic wildlife diseases pose significant health risks not only to their primary vectors but also to humans and domestic animals. Rabies is a lethal encephalitis caused by rabies virus (RV). This RNA virus can infect a range of terrestrial mammals but each viral variant persists in a particular reservoir host. Active management of these host vectors is needed to minimize the negative impacts of this disease, and an understanding of the immune response to RV infection aids strategies for host vaccination. Current knowledge of immune responses to RV infection comes primarily from rodent models in which an innate immune response triggers activation of several genes and signalling pathways. It is unclear, however, how well rodent models represent the immune response of natural hosts. This study investigates the innate immune response of a primary host, the raccoon, to a peripheral challenge using the raccoon rabies virus (RRV). The extent and temporal course of this response during RRV infection was analysed using genes predicted to be upregulated during infection (IFNs; IFN regulatory factors; IL-6; Toll like receptor-3; TNF receptor). We found that RRV activated components of the innate immune system, with changes in levels of transcripts correlated with presence of viral RNA. Our results suggest that natural reservoirs of rabies may not mimic the immune response triggered in rodent models, highlighting the need for further studies of infection in primary hosts.

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2014-01-01
2019-11-22
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References

  1. Alexopoulou L. , Holt A. C. , Medzhitov R. , Flavell R. A. . ( 2001; ). Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. . Nature 413:, 732–738. [CrossRef] [PubMed]
    [Google Scholar]
  2. Baer G. M. , Cleary W. F. . ( 1972; ). A model in mice for the pathogenesis and treatment of rabies. . J Infect Dis 125:, 520–527. [CrossRef] [PubMed]
    [Google Scholar]
  3. Baloul L. , Lafon M. . ( 2003; ). Apoptosis and rabies virus neuroinvasion. . Biochimie 85:, 777–788. [CrossRef] [PubMed]
    [Google Scholar]
  4. Biek R. , Henderson J. C. , Waller L. A. , Rupprecht C. E. , Real L. A. . ( 2007; ). A high-resolution genetic signature of demographic and spatial expansion in epizootic rabies virus. . Proc Natl Acad Sci U S A 104:, 7993–7998. [CrossRef] [PubMed]
    [Google Scholar]
  5. Brzózka K. , Finke S. , Conzelmann K. K. . ( 2006; ). Inhibition of interferon signaling by rabies virus phosphoprotein P: activation-dependent binding of STAT1 and STAT2. . J Virol 80:, 2675–2683. [CrossRef] [PubMed]
    [Google Scholar]
  6. Camelo S. , Lafage M. , Lafon M. . ( 2000; ). Absence of the p55 Kd TNF-α receptor promotes survival in rabies virus acute encephalitis. . J Neurovirol 6:, 507–518. [CrossRef] [PubMed]
    [Google Scholar]
  7. Carey A. , Mclean R. . ( 1983; ). The ecology of rabies–evidence of co-adaptation. . J Appl Ecol 20:, 777–800. [CrossRef]
    [Google Scholar]
  8. Charlton K. M. , Nadin-Davis S. , Casey G. A. , Wandeler A. I. . ( 1997; ). The long incubation period in rabies: delayed progression of infection in muscle at the site of exposure. . Acta Neuropathol 94:, 73–77. [CrossRef] [PubMed]
    [Google Scholar]
  9. Chelbi-Alix M. K. , Vidy A. , El Bougrini J. , Blondel D. . ( 2006; ). Rabies viral mechanisms to escape the IFN system: the viral protein P interferes with IRF-3, Stat1, and PML nuclear bodies. . J Interferon Cytokine Res 26:, 271–280. [CrossRef] [PubMed]
    [Google Scholar]
  10. Conzelmann K. K. . ( 2005; ). Transcriptional activation of alpha/beta interferon genes: interference by nonsegmented negative-strand RNA viruses. . J Virol 79:, 5241–5248. [CrossRef] [PubMed]
    [Google Scholar]
  11. Cussigh A. , Falleti E. , Fabris C. , Bitetto D. , Cmet S. , Fontanini E. , Bignulin S. , Fornasiere E. , Fumolo E. . & other authors ( 2011; ). Interleukin 6 promoter polymorphisms influence the outcome of chronic hepatitis C. . Immunogenetics 63:, 33–41. [CrossRef] [PubMed]
    [Google Scholar]
  12. Daszak P. , Cunningham A. A. , Hyatt A. D. . ( 2000; ). Emerging infectious diseases of wildlife – threats to biodiversity and human health. . Science 287:, 443–449. [CrossRef] [PubMed]
    [Google Scholar]
  13. Daszak P. , Cunningham A. A. , Hyatt A. D. . ( 2001; ). Anthropogenic environmental change and the emergence of infectious diseases in wildlife. . Acta Trop 78:, 103–116. [CrossRef] [PubMed]
    [Google Scholar]
  14. Faber M. , Bette M. , Preuss M. A. , Pulmanausahakul R. , Rehnelt J. , Schnell M. J. , Dietzschold B. , Weihe E. . ( 2005; ). Overexpression of tumor necrosis factor alpha by a recombinant rabies virus attenuates replication in neurons and prevents lethal infection in mice. . J Virol 79:, 15405–15416. [CrossRef] [PubMed]
    [Google Scholar]
  15. Faul E. J. , Wanjalla C. N. , Suthar M. S. , Gale M. , Wirblich C. , Schnell M. J. . ( 2010; ). Rabies virus infection induces type I interferon production in an IPS-1 dependent manner while dendritic cell activation relies on IFNAR signaling. . PLoS Pathog 6:, e1001016. [CrossRef] [PubMed]
    [Google Scholar]
  16. Frei K. , Malipiero U. V. , Leist T. P. , Zinkernagel R. M. , Schwab M. E. , Fontana A. . ( 1989; ). On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. . Eur J Immunol 19:, 689–694. [CrossRef] [PubMed]
    [Google Scholar]
  17. Fu Z. F. . ( 1997; ). Rabies and rabies research: past, present and future. . Vaccine 15: (Suppl.), S20–S24. [CrossRef] [PubMed]
    [Google Scholar]
  18. Haller O. , Kochs G. , Weber F. . ( 2006; ). The interferon response circuit: induction and suppression by pathogenic viruses. . Virology 344:, 119–130. [CrossRef] [PubMed]
    [Google Scholar]
  19. Harmon M. W. , Janis B. , Levy H. B. . ( 1974; ). Post-exposure prophylaxis of murine rabies with polyinosinic-polycytidylic acid and chlorite-oxidized amylose. . Antimicrob Agents Chemother 6:, 507–511. [CrossRef] [PubMed]
    [Google Scholar]
  20. Harvell C. D. , Mitchell C. E. , Ward J. R. , Altizer S. , Dobson A. P. , Ostfeld R. S. , Samuel M. D. . ( 2002; ). Climate warming and disease risks for terrestrial and marine biota. . Science 296:, 2158–2162. [CrossRef] [PubMed]
    [Google Scholar]
  21. Hilfenhaus J. , Karges H. E. , Weinmann E. , Barth R. . ( 1975; ). Effect of administered human interferon on experimental rabies in monkeys. . Infect Immun 11:, 1156–1158.[PubMed]
    [Google Scholar]
  22. Hooper D. C. , Morimoto K. , Bette M. , Weihe E. , Koprowski H. , Dietzschold B. . ( 1998; ). Collaboration of antibody and inflammation in clearance of rabies virus from the central nervous system. . J Virol 72:, 3711–3719.[PubMed]
    [Google Scholar]
  23. Jackson A. C. . ( 2007; ). Pathogenesis. . In Rabies, , 2nd edn., pp. 341–381. Edited by Jackson A. C. , Wunner W. H. . . San Diego, CA:: Academic Press;. [CrossRef]
    [Google Scholar]
  24. Jackson A. C. , Reimer D. L. . ( 1989; ). Pathogenesis of experimental rabies in mice: an immunohistochemical study. . Acta Neuropathol 78:, 159–165. [CrossRef] [PubMed]
    [Google Scholar]
  25. Johnson N. , McKimmie C. S. , Mansfield K. L. , Wakeley P. R. , Brookes S. M. , Fazakerley J. K. , Fooks A. R. . ( 2006; ). Lyssavirus infection activates interferon gene expression in the brain. . J Gen Virol 87:, 2663–2667. [CrossRef] [PubMed]
    [Google Scholar]
  26. Kelly R. M. , Strick P. L. . ( 2000; ). Rabies as a transneuronal tracer of circuits in the central nervous system. . J Neurosci Methods 103:, 63–71. [CrossRef] [PubMed]
    [Google Scholar]
  27. Knobel D. L. , Cleaveland S. , Coleman P. G. , Fèvre E. M. , Meltzer M. I. , Miranda M. E. , Shaw A. , Zinsstag J. , Meslin F. X. . ( 2005; ). Re-evaluating the burden of rabies in Africa and Asia. . Bull World Health Organ 83:, 360–368.[PubMed]
    [Google Scholar]
  28. Lafon M. , Mégret F. , Meuth S. G. , Simon O. , Velandia Romero M. L. , Lafage M. , Chen L. , Alexopoulou L. , Flavell R. A. . & other authors ( 2008; ). Detrimental contribution of the immuno-inhibitor B7-H1 to rabies virus encephalitis. . J Immunol 180:, 7506–7515.[PubMed] [CrossRef]
    [Google Scholar]
  29. Mansfield K. L. , Johnson N. , Nuñez A. , Hicks D. , Jackson A. C. , 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. . J Neurovirol 14:, 218–228. [CrossRef] [PubMed]
    [Google Scholar]
  30. Marié I. , Durbin J. E. , Levy D. E. . ( 1998; ). Differential viral induction of distinct interferon-α genes by positive feedback through interferon regulatory factor-7. . EMBO J 17:, 6660–6669. [CrossRef] [PubMed]
    [Google Scholar]
  31. Marquette C. , Van Dam A. M. , Ceccaldi P. E. , Weber P. , Haour F. , Tsiang H. . ( 1996; ). Induction of immunoreactive interleukin-1β and tumor necrosis factor-α in the brains of rabies virus infected rats. . J Neuroimmunol 68:, 45–51. [CrossRef] [PubMed]
    [Google Scholar]
  32. McKimmie C. S. , Johnson N. , Fooks A. R. , Fazakerley J. K. . ( 2005; ). Viruses selectively upregulate Toll-like receptors in the central nervous system. . Biochem Biophys Res Commun 336:, 925–933. [CrossRef] [PubMed]
    [Google Scholar]
  33. Osterlund P. , Veckman V. , Sirén J. , Klucher K. M. , Hiscott J. , Matikainen S. , Julkunen I. . ( 2005; ). Gene expression and antiviral activity of alpha/beta interferons and interleukin-29 in virus-infected human myeloid dendritic cells. . J Virol 79:, 9608–9617. [CrossRef] [PubMed]
    [Google Scholar]
  34. Ovsyannikova I. G. , Haralambieva I. H. , Kennedy R. B. , Pankratz V. S. , Vierkant R. A. , Jacobson R. M. , Poland G. A. . ( 2012; ). Impact of cytokine and cytokine receptor gene polymorphisms on cellular immunity after smallpox vaccination. . Gene 510:, 59–65. [CrossRef] [PubMed]
    [Google Scholar]
  35. Prosniak M. , Hooper D. C. , Dietzschold B. , Koprowski H. . ( 2001; ). Effect of rabies virus infection on gene expression in mouse brain. . Proc Natl Acad Sci U S A 98:, 2758–2763. [CrossRef] [PubMed]
    [Google Scholar]
  36. Rieder M. , Brzózka K. , Pfaller C. K. , Cox J. H. , Stitz L. , Conzelmann K. K. . ( 2011; ). Genetic dissection of interferon-antagonistic functions of rabies virus phosphoprotein: inhibition of interferon regulatory factor 3 activation is important for pathogenicity. . J Virol 85:, 842–852. [CrossRef] [PubMed]
    [Google Scholar]
  37. Rosatte R. , Allan M. . ( 2009; ). The ecology of red foxes, Vulpes vulpes, in metropolitan Toronto, Ontario: disease management implications. . Can Field Nat 123:, 215–220.
    [Google Scholar]
  38. Rosatte R. , Ryckman M. , Ing K. , Proceviat S. , Allan M. , Bruce L. , Donovan D. , Davies J. C. . ( 2010; ). Density, movements, and survival of raccoons in Ontario, Canada: implications for disease spread and management. . J Mammal 91:, 122–135. [CrossRef]
    [Google Scholar]
  39. Rosatte R. , Kelly P. , Power M. . ( 2011; ). Home range, movements, and habitat utilization of striped skunk (Mephitis mephitis) in Scarborough, Ontario, Canada: disease management implications. . Can Field Nat 125:, 27–33.
    [Google Scholar]
  40. Rupprecht C. E. , Hamir A. N. , Johnston D. H. , Koprowski H. . ( 1988; ). Efficacy of a vaccinia-rabies glycoprotein recombinant virus vaccine in raccoons (Procyon lotor). . Rev Infect Dis 10: (Suppl 4), S803–S809. [CrossRef] [PubMed]
    [Google Scholar]
  41. Saha S. , Rangarajan P. N. . ( 2003; ). Common host genes are activated in mouse brain by Japanese encephalitis and rabies viruses. . J Gen Virol 84:, 1729–1735. [CrossRef] [PubMed]
    [Google Scholar]
  42. Samuel C. E. . ( 2001; ). Antiviral actions of interferons. . Clin Microbiol Rev 14:, 778–809. [CrossRef] [PubMed]
    [Google Scholar]
  43. Schmittgen T. D. , Livak K. J. . ( 2008; ). Analyzing real-time PCR data by the comparative C T method. . Nat Protoc 3:, 1101–1108. [CrossRef] [PubMed]
    [Google Scholar]
  44. Shankar V. , Dietzschold B. , Koprowski H. . ( 1991; ). Direct entry of rabies virus into the central nervous system without prior local replication. . J Virol 65:, 2736–2738.[PubMed]
    [Google Scholar]
  45. Solanki A. , Radotra B. D. , Vasishta R. K. . ( 2009; ). Correlation of cytokine expression with rabies virus distribution in rabies encephalitis. . J Neuroimmunol 217:, 85–89. [CrossRef] [PubMed]
    [Google Scholar]
  46. Szanto A. . ( 2009; ). Molecular genetics of the raccoon rabies virus. PhD dissertation, Trent University;, UK:.
    [Google Scholar]
  47. Tamura K. , Dudley J. , Nei M. , Kumar S. . ( 2007; ). mega4: Molecular evolutionary genetics analysis (mega) software version 4.0. . Mol Biol Evol 24:, 1596–1599. [CrossRef] [PubMed]
    [Google Scholar]
  48. Totton S. C. , Tinline R. R. , Rosatte R. C. , Bigler L. L. . ( 2002; ). Contact rates of raccoons (Procyon lotor) at a communal feeding site in rural eastern Ontario. . J Wildl Dis 38:, 313–319. [CrossRef] [PubMed]
    [Google Scholar]
  49. Tsiang H. , de la Porte S. , Ambroise D. J. , Derer M. , Koenig J. . ( 1986; ). Infection of cultured rat myotubes and neurons from the spinal cord by rabies virus. . J Neuropathol Exp Neurol 45:, 28–42. [CrossRef] [PubMed]
    [Google Scholar]
  50. Vidy A. , El Bougrini J. , Chelbi-Alix M. K. , Blondel D. . ( 2007; ). The nucleocytoplasmic rabies virus P protein counteracts interferon signaling by inhibiting both nuclear accumulation and DNA binding of STAT1. . J Virol 81:, 4255–4263. [CrossRef] [PubMed]
    [Google Scholar]
  51. Wang Z. W. , Sarmento L. , Wang Y. , Li X. Q. , Dhingra V. , Tseggai T. , Jiang B. , Fu Z. F. . ( 2005; ). Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system. . J Virol 79:, 12554–12565. [CrossRef] [PubMed]
    [Google Scholar]
  52. World Health Organization ( 2005; ). WHO expert consultation on Rabies, 2004. First Report: WHO technical report series no.931. Geneva:: WHO;.
    [Google Scholar]
  53. Zhao P. , Zhao L. , Zhang T. , Qi Y. , Wang T. , Liu K. , Wang H. , Feng H. , Jin H. . & other authors ( 2011; ). Innate immune response gene expression profiles in central nervous system of mice infected with rabies virus. . Comp Immunol Microbiol Infect Dis 34:, 503–512. [CrossRef] [PubMed]
    [Google Scholar]
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