Volume 94, Issue 2
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Rabies is a lethal infectious disease that causes 55,000 human deaths per year and is transmitted by various mammalian species, such as dogs and bats. The host immune response is essential for avoiding viral progression and promoting viral clearance. Cytokines and chemokines are crucial in the development of an immediate antiviral response; the rabies virus (RABV) attempts to evade this immune response. The virus's capacity for evasion is correlated with its pathogenicity and the host's inflammatory response, with highly pathogenic strains being the most efficient at hijacking the host's defense mechanisms and thereby decreasing inflammation. The purpose of this study was to evaluate the expression of a set of cytokine and chemokine genes that are related to the immune response in the brains of mice inoculated intramuscularly or intracerebrally with two wild-type strains of RABV, one from dog and the other from vampire bat. The results demonstrated that the gene expression profile is intrinsic to the specific rabies variant. The prompt production of cytokines and chemokines seems to be more important than their levels of expression for surviving a rabies infection.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Knobell DL, Cleaveland S, Coleman PG, Fevre MI, Meltzer MI, Miranda MEG, Shaw A, Zinsstag J, Meslin F-X, , 2005. Re-evaluating the burden of rabies in Africa and Asia. Bull World Health Organ 83: 360368. [Google Scholar]
  2. Ito M, Arai YT, Itou T, Sakei T, Ito FH, Takasaki T, Kurane I, , 2001. Genetic characterization and the geographic distribution of rabies virus isolates in Brazil: identification of two reservoirs, dogs and vampire bats. Virology 284: 214222.[Crossref] [Google Scholar]
  3. Schneider MC, Romijn PC, Uieda W, Tamayo H, da Silva DF, Belotto A, da Silva JB, Leanes LF, , 2009. Rabies transmitted by vampire bats to humans: an emerging zoonotic disease in Latin America? Rev Panam Salud Publica 25: 260268.[Crossref] [Google Scholar]
  4. Brasil, 2010. Brasil: Ministério da Saúde. Secretaria da Vigilância Sanitária. Available at: http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/svs/raiva. Accessed May 22, 2014.
  5. Aguiar TDF, Costa EC, Rolim BN, Romijn PC, Morais NB, Teixeira MFS, , 2011. Risco de transmissão do vírus da raiva oriundo de sagüi (Callithrix jacchus), domiciliado e semi-domiciliado, para o homem na região metropolitana de Fortaleza, estado do Ceará [in Portuguese]. Rev Soc Bras Med Trop 44: 356363.[Crossref] [Google Scholar]
  6. Wang ZW, Sarmento L, Wang Y, Li XQ, Dhingra V, Tseggai T, Jiang B, Fu ZF, , 2005. Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system. J Virol 79: 1255412565.[Crossref] [Google Scholar]
  7. Jackson AC, Randle E, Lawrance G, Rossiter JP, , 2008. Neuronal apoptosis does not play an important role in human rabies encephalitis. J Neurovirol 14: 368375.[Crossref] [Google Scholar]
  8. Hemachudha T, Ugolini G, Wacharapluesadee S, Sungkarat W, Shuangshoti S, Laothamatas J, , 2013. Human rabies: neuropathogenesis, diagnosis, and management. Lancet Neurol 12: 498513.[Crossref] [Google Scholar]
  9. Lafon M, , 2011. Evasive strategies in rabies virus infection. Adv Virus Res 79: 3353.[Crossref] [Google Scholar]
  10. Griffin D, , 2003. Immune response to RNA-virus infections of the CNS. Natl Rev 3: 493502. [Google Scholar]
  11. Ransohoff RM, Cardona AE, , 2010. The myeloid cells of the central nervous system parenchyma. Nature 468: 253262.[Crossref] [Google Scholar]
  12. Prehaud C, Megret F, Lafage M, Lafon M, , 2005. Virus infection switches TLR-3- positive human neurons to become strong producers of beta interferon. J Virol 79: 1289312904.[Crossref] [Google Scholar]
  13. Taniguchi T, Takaoka A, , 2002. The interferon-α/β system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors. Curr Opin Immunol 14: 111116.[Crossref] [Google Scholar]
  14. Masatani T, Ito N, Shimizu K, Ito Y, Nakagawa K, Sawaki Y, Koyama H, Sugiyama M, , 2010. Rabies virus nucleoprotein functions to evade activation of the RIG-I-mediated antiviral response. J Virol 84: 40024012.[Crossref] [Google Scholar]
  15. Chopy D, Detje CN, Lafage M, Kalinke U, Lafon M, , 2011. The type I interferon response bridles rabies virus infection and reduces pathogenicity. J Neurovirol 17: 353367.[Crossref] [Google Scholar]
  16. Nakamichi K, Inoue S, Takasaki T, Morimoto K, Kurane I, , 2004. Rabies virus stimulates nitric oxide production and CXC chemokine ligand 10 expression in macrophages through activation of extracellular signal regulated kinase 1 and 2. J Virol 78: 93769388.[Crossref] [Google Scholar]
  17. Faul EJ, Wanjalla CN, Suthar MS, Gale M, Jr Wirblich C, Schnell J, , 2010. Rabies virus infection induce type I interferon production in an IPS-1 dependent manner while dendritic cell activation relies on IFNAR signaling. PLoS Pathog 6: e1001016.[Crossref] [Google Scholar]
  18. Biron CA, , 2001. Interferons α and β as immune regulators—a new look. Immunity 14: 661664.[Crossref] [Google Scholar]
  19. Faber M, Pulmanausahakul R, Nagao K, Prosniak M, Rice AB, Koprowski H, Schnell MJ, Dietzschold B, , 2004. Identification of viral genomic elements responsible for rabies virus neuroinvasiveness. PLoS Pathog 101: 1632816332. [Google Scholar]
  20. Li J, McGettigan JP, Faber M, Schnell MJ, Dietzschold B, , 2008. Infection of monocytes or immature dendritic cells (DCs) with an attenuated rabies virus results in dc maturation and a strong activation of the NFkappaB signaling pathway. Vaccine 26: 419426.[Crossref] [Google Scholar]
  21. Wang CX, Shuaib A, , 2002. Involvement of inflammatory cytokines in central nervous system injury. Prog Neurobiol 67: 161172.[Crossref] [Google Scholar]
  22. Mansfield KL, Johnson N, Nunez A, Hicks D, Jackson AC, Fooks AR, , 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: 218228.[Crossref] [Google Scholar]
  23. Fu ZF, Weihe E, Zheng YM, Schafer MK, Sheng H, Corisdeo S, Rauscher FJ, Koprowski H, Dietzschold B, , 1993. Differential effects of rabies and borna disease viruses on immediate- early- and late-response gene expression in brain tissues. J Virol 67: 66746681. [Google Scholar]
  24. Niu X, Wang H, Fu ZF, , 2011. Role of chemokines in rabies pathogenesis and protection. Adv Virus Res 79: 7389.[Crossref] [Google Scholar]
  25. Zhao L, Toriumi H, Kuang Y, Chen H, Fu ZF, , 2009. The roles of chemokines in rabies virus infection: overexpression may not always be beneficial. J Virol 83: 1180811818.[Crossref] [Google Scholar]
  26. Zhang B, Chan YK, Lu B, Diamond MS, Klein RS, , 2008. CXCR3 mediates region-specific antiviral T cell trafficking within the central nervous system during West Nile encephalitis. J Immunol 180: 26412649.[Crossref] [Google Scholar]
  27. Roy A, Hooper DC, , 2007. Lethal silver-haired bat rabies virus infection can be prevented by opening the blood-brain barrier. J Virol 81: 79937998.[Crossref] [Google Scholar]
  28. Lafon M, , 2005. Modulation of the immune response in the nervous system by rabies virus. Curr Top Microbiol Immunol 289: 239258. [Google Scholar]
  29. Weihe E, Bette M, Preuss MA, Faber M, Schafer MK, Rehnelt J, Schnell MJ, Dietzschold B, , 2008. Role of virus-induced neuropeptides in the brain in the pathogenesis of rabies. Dev Biol (Basel) 131: 7381. [Google Scholar]
  30. Lafon M, , 2008. Immune evasion, a critical strategy for rabies virus. Dev Biol (Basel) 131: 413419. [Google Scholar]
  31. Sarkar SN, Sen GC, , 2004. Novel functions of proteins encoded by viral stress-inducible genes. Pharmacol Ther 103: 245259.[Crossref] [Google Scholar]
  32. Baloul L, Lafon M, , 2003. Apoptosis and rabies virus neuroinvasion. Biochimie 85: 777788.[Crossref] [Google Scholar]
  33. Fernandes ER, Andrade HF, Jr Lancellotti CLP, Quaresma JAS, Demanchki S, Vasconselos PFC, Duarte MIS, , 2011. In situ apoptosis of adaptive immune cells and the cellular escape of rabies virus in CNS from patients with human rabies transmitted by Desmodus rotundus . Virus Res 156: 121126.[Crossref] [Google Scholar]
  34. Hooper DC, Roy A, Barkhouse DA, Li J, Kean RB, , 2011. Rabies virus clearance from the central nervous system. Adv Virus Res 79: 5666. [Google Scholar]
  35. Sugiura N, Uda A, Inoue S, Kojima D, Hamamoto N, Kaku Y, Okutani A, Park C, Yamada A, , 2011. Gene expression analysis of host immune response in the central nervous system following lethal CVS-11 infection in mice. Jpn J Infect Dis 64: 463472. [Google Scholar]
  36. Phares TW, Kean RB, Mikheeva T, Hooper DC, , 2006. Regional differenced in blood-brain barrier permeability changes and inflammation in the apathogenic clearance of virus from the central nervous system. J Immunol 176: 76667675.[Crossref] [Google Scholar]
  37. Phares TW, Fabis MJ, Brimer CM, Kean RB, Hooper DC, , 2007. A peroxynitrite-dependent pathway is responsible for blood-brain barrier permeability changes during a central nervous system inflammatory response: TNF-α is neither necessary nor sufficient. J Immunol 178: 73347343.[Crossref] [Google Scholar]
  38. Roy A, Phares TW, Koprowski H, Hooper DC, , 2007. Failure to open the blood-brain barrier and deliver immune effectors to the CNS tissues leads to the lethal outcome of silver-haired bat rabies virus infection. J Virol 81: 11101118.[Crossref] [Google Scholar]
  39. Spindler KR, Hsu TH, , 2012. Viral disruption of blood-brain barrier. Trends Microbiol 20: 282290.[Crossref] [Google Scholar]
  40. Kuang Y, Lackay SN, Zhao L, Fu ZF, , 2009. Role of chemokines in the enhancement of BBB permeability and inflammatory infiltration after rabies virus infection. Virus Res 144: 1826.[Crossref] [Google Scholar]
  41. Zlotnik A, Yoshie O, , 2000. Chemokines: a new classification system and their role in immunity. Immunity 12: 121127.[Crossref] [Google Scholar]
  42. Borish LC, Steinke JW, , 2003. Cytokines and chemokines. J Allergy Clin Immunol 111: S460S475.[Crossref] [Google Scholar]
  43. Soares RM, Bernardi F, Sakamoto SM, Heinemann MB, Cortez A, Alves LM, Meyer AD, Ito FH, Richtzenhain LJ, , 2002. A heminested polymerase chain reaction for the detection of Brazilian isolates from vampires bats and herbivores. Mem Inst Oswaldo Cruz 97: 109111.[Crossref] [Google Scholar]
  44. Udow SJ, Marrie RA, Jackson AC, , 2013. Clinical features of dog- and bat-acquired rabies in humans. Clin Infect Dis 57: 689696.[Crossref] [Google Scholar]
  45. Solanki A, Radotra BD, Vasishta RK, , 2009. Correlation of cytokine expression with rabies virus distribution in rabies encephalitis. J Neuroimmunol 217: 8589.[Crossref] [Google Scholar]
  46. Zhao P, Yang Y, Feng H, Zhao L, Qin J, Zhang T, Wang H, Yang S, Xia X, , 2013. Global gene expression changes in BV2 microglial cell line during rabies virus infection. Infect Genet Evol 20: 257269.[Crossref] [Google Scholar]

Data & Media loading...

  • Received : 15 May 2015
  • Accepted : 02 Nov 2015
  • Published online : 03 Feb 2016

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error