Abstract
Rabies virus is a neurotropic virus that replicates and propagates into the nervous system of the infected host. Successful achievement of the virus cycle from the site of entry (usually due to a bite) up to the site of exit (salivary glands) relies on the preservation of the neuronal network. Once the rabies virus has entered the nervous system, its progression is not interrupted by the host defence mechanisms. This virus has evolved sophisticated strategies to (1) disarm premature destruction of the infected neurons and prolong the life span of the infected neurons, (2) evade the innate immune response launched by the infected neurons, and (3) eliminate the protective T cells migrating into the nervous system. In addition, by targeting the nervous system that has the striking capacity to centrally control the immune response, the rabies virus infection benefits also from disarmed host defences. The successful adaptation of the virus to the mammalian nervous system may explain why rabies is fatal in almost all the cases.
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References
Babault N et al (2011) Peptides targeting the PDZ domain of PTPN4 are efficient inducers of glioblastoma cell death. Structure 19:1518–1524
Baloul L, Lafon M (2003) Apoptosis and rabies virus neuroinvasion. Biochimie 85:777–788
Baloul L, Camelo S, Lafon M (2004) Up-regulation of Fas ligand (FasL) in the central nervous system: a mechanism of immune evasion by rabies virus. J Neurovirol 10:372–382
Barajon I et al (2009) Toll-like receptors 3, 4, and 7 are expressed in the enteric nervous system and dorsal root ganglia. J Histochem Cytochem 57:1013–1023
Blondel D, Kheddache S, Lahaye X, Dianoux L, Chelbi-Alix MK (2010) Resistance to rabies virus infection conferred by the PMLIV isoform. J Virol 84:10719–10726
Boivin G, Coulombe Z, Rivest S (2002) Intranasal herpes simplex virus type 2 inoculation causes a profound thymidine kinase dependent cerebral inflammatory response in the mouse hindbrain. Eur J Neurosci 16:29–43
Bottcher T et al (2003) Differential regulation of Toll-like receptor mRNAs in experimental murine central nervous system infections. Neurosci Lett 344:17–20
Brown GC, Neher JJ (2010) Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol Neurobiol 41:242–247
Brzozka K, Finke S, Conzelmann KK (2005) Identification of the rabies virus alpha/beta interferon antagonist: phosphoprotein P interferes with phosphorylation of interferon regulatory factor 3. J Virol 79:7673–7681
Brzozka K, Finke S, Conzelmann KK (2006) Inhibition of interferon signaling by rabies virus phosphoprotein P: activation-dependent binding of STAT1 and STAT2. J Virol 80:2675–2683
Bsibsi M, Persoon-Deen C, Verwer RW, Meeuwsen S, Ravid R, Van Noort JM (2006) Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia 53:688–695
Camelo S, Lafage M, Lafon M (2000) Absence of the p55 Kd TNF-alpha receptor promotes survival in rabies virus acute encephalitis. J Neurovirol 6:507–518
Camelo S, Lafage M, Galelli A, Lafon M (2001) Selective role for the p55 Kd TNF-alpha receptor in immune unresponsiveness induced by an acute viral encephalitis. J Neuroimmunol 113:95–108
Cameron JS et al (2007) Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J Neurosci 27:13033–13041
Carosella ED, Moreau P, Aractingi S, Rouas-Freiss N (2001) HLA-G: a shield against inflammatory aggression. Trends Immunol 22:553–555
Charlton KM, Casey GA (1979) Experimental rabies in skunks: immunofluorescence light and electron microscopic studies. Lab Invest 41:36–44
Charlton KM, Casey GA (1981) Experimental rabies in skunks: persistence of virus in denervated muscle at the inoculation site. Can J Comp Med 45:357–362
Charlton KM, Casey GA, Campbell JB (1984) Experimental rabies in skunks: effects of immunosuppression induced by cyclophosphamide. Can J Comp Med 48:72–77
Chopy D, Detje CN, Lafage M, Kalinke U, Lafon M (2011a) The type I interferon response bridles rabies virus infection and reduces pathogenicity. J Neurovirol 17:353–367
Chopy D et al (2011b) Ambivalent role of the innate immune response in rabies virus pathogenesis. J Virol 85:6657–6668
Delhaye S et al (2006) Neurons produce type I interferon during viral encephalitis. Proc Natl Acad Sci USA 103:7835–7840
Diebold SS et al (2003) Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 424:324–328
Dierks RE, Murphy FA, Harrison AK (1969) Extraneural rabies virus infection. Virus development in fox salivary gland. Am J Pathol 54:251–273
Dong H et al (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800
Eisenacher K, Steinberg C, Reindl W, Krug A (2007) The role of viral nucleic acid recognition in dendritic cells for innate and adaptive antiviral immunity. Immunobiology 212:701–714
Faul EJ, Wanjalla CN, Suthar MS, Gale M, Wirblich C, Schnell MJ (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
Fu ZF et al (1993) Differential effects of rabies and borna disease viruses on immediate-early- and late-response gene expression in brain tissues. J Virol 67:6674–6681
Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28:12–18
Galelli A, Baloul L, Lafon M (2000) Abortive rabies virus central nervous infection is controlled by T lymphocyte local recruitment and induction of apoptosis. J Neurovirol 6:359–372
Goethals S, Ydens E, Timmerman V, Janssens S (2010) Toll-like receptor expression in the peripheral nerve. Glia 58:1701–1709
Gratas C, Tohma Y, Barnas C, Taniere P, Hainaut P, Ohgaki H (1998) Up-regulation of Fas (APO-1/CD95) ligand and down-regulation of Fas expression in human esophageal cancer. Cancer Res 58:2057–2062
Guigoni C, Coulon P (2002) Rabies virus is not cytolytic for rat spinal motoneurons in vitro. J Neurovirol 8:306–317
Hemachudha T, Wacharapluesadee S, Mitrabhakdi E, Wilde H, Morimoto K, Lewis RA (2005) Pathophysiology of human paralytic rabies. J Neurovirol 11:93–100
Hicks DJ, Nunez A, Healy DM, Brookes SM, Johnson N, Fooks AR (2009) Comparative pathological study of the murine brain after experimental infection with classical rabies virus and European bat lyssaviruses. J Comp Pathol 140:113–126
Hirai K et al (1992) Suppression of cell-mediated immunity by street rabies virus infection. Microbiol Immunol 36:1277–1290
Hooper DC, Phares TW, Fabis MJ, Roy A (2009) The production of antibody by invading B cells is required for the clearance of rabies virus from the central nervous system. PLoS Negl Trop Dis 3:e535
Hornung V et al (2006) 5′-Triphosphate RNA is the ligand for RIG-I. Science 314:994–997
Hunter M et al (2010) Immunovirological correlates in human rabies treated with therapeutic coma. J Med Virol 82:1255–1265
Jackson AC (2014) Rabies: neurology. In: Bentivoglio M, Cavalheiro EA, Kristensson K, Patel N (eds) Neglected tropical diseases and conditions of the nervous system. Springer, New York
Jackson AC, Randle E, Lawrance G, Rossiter JP (2008) Neuronal apoptosis does not play an important role in human rabies encephalitis. J Neurovirol 14:368–375
Jackson AC, Kammouni W, Zherebitskaya E, Fernyhough P (2010) Role of oxidative stress in rabies virus infection of adult mouse dorsal root ganglion neurons. J Virol 84:4697–4705
Johnston GR, Webster NR (2009) Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesth 102:453–462
Juntrakul S, Ruangvejvorachai P, Shuangshoti S, Wacharapluesadee S, Hemachudha T (2005) Mechanisms of escape phenomenon of spinal cord and brainstem in human rabies. BMC Infect Dis 5:104
Kasempimolporn S, Saengseesom W, Mitmoonpitak C, Akesowan S, Sitprija V (1997) Cell-mediated immunosuppression in mice by street rabies virus not restored by calcium ionophore or PMA. Asian Pac J Allergy Immunol 15:127–132
Kasempimolporn S, Tirawatnapong T, Saengseesom W, Nookhai S, Sitprija V (2001) Immunosuppression in rabies virus infection mediated by lymphocyte apoptosis. Jpn J Infect Dis 54:144–147
Kassis R, Larrous F, Estaquier J, Bourhy H (2004) Lyssavirus matrix protein induces apoptosis by a TRAIL-dependent mechanism involving caspase-8 activation. J Virol 78:6543–6555
Kim D et al (2007) A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem 282:14975–14983
Klein RS et al (2005) Neuronal CXCL10 directs CD8+ T-cell recruitment and control of West Nile virus encephalitis. J Virol 79:11457–11466
Klingen Y, Conzelmann KK, Finke S (2008) Double-labeled rabies virus: live tracking of enveloped virus transport. J Virol 82:237–245
Koedel U et al (2004) MyD88 is required for mounting a robust host immune response to Streptococcus pneumoniae in the CNS. Brain 127:1437–1445
Kojima D, Park CH, Satoh Y, Inoue S, Noguchi A, Oyamada T (2009) Pathology of the spinal cord of C57BL/6J mice infected with rabies virus (CVS-11 strain). J Vet Med Sci 71:319–324
Kwidzinski E et al (2003) IDO (indolamine 2,3-dioxygenase) expression and function in the CNS. Adv Exp Med Biol 527:113–118
Lafon M (2005a) Modulation of the immune response in the nervous system by rabies virus. Curr Top Microbiol Immunol 289:239–258
Lafon M (2005b) Rabies virus receptors. J Neurovirol 11:82–87
Lafon M (2008) Immune evasion, a critical strategy for rabies virus. Dev Biol (Basel) 131:413–419
Lafon M (2011) Evasive strategies in rabies virus infection. Adv Virus Res 79:33–53
Lafon M et al (2005) Modulation of HLA-G expression in human neural cells after neurotropic viral infections. J Virol 79:15226–15237
Lafon M, Megret F, Lafage M, Prehaud C (2006) The innate immune facet of brain: human neurons express TLR-3 and sense viral dsRNA. J Mol Neurosci 29:185–194
Lafon M et al (2008) Detrimental contribution of the immuno-inhibitor b7-h1 to rabies virus encephalitis. J Immunol 180:7506–7515
Laothamatas J et al (2008) Furious and paralytic rabies of canine origin: neuroimaging with virological and cytokine studies. J Neurovirol 14:119–129
Larrous F, Gholami A, Mouhamad S, Estaquier J, Bourhy H (2010) Two overlapping domains of a lyssavirus matrix protein that acts on different cell death pathways. J Virol 84:9897–9906
Li XQ, Sarmento L, Fu ZF (2005) Degeneration of neuronal processes after infection with pathogenic, but not attenuated, rabies viruses. J Virol 79:10063–10068
Liu L et al (2008) Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science 320:379–381
Ma Y et al (2006) Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. J Cell Biol 175:209–215
Ma Y, Haynes RL, Sidman RL, Vartanian T (2007) TLR8: an innate immune receptor in brain, neurons and axons. Cell Cycle 6:2859–2868
Masatani T et al (2010) Rabies virus nucleoprotein functions to evade activation of the RIG-I-mediated antiviral response. J Virol 84:4002–4012
Masatani T et al (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 Res 155(1):168–174
McKimmie CS, Johnson N, Fooks AR, Fazakerley JK (2005) Viruses selectively upregulate Toll-like receptors in the central nervous system. Biochem Biophys Res Commun 336:925–933
Megret F et al (2005) Immunopotentiation of the antibody response against influenza HA with apoptotic bodies generated by rabies virus G-ERA protein-driven apoptosis. Vaccine 23:5342–5350
Megret F et al (2007) Modulation of HLA-G and HLA-E expression in human neuronal cells after rabies virus or herpes virus simplex type 1 infections. Hum Immunol 68:294–302
Menager P et al (2009) Toll-like receptor 3 (TLR3) plays a major role in the formation of rabies virus Negri Bodies. PLoS Pathog 5:e1000315
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 kinases 1 and 2. J Virol 78:9376–9388
Nguyen MD, Julien JP, Rivest S (2002) Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 3:216–227
Nuovo GJ, DeFaria DL, Chanona-Vilchi JG, Zhang Y (2005) Molecular detection of rabies encephalitis and correlation with cytokine expression. Mod Pathol 18(1):62–67
Park C et al (2006) TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression. Glia 53:248–256
Peltier DC, Simms A, Farmer JR, Miller DJ (2010) Human neuronal cells possess functional cytoplasmic and TLR-mediated innate immune pathways influenced by phosphatidylinositol-3 kinase signaling. J Immunol 184:7010–7021
Perry LL, Hotchkiss JD, Lodmell DL (1990) Murine susceptibility to street rabies virus is unrelated to induction of host lymphoid depletion. J Immunol 144:3552–3557
Phares TW, Kean RB, Mikheeva T, Hooper DC (2006) Regional differences in blood-brain barrier permeability changes and inflammation in the apathogenic clearance of virus from the central nervous system. J Immunol 176:7666–7675
Phares TW, Stohlman SA, Hinton DR, Atkinson R, Bergmann CC (2010) Enhanced antiviral T cell function in the absence of B7-H1 is insufficient to prevent persistence but exacerbates axonal bystander damage during viral encephalomyelitis. J Immunol 185:5607–5618
Pichlmair A et al (2006) RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314:997–1001
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 79:12893–12904
Prehaud C et al (2010) Attenuation of rabies virulence: takeover by the cytoplasmic domain of its envelope protein. Sci Signal 3:ra5
Randall RE, Goodbourn S (2008) Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 89:1–47
Rieder M, Conzelmann KK (2009) Rhabdovirus evasion of the interferon system. J Interferon Cytokine Res 29:499–509
Rieder M, Brzozka K, Pfaller CK, Cox JH, Stitz L, Conzelmann KK (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
Rossiter JP, Hsu L, Jackson AC (2009) Selective vulnerability of dorsal root ganglia neurons in experimental rabies after peripheral inoculation of CVS-11 in adult mice. Acta Neuropathol 118:249–259
Rouas-Freiss N, Moreau P, Menier C, Carosella ED (2003) HLA-G in cancer: a way to turn off the immune system. Semin Cancer Biol 13:325–336
Roy A, Hooper DC (2007) Lethal silver-haired bat rabies virus infection can be prevented by opening the blood-brain barrier. J Virol 81:7993–7998
Roy A, Phares TW, Koprowski H, Hooper DC (2007) Failure to open the blood-brain barrier and deliver immune effectors to central nervous system tissues leads to the lethal outcome of silver-haired bat rabies virus infection. J Virol 81:1110–1118
Scott CA, Rossiter JP, Andrew RD, Jackson AC (2008) Structural abnormalities in neurons are sufficient to explain the clinical disease and fatal outcome of experimental rabies in yellow fluorescent protein-expressing transgenic mice. J Virol 82:513–521
Shankar V, Kao M, Hamir AN, Sheng H, Koprowski H, Dietzschold B (1992) Kinetics of virus spread and changes in levels of several cytokine mRNAs in the brain after intranasal infection of rats with Borna disease virus. J Virol 66:992–998
Shimizu K, Ito N, Sugiyama M, Minamoto N (2006) Sensitivity of rabies virus to type I interferon is determined by the phosphoprotein gene. Microbiol Immunol 50:975–978
Sommereyns C, Paul S, Staeheli P, Michiels T (2008) IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog 4:e1000017
Steinman RM (1991) The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9:271–296
Sugiura N et al (2011) Gene expression analysis of host innate immune responses in the central nervous system following lethal CVS-11 infection in mice. Jpn J Infect Dis 64:463–472
Tang SC et al (2007) Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci USA 104:13798–13803
Terrien E et al (2012) Interference with the PTEN-MAST2 interaction by a viral protein leads to cellular relocalization of PTEN. Sci Signal 5:ra58
Thoulouze MI, Lafage M, Montano-Hirose JA, Lafon M (1997) Rabies virus infects mouse and human lymphocytes and induces apoptosis. J Virol 71:7372–7380
Tobiume M et al (2009) Rabies virus dissemination in neural tissues of autopsy cases due to rabies imported into Japan from the Philippines: immunohistochemistry. Pathol Int 59:555–566
Torres-Anjel MJ, Volz D, Torres MJ, Turk M, Tshikuka JG (1988) Failure to thrive, wasting syndrome, and immunodeficiency in rabies: a hypophyseal/hypothalamic/thymic axis effect of rabies virus. Rev Infect Dis 10(Suppl 4):S710–S725
Tracey KJ (2009) Reflex control of immunity. Nat Rev Immunol 9:418–428
Tshikuka JG, Torres-Anjel MJ, Blenden DC, Elliott SC (1992) The microepidemiology of wasting syndrome, a common link to diarrheal disease, cancer, rabies, animal models of AIDS, and HIV-AIDS YHAIDS). The feline leukemia virus and rabies virus models. Ann N Y Acad Sci 653:274–296
Ugolini G (1995) Specificity of rabies virus as a transneuronal tracer of motor networks: transfer from hypoglossal motoneurons to connected second-order and higher order central nervous system cell groups. J Comp Neurol 356:457–480
Ugolini G (2010) Advances in viral transneuronal tracing. J Neurosci Methods 194(1):2–20, Epub ahead of print
Versteeg GA, Garcia-Sastre A (2010) Viral tricks to grid-lock the type I interferon system. Curr Opin Microbiol 13:508–516
Vidy A, El Bougrini J, Chelbi-Alix MK, 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
Vuaillat C et al (2008) High CRMP2 expression in peripheral T lymphocytes is associated with recruitment to the brain during virus-induced neuroinflammation. J Neuroimmunol 193:38–51
Wang ZW et al (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
Wiktor TJ, Doherty PC, Koprowski H (1977a) In vitro evidence of cell-mediated immunity after exposure of mice to both live and inactivated rabies virus. Proc Natl Acad Sci USA 74:334–338
Wiktor TJ, Doherty PC, Koprowski H (1977b) Suppression of cell-mediated immunity by street rabies virus. J Exp Med 145:1617–1622
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 virus encephalitis. J Immunol 180:2641–2649
Zhao P et al (2011) Innate immune response gene expression profiles in central nervous system of mice infected with rabies virus. Comp Immunol Microbiol Infect Dis 34(6):503–512
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Lafon, M. (2014). Rabies: Neurobiology. In: Bentivoglio, M., Cavalheiro, E., Kristensson, K., Patel, N. (eds) Neglected Tropical Diseases and Conditions of the Nervous System. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8100-3_14
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