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Modulation of the Immune Response in the Nervous System by Rabies Virus

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Role of Apoptosis in Infection

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 289))

Abstract

Rabies virus (RABV) is a pathogen well-adapted to the nervous system, where it infects neurons. RABV is transmitted by the bite of an infected animal. It enters the nervous system via a motor neuron through the neuromuscular junction, or via a sensory nerve through nerve spindles. It then travels from one neuron to the next, along the spinal cord to the brain and the salivary glands. The virions are then excreted in the saliva of the animal and can be transmitted to another host by bite. Thus preservation of neuronal network integrity is crucial for the virus to be transmitted. Successful invasion of the nervous system by RABV seems to be the result of a subversive strategy based on the survival of infected neurons. This strategy includes protection against virus-mediated apoptosis and destruction of T cells that invade the CNS in response to infection.

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References

  • Akaike T, Weihe E, Schaefer M, Fu ZF, Zheng YM, Vogel W, Schmidt H, Koprowski H, Dietzschold B (1995) Effect of neurotropic virus infection on neuronal and inducible nitric oxide synthase activity in rat brain. J Neurovirol 1:118–125

    PubMed  Google Scholar 

  • Alcami A, Koszinowski UH (2000) Viral mechanisms of immune evasion. Trends Microbiol 8:410–418

    Article  PubMed  Google Scholar 

  • Anilionis A, Wunner WH, Curtis PJ (1981) Structure of the glycoprotein gene in rabies virus. Nature 294:275–278

    Article  PubMed  Google Scholar 

  • Badley AD, McElhinny JA, Leibson PJ, Lynch DH, Alderson MR, Paya CV (1996) Upregulation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes. J Virol 70:199–206

    PubMed  Google Scholar 

  • Baloul L, Lafon M (2003) Apoptosis and rabies virus neuroinvasion. Biochimie 85:777–788

    Article  PubMed  Google Scholar 

  • Baloul L, Camelo S, Lafon M (2004) Up-regulation of FasL in the CNS: a mechanism of immune evasion by rabies virus. Journal of Neurovirology (in press)

    Google Scholar 

  • Bechmann I, Mor G, Nilsen J, Eliza M, Nitsch R, Naftolin F (1999) FasL (CD95L, ApolL) is expressed in the normal rat and human brain: evidence for the existence of an immunological brain barrier. Glia 27:62–74

    Article  PubMed  Google Scholar 

  • Binder GK, Griffin DE (2001) Interferon-gamma-mediated site-specific clearance of alphavirus from CNS neurons. Science 293:303–306

    Article  PubMed  Google Scholar 

  • Bonetti B, Pohl J, Gao YL, Raine CS (1997) Cell death during autoimmune demyelination: effector but not target cells are eliminated by apoptosis. J Immunol 159:5733–5741

    PubMed  Google Scholar 

  • Camelo S, Castellanos J, Lafage M, Lafon M (2001a) Rabies virus ocular disease: T-cell-dependent protection is under the control of signaling by the p55 tumor necrosis factor alpha receptor, p55TNFR. J Virol 75:3427–3434

    Article  PubMed  Google Scholar 

  • Camelo S, Lafage M, Galelli A, Lafon M (2001b) Selective role for the p55 Kd TNF-alpha receptor in immune unresponsiveness induced by an acute viral encephalitis. J Neuroimmunol 113:95–108

    Article  PubMed  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • Chesler DA, Reiss CS (2002) The role of IFN-gamma in immune responses to viral infections of the central nervous system. Cytokine Growth Factor Rev 13:441–454

    Article  PubMed  Google Scholar 

  • Chiou SH, Liu JH, Hsu WM, Chen SS, Chang SY, Juan LJ, Lin JC, Yang YT, Wong WW, Liu CY, Lin YS, Liu WT, Wu CW (2001) Up-regulation of Fas ligand expression by human cytomegalovirus immediate-early gene product 2: a novel mechanism in cytomegalovirus-induced apoptosis in human retina. J Immunol 167:4098–4103

    PubMed  Google Scholar 

  • Choi C, Park JY, Lee J, Lim JH, Shin EC, Ahn YS, Kim CH, Kim SJ, Kim JD, Choi IS, Choi IH (1999) Fas ligand and Fas are expressed constitutively in human astrocytes and the expression increases with IL-1, IL-6, TNF-alpha, or IFN-gamma. J Immunol 162:1889–1895

    PubMed  Google Scholar 

  • Cippitelli M, Fionda C, Di Bona D, Di Rosa F, Lupo A, Piccoli M, Frati L, Santoni A (2002) Negative regulation of CD95 ligand gene expression by vitamin D3 in T lymphocytes. J Immunol 168:1154–1166

    PubMed  Google Scholar 

  • Corriveau RA, Huh GS, Shatz CI (1998) Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21:505–520

    Article  PubMed  Google Scholar 

  • Dietzschold B, Wunner WH, Wiktor TJ, Lopes AD, Lafon M, Smith CL, Koprowski H (1983) Characterization of an antigenic determinant of the glycoprotein that correlates with pathogenicity of rabies virus. Proc Natl Acad Sci USA 80:70–74

    PubMed  Google Scholar 

  • Dockrell DH (2003) The multiple roles of Fas ligand in the pathogenesis of infectious diseases. Clin Microbiol Infect 9:766–779

    Article  PubMed  Google Scholar 

  • Dockrell DH, Badley AD, Villacian IS, Heppelmann CJ, Algeciras A, Ziesmer S, Yagita H, Lynch DH, Roche PC, Leibson PJ, Paya CV (1998) The expression of Fas ligand by macrophages and its upregulation by human immunodeficiency virus infection. J Clin Invest 101:2394–2405

    PubMed  Google Scholar 

  • Etessami R, Conzelmann KK, Fadai-Ghotbi B, Natelson B, Tsiang H, Ceccaldi PE (2000) Spread and pathogenic characteristics of a G-deficient rabies virus recombinant: an in vitro and in vivo study. J Gen Virol 81:2147–2153

    PubMed  Google Scholar 

  • Flugel A, Schwaiger FW, Neumann H, Medana I, Willem M, Wekerle H, Kreutzberg GW, Graeber MB (2000) Neuronal FasL induces cell death of encephalitogenic T lymphocytes. Brain Pathol 10:353–364

    PubMed  Google Scholar 

  • 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

    Google Scholar 

  • Ghorpade A, Holter S, Borgmann K, Persidsky R, Wu L (2003) HIV-1 and IL-1 beta regulate Fas ligand expression in human astrocytes through the NF-kappa B pathway. J Neuroimmunol 141:141–149

    Article  PubMed  Google Scholar 

  • Gillet JP, Derer P, Tsiang H (1986) Axonal transport of rabies virus in the central nervous system of the rat. J Neuropathol Exp Neurol 45:619–634

    PubMed  Google Scholar 

  • Giuliani F, Goodyer CG, Antel JP, Yong VW (2003) Vulnerability of human neurons to T cell-mediated cytotoxicity. J Immunol 171:368–379

    PubMed  Google Scholar 

  • Green DR, Ferguson TA (2001) The role of Fas ligand in immune privilege. Nat Rev Mol Cell Biol 2:917–924

    Article  PubMed  Google Scholar 

  • Griffin DE (2003) Immune responses to RNA-virus infections of the CNS. Nat Rev Immunol 3:493–502

    Article  PubMed  Google Scholar 

  • Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA (1995) Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270:1189–1192

    PubMed  Google Scholar 

  • Havert MB, Schofield B, Griffin DE, Irani DN (2000) Activation of divergent neuronal cell death pathways in different target cell populations during neuroadapted sindbis virus infection of mice. J Virol 74:5352–5356

    Article  PubMed  Google Scholar 

  • Hooper DC, 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 

  • Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CI (2000) Functional requirement for class I MHC in CNS development and plasticity. Science 290:2155–2159

    Article  PubMed  Google Scholar 

  • Irwin DJ, Wunner WH, Ertl HC, Jackson AC (1999) Basis of rabies virus neurovirulence in mice: expression of major histocompatibility complex class I and class II mRNAs. J Neurovirol 5:485–494

    PubMed  Google Scholar 

  • Iwasaki Y, Gerhard W, Clark HF (1977) Role of host immune response in the development of either encephalitic or paralytic disease after experimental rabies infection in mice. Infect Immun 18:220–225

    PubMed  Google Scholar 

  • Joly E, Oldstone MB (1992) Neuronal cells are deficient in loading peptides onto MHC class I molecules. Neuron 8:1185–1190

    Article  PubMed  Google Scholar 

  • Kelly RM, Strick PL (2000) Rabies as a transneuronal tracer of circuits in the central nervous system. J Neurosci Methods 103:63–71

    Article  PubMed  Google Scholar 

  • Kimura T, Griffin DE (2000) The role of CD8+ T cells and major histocompatibility complex class I expression in the central nervous system of mice infected with neurovirulent Sindbis virus. J Virol 74:6117–6125

    Article  PubMed  Google Scholar 

  • Kohji T, Matsumoto Y (2000) Coexpression of Fas/FasL and Bax on brain and infiltrating T cells in the central nervous system is closely associated with apoptotic cell death during autoimmune encephalomyelitis. J Neuroimmunol 106:165–171

    Article  PubMed  Google Scholar 

  • Komatsu T, Bi Z, Reiss CS (1996) Interferon-gamma induced type I nitric oxide synthase activity inhibits viral replication in neurons. J Neuroimmunol 68:101–108

    Article  PubMed  Google Scholar 

  • Koprowski H, Zheng YM, Heber-Katz E, Fraser N, Rorke L, Fu ZF, Hanlon C, Dietzschold B (1993) In vivo expression of inducible nitric oxide synthase in experimentally induced neurologic diseases. Proc Natl Acad Sci USA 90:3024–3027

    PubMed  Google Scholar 

  • Kundig TM, Hengartner H, Zinkernagel RM (1993) T cell-dependent IFN-gamma exerts an antiviral effect in the central nervous system but not in peripheral solid organs. J Immunol 150:2316–2321

    PubMed  Google Scholar 

  • Lafon M (2004) Subversive neuroinvasive strategy of rabies virus. Archives of Virology S18:149–159

    Google Scholar 

  • Lafon M, Edelman L, Bouvet JP, Lafage M, Montchatre E (1990) Human monoclonal antibodies specific for the rabies virus glycoprotein and N protein. J Gen Virol 71:1689–1696

    PubMed  Google Scholar 

  • Lafon M, Wiktor TJ, Macfarlan RI (1983) Antigenic sites on the CVS rabies virus glycoprotein: analysis with monoclonal antibodies. J Gen Virol 64:843–851

    PubMed  Google Scholar 

  • Lay S, Prehaud C, Dietzschold B, Lafon M (2003) Glycoprotein of nonpathogenic rabies viruses is a major inducer of apoptosis in human jurkat T cells. Ann NY Acad Sci 1010:577–581

    Article  PubMed  Google Scholar 

  • Lee MO, Choi YH, Shin EC, Kang HI, Kim YM, Jeong SY, Seong JK, Yu DY, Cho H, Park JH, Kim SJ (2002) Hepatitis B virus X protein induced expression of interleukin 18 (IL-18): a potential mechanism for liver injury caused by hepatitis B virus (HBV) infection. J Hepatol 37:380–386

    Article  PubMed  Google Scholar 

  • Licon Luna RM, Lee E, Mullbacher A, Blanden RV, Langman R, Lobigs M (2002) Lack of both Fas ligand and perforin protects from flavivirus-mediated encephalitis in mice. J Virol 76:3202–3211

    Article  PubMed  Google Scholar 

  • Li-Weber M, Krammer PH (2003) Function and regulation of the CD95 (APO-1/Fas) ligand in the immune system. Semin Immunol 15:145–157

    Article  PubMed  Google Scholar 

  • Li-Weber M, Laur O, Dern K, Krammer PH (2000) T cell activation-induced and HIV tat-enhanced CD95(APO-1/Fas) ligand transcription involves NF-kappaB. Eur J Immunol 30:661–670

    Article  PubMed  Google Scholar 

  • Mazarakis ND, Azzouz M, Rohll JB, Ellard FM, Wilkes FJ, Olsen AL, Carter EE, Barber RD, Baban DF, Kingsman SM, Kingsman AJ, O’Malley K, Mitrophanous KA (2001) Rabies virus glycoprotein pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery. Hum Mol Genet 10:2109–2121

    Article  PubMed  Google Scholar 

  • Medana I, Li Z, Flugel A, Tschopp J, Wekerle H, Neumann H (2001) Fas ligand (CD95L) protects neurons against perforin-mediated T lymphocyte cytotoxicity. J Immunol 167:674–681

    PubMed  Google Scholar 

  • Medana IM, Gallimore A, Oxenius A, Martinic MM, Wekerle H, Neumann H (2000) MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Eur J Immunol 30:3623–3633

    Article  PubMed  Google Scholar 

  • Miller A, Morse HC, 3rd, Winkelstein J, Nathanson N (1978) The role of antibody in recovery from experimental rabies. I. Effect of depletion of B and T cells. J Immunol 121:321–326

    PubMed  Google Scholar 

  • 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 6:373–381

    PubMed  Google Scholar 

  • Morimoto K, Hooper DC, Carbaugh H, Fu ZF, Koprowski H, Dietzschold B (1998) Rabies virus quasispecies: implications for pathogenesis. Proc Natl Acad Sci USA 95:3152–3156

    Article  PubMed  Google Scholar 

  • Morimoto K, Hooper DC, Spitsin S, Koprowski H, Dietzschold B (1999) Pathogenicity of different rabies virus variants inversely correlates with apoptosis and rabies virus glycoprotein expression in infected primary neuron cultures. J Virol 73:510–518

    PubMed  Google Scholar 

  • Pereira RA, Simmons A (1999) Cell surface expression of H2 antigens on primary sensory neurons in response to acute but not latent herpes simplex virus infection in vivo. J Virol 73:6484–6489

    PubMed  Google Scholar 

  • Pereira RA, Tscharke DC, Simmons A (1994) Upregulation of class I major histocom-patibility complex gene expression in primary sensory neurons, satellite cells, and Schwann cells of mice in response to acute but not latent herpes simplex virus infection in vivo. J Exp Med 180:841–850

    Article  PubMed  Google Scholar 

  • Poch O, Tordo N, Keith G (1988) Sequence of the 3386 3’ nucleotides of the genome of the AVO1 strain rabies virus: structural similarities in the protein regions involved in transcription. Biochimie 70:1019–1029

    Article  PubMed  Google Scholar 

  • Prehaud C, Lay S, Dietzschold B, Lafon M (2003) Glycoprotein of nonpathogenic rabies viruses is a key determinant of human cell apoptosis. J Virol 77:10537–10547

    Article  PubMed  Google Scholar 

  • Raftery MJ, Schwab M, Eibert SM, Samstag Y, Walczak H, Schonrich G (2001) Targeting the function of mature dendritic cells by human cytomegalovirus: a multilayered viral defense strategy. Immunity 15:997–1009

    Article  PubMed  Google Scholar 

  • Redwine JM, Buchmeier MJ, Evans CF (2001) In vivo expression of major histocompatibility complex molecules on oligodendrocytes and neurons during viral infection. Am J Pathol 159:1219–1224

    PubMed  Google Scholar 

  • Schlitt BP, Felrice M, Jelachich ML, Lipton HL (2003) Apoptotic cells, including macrophages, are prominent in Theiler’s virus-induced inflammatory, demyelinating lesions. J Virol 77:4383–4388

    Article  PubMed  Google Scholar 

  • Seabrook TJ, Hay JB (2001) Intracerebroventricular infusions of TNF-alpha preferentially recruit blood lymphocytes and induce a perivascular leukocyte infiltrate. J Neuroimmunol 113:81–88

    Article  PubMed  Google Scholar 

  • Seif I, Coulon P, Rollin PE, Flamand A (1985) Rabies virulence: effect on pathogenicity and sequence characterization of rabies virus mutations affecting antigenic site III of the glycoprotein. J Virol 53:926–934

    PubMed  Google Scholar 

  • Shin DH, Lee E, Kim HJ, Kim S, Cho SS, Chang KY, Lee WJ (2002) Fas ligand mRNA expression in the mouse central nervous system. J Neuroimmunol 123:50–57

    Article  PubMed  Google Scholar 

  • Smith JS, McCelland CL, Reid FL, Baer GM (1982) Dual role of the immune response in street rabiesvirus infection of mice. Infect Immun 35:213–221

    PubMed  Google Scholar 

  • Suda T, Nagata S (1994) Purification and characterization of the Fas-ligand that induces apoptosis. J Exp Med 179:873–879

    Article  PubMed  Google Scholar 

  • Sugamata M, Miyazawa M, Mori S, Spangrude GJ, Ewalt LC, Lodmell DL (1992) Paralysis of street rabies virus-infected mice is dependent on T lymphocytes. J Virol 66:1252–1260

    PubMed  Google Scholar 

  • Tanner JE, Alfieri C (1999) Epstein-Barr virus induces Fas (CD95) in T cells and Fas ligand in B cells leading to T-cell apoptosis. Blood 94:3439–3447

    PubMed  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • Thoulouze MI, Lafage M, Yuste VJ, Baloul L, Edelman L, Kroemer G, Israel N, Susin SA, Lafon M (2003a) High level of Bcl-2 counteracts apoptosis mediated by a live rabies virus vaccine strain and induces long-term infection. Virology 314:549–561

    Article  PubMed  Google Scholar 

  • Thoulouze MI, Lafage M, Yuste VJ, Kroemer G, Susin SA, Israel N, Lafon M (2003b) Apoptosis inversely correlates with rabies virus neurotropism. Ann NY Acad Sci 1010:598–603

    Article  PubMed  Google Scholar 

  • Tordo N, Poch O, Ermine A, Keith G, Rougeon F (1986) Walking along the rabies genome: is the large G-L intergenic region a remnant gene? Proc Natl Acad Sci USA 83:3914–3918

    PubMed  Google Scholar 

  • Ubol S, Hiriote W, Anuntagool N, Utaisincharoen P (2001) A radical form of nitric oxide suppresses RNA synthesis of rabies virus. Virus Res 81:125–132

    Article  PubMed  Google Scholar 

  • Van Dam AM, Bauer J, Man AHWK, Marquette C, Tilders FJ, Berkenbosch F (1995) Appearance of inducible nitric oxide synthase in the rat central nervous system after rabies virus infection and during experimental allergic encephalomyelitis but not after peripheral administration of endotoxin. J Neurosci Res 40:251–260

    Article  PubMed  Google Scholar 

  • Weiland F, Cox JH, Meyer S, Dahme E, Reddehase MJ (1992) Rabies virus neuritic paralysis: immunopathogenesis of nonfatal paralytic rabies. J Virol 66:5096–5099

    PubMed  Google Scholar 

  • Xiang ZQ, Knowles BB, McCarrick JW, Ertl HC (1995) Immune effector mechanisms required for protection to rabies virus. Virology 214:398–404

    Article  PubMed  Google Scholar 

  • Xu XN, Screaton GR, Gotch FM, Dong T, Tan R, Almond N, Walker B, Stebbings R, Kent K, Nagata S, Stott JE, McMichael AJ (1997) Evasion of cytotoxic T lymphocyte (CTL) responses by nef-dependent induction of Fas ligand (CD95L) expression on simian immunodeficiency virus-infected cells. J Exp Med 186:7–16

    Article  PubMed  Google Scholar 

  • Zuniga E, Motran CC, Montes CL, Yagita H, Gruppi A (2002) Trypanosoma cruzi infection selectively renders parasite-specific IgG+ B lymphocytes susceptible to Fas/Fas ligand-mediated fratricide. J Immunol 168:3965–3973

    PubMed  Google Scholar 

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Lafon, M. (2005). Modulation of the Immune Response in the Nervous System by Rabies Virus. In: Griffin, D.E. (eds) Role of Apoptosis in Infection. Current Topics in Microbiology and Immunology, vol 289. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27320-4_11

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