The rabies virus glycoprotein determines the distribution of different rabies virus strains in the brain
Received: 14 March 2002 Revised: 29 April 2002 Accepted: 01 May 2002 DOI:
10.1080/13550280290100707 Cite this article as: Yan, X., Mohankumar, P.S., Dietzschold, B. et al. Journal of NeuroVirology (2002) 8: 345. doi:10.1080/13550280290100707 Abstract
The contribution of rabies virus (RV) glycoprotein (G) in viral distribution in the brain was examined by immunohistochemistry following stereotaxic inoculation into the rat hippocampus. Viruses used in this study include the highly neuroinvasive challenge virus standard strains (CVS-N2C and CVS-B2C) and the nonneuroinvasive attenuated SN-10 strain, as well as SN-10-derived recombinant viruses expressing the G gene from CVS-N2C (RN2C) or CVS-B2C (RB2C). The distribution of recombinant viruses in the brain was similar to those of the parental viruses from which the G was derived. For example, while CVS-B2C- and RB2C-infected neurons were seen preferentially in the hippocampus, cortex, and hypothalamus, CVS-N2C- and RN2C-infected neurons were preferentially found in the hippocampus, cortex, and thalamus. SN-10 infected efficiently almost all the brain regions. To further study the role of the RV G in virus spreading, we examined the distribution of RV antigen in brains infected with a recombinant RV in which the SN-10 G was replaced with vesicular stomatitis virus (VSV) G (SN-10-VG) was examined. The spreading of SN-10-VG to the cortex and the thalamus was drastically reduced, but the number of infected neurons in hippocampus and hypothalamus, particularly the paraventricular nucleus, was similar to the SN-10 virus. This pattern of spreading resembles that of VSV. Together, our data demonstrate that it is the G protein that determines the distribution pattern of RV in the brain.
Keywords rabies virus spreading distribution glycoprotein reverse genetics References
Astic L, Saucier D, Coulon P, Lafay F, Flamand A (1993). The CVS strain of rabies virus as transneuronal tracer in the olfactory system of mice.
Coulon P, Ternaux JP, Flamand A, Tuffereau C (1998). An avirulent mutant of rabies virus is unable to infect motoneurons
Cox JH, Dietzschold B, Schneider LG (1977). Rabies virus glycoprotein. II. Biological and serological characterization.
Dietzschold B, Rupprecht CE, Fu ZF, Koprowski H (1996). Rhabdoviruses. In
Fields’ virology. Fields B, Knipe D, Howley PM, Chanock RM, Melnick JL, Monath TP, Roizman B (eds). 3rd ed, Lippincott-Raven Press: Philadelphia, pp 1137–1159.
Dietzschold B, Wiktor TJ, Maul GG, Wunner WH (1987). Differences in cell-to-cell spread of pathogenic and non-pathogenic rabies viruses
in vivo and in vitro. In The biology of negative strand viruses. Mahy B, Kolakofsky D (eds). Elsevier Science: Amsterdam, pp 333–340.
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
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
Foley HD, McGettigan JP, Siler CA, Dietzschold B, Schnell MJ (2000). A recombinant rabies virus expressing vesicular stomatitis virus glycoprotein fails to protect against rabies virus infection.
Proc Natl Acad Sci USA
Gillet JP, Derer P, Tsiang H (1986). Axonal transport of rabies virus in the central nervous system of the rat.
J Neuropathol Exp Neurol
Gosztonyi G, Dietzschold B, Kao M, Rupprecht CE, Ludwig H, Koprowski H (1993). Rabies and borna disease. A comparative pathogenetic study of two neurovirulent agents.
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.
Huneycutt BS, Plakhov IV, Shusterman Z, Bartido SM, Huang A, Reiss CS, Aoki C (1994). Distribution of vesicular stomatitis virus proteins in the brains of BALB/c mice following intranasal inoculation: An immunohistochemical analysis.
Iwasaki Y (1991). Spread of virus within the central nervous system. In
The natural history of rabies, Baer GM (ed). 2nd ed, CRC Press: Boca Raton, Florida, pp 121–132.
Jacob Y, Badrane H, Ceccaldi PE, Tordo N (2000). Cytoplasmic dynein LC8 interacts with lyssavirus phosphoprotein.
Kucera P, Dolivo M, Coulon P, Flamand A (1985). Pathways of the early propagation of virulent and avirulent rabies strains from the eye to the brain.
Lentz TL, Burrage TG, Smith AL, Crick J, Tignor GH (1982). Is the acetylcholine receptor a rabies virus receptor?
Mebatsion T, Konig M, Conzelmann KK (1996). Budding of rabies virus particles in the absence of the spike glycoprotein.
Miyoshi K, Harter DH, Hsu KC (1971). Neuropathological and immunofluorescence studies of experimental vesicular stomatitis virus encephalitis in mice.
J Neuropathol Exp Neurol
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.
Morimoto K, Hooper DC, Carbaugh H, Fu ZF, Koprowski H, Dietzschold B (1998). Rabies virus quasispecies: Implication for pathogenesis.
Proc Natl Acad Sci USA
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.
Morimoto K, McGettigan JP, Foley HD, Hooper DC, Dietzschold B, Schnell MJ 2001. Genetic engineering of live rabies vaccines.
Morimoto K, Ni YJ, Kawai A (1992). Syncytium formation is induced in the murine neuroblastoma cell cultures which produce pathogenic type G proteins of the rabies virus.
Paxinos G, Watson C (1986).
The rat brain in stereotaxic co-ordinators. 2nd ed, Academic Press: New York.
Plakhov IV, Arlund EE, Aoki C, Reiss CS (1995). The earliest events in vesicular stomatitis virus infection of the murine olfactory neuroepithelium and entry of the central nervous system.
Raux H, Flamand A, Blondel D (2000). Interaction of the rabies virus P protein with the LC8 dynein light chain.
Schnell MJ, Mebatsion T, Conzelmann KK (1994). Infectious rabies viruses from cloned cDNA.
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.
Thoulouze MI, Lafage M, Schachner M, Hartmann U, Cremer H, Lafon M (1998). The neural cell adhesion molecule is a receptor for rabies virus.
Tuffereau C, Benejean J, Blondel D, Kieffer B, Flamand A (1998). Low-affinity nerve-growth factor receptor (P75NTR) can serve as a receptor for rabies virus.
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
Wagner RR, Rose JK (1996). Rhabdoviridae: The viruses and their replication. In
Fields’ virology. Fields B, Knipe D, Howley PM, Chanock RM, Melnick JL, Monath TP, Roizman B (eds). 3rd ed, Lippincott-Raven: Philadelphia, pp 1121–1136.
Yan X, Prosniak M, Curtis MT, Weiss ML, Faber M, Dietzschold B, Fu ZF (2001). Silver-haired bat rabies virus variant does not induce apoptosis in the brain of experimentally infected mice.
Yang C, Jackson AC (1992). Basis of neurovirulence of avirulent rabies virus variant Av01 with stereotaxic brain inoculation in mice.
J Gen Virol