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Journal of Virology, November 2001, p. 10800-10807, Vol. 75, No. 22
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.22.10800-10807.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Overexpression of Cytochrome c by a Recombinant Rabies Virus Attenuates Pathogenicity and Enhances Antiviral Immunity

Rojjanaporn Pulmanausahakul,1 Milosz Faber,1 Kinjiro Morimoto,1 Sergei Spitsin,1 Eberhard Weihe,2 D. Craig Hooper,1 Matthias J. Schnell,3 and Bernhard Dietzschold1,*

Departments of Microbiology and Immunology1 and Biochemistry and Molecular Pharmacology,3 Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and Institute of Anatomy and Cell Biology, Philipps University Marburg, 65033 Marburg, Germany2

Received 15 May 2001/Accepted 6 August 2001

The pathogenicity of individual rabies virus strains appears to correlate inversely with the extent of apoptotic cell death they induce and with the expression of rabies virus glycoprotein, a major inducer of an antiviral immune response. To determine whether the induction of apoptosis by rabies virus contributes to a decreased pathogenicity by stimulating antiviral immunity, we have analyzed these parameters in tissue cultures and in mice infected with a recombinant rabies virus construct that expresses the proapoptotic protein cytochrome c. The extent of apoptosis was strongly increased in primary neuron cultures infected with the recombinant virus carrying the active cytochrome c gene [SPBN-Cyto c(+)], compared with cells infected with the recombinant virus containing the inactive cytochrome c gene [SPBN-Cyto c(-)]. Mortality in mice infected intranasally with SPBN-Cyto c(+) was substantially lower than in SPBN-Cyto c(-)-infected mice. Furthermore, virus-neutralizing antibody (VNA) titers were significantly higher in mice immunized with SPBN-Cyto c(+) at the same dose. The VNA titers induced by these recombinant viruses paralleled their protective activities against a lethal rabies virus challenge infection, with SPBN-Cyto c(+) revealing an effective dose 20 times lower than that of SPBN-Cyto c(-). The strong increase in immunogenicity, coupled with the marked reduction in pathogenicity, identifies the SPBN-Cyto c(+) construct as a candidate for a live rabies virus vaccine.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107. Phone: (215) 503-4692. Fax: (215) 923-7145. E-mail: bdietzschold{at}reddi1.uns.tju.edu.

Journal of Virology, November 2001, p. 10800-10807, Vol. 75, No. 22
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.22.10800-10807.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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