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Journal of Virology, December 2003, p. 13161-13170, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.13161-13170.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Protection against Murine Leukemia Virus-Induced Spongiform Myeloencephalopathy in Mice Overexpressing Bcl-2 but Not in Mice Deficient for Interleukin-6, Inducible Nitric Oxide Synthetase, ICE, Fas, Fas Ligand, or TNF-R1 Genes

Paul Jolicoeur,1,2,3* Chunyan Hu,1 Tak W. Mak,4 Jean-Claude Martinou,5 and Denis G. Kay1

Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7,1 Department of Microbiology and Immunology, Université de Montréal, Montreal, Quebec H3C 3J7,2 Division of Experimental Medicine, McGill University, Montreal, Quebec H3G 1A4,3 Amgen Institute, Toronto, Ontario M5G 2C1, Canada,4 Glaxo Institute and Department of Cell Biology, University of Geneva, Geneva, Switzerland5

Received 6 June 2003/ Accepted 18 August 2003

Some murine leukemia viruses (MuLVs), among them Cas-Br-E and ts-1 MuLVs, are neurovirulent, inducing spongiform myeloencephalopathy and hind limb paralysis in susceptible mice. It has been shown that the env gene of these viruses harbors the determinant of neurovirulence. It appears that neuronal loss occurs by an indirect mechanism, since the target motor neurons have not been found to be infected. However, the pathogenesis of the disease remains unclear. Several lymphokines, cytokines, and other cellular effectors have been found to be aberrantly expressed in the brains of infected mice, but whether these are required for the development of the neurodegenerative lesions is not known. In an effort to identify the specific effectors which are indeed required for the initiation and/or development of spongiform myeloencephalopathy, we inoculated gene-deficient (knockout [KO]) mice with ts-1 MuLV. We show here that interleukin-6 (IL-6), inducible nitric oxide synthetase (iNOS), ICE, Fas, Fas ligand (FasL), and TNF-R1 KO mice still develop signs of disease. However, transgenic mice overexpressing Bcl-2 in neurons (NSE/Bcl-2) were largely protected from hind limb paralysis and had less-severe spongiform lesions. These results indicate that motor neuron death occurs in this disease at least in part by a Bcl-2-inhibitable pathway not requiring the ICE, iNOS, Fas/FasL, TNF-R1, and IL-6 gene products.

* Corresponding author. Mailing address: Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7. Phone: (514) 987-5569. Fax: (514) 987-5794. E-mail: jolicop{at}ircm.qc.ca.

Journal of Virology, December 2003, p. 13161-13170, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.13161-13170.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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