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Journal of Virology, December 2005, p. 15405-15416, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15405-15416.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Overexpression of Tumor Necrosis Factor Alpha by a Recombinant Rabies Virus Attenuates Replication in Neurons and Prevents Lethal Infection in Mice

Milosz Faber,1,{dagger} Michael Bette,2,{dagger} Mirjam A. R. Preuss,2,3 Rojjanaporn Pulmanausahakul,1 Jennifer Rehnelt,2 Matthias J. Schnell,3 Bernhard Dietzschold,1 and Eberhard Weihe2*

Department of Microbiology and Immunology, Center for Neurovirology,1 Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania,3 Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University Marburg, Marburg, Germany2

Received 7 June 2005/ Accepted 19 September 2005

The effect of tumor necrosis factor alpha (TNF-{alpha}) on rabies virus (RV) infection of the mouse central nervous system (CNS) was studied, using recombinant RV engineered to express either soluble TNF-{alpha} [SPBN-TNF-{alpha}(+)] or insoluble membrane-bound TNF-{alpha} [SPBN-TNF-{alpha}(MEM)]. Growth curves derived from infections of mouse neuroblastoma NA cells revealed significantly less spread and production of SPBN-TNF-{alpha}(+) than of SPBN-TNF-{alpha}(MEM) or SPBN-TNF-{alpha}(–), which carries an inactivated TNF-{alpha} gene. The expression of soluble or membrane-bound TNF-{alpha} was not associated with increased cell death or induction of alpha/beta interferons. Brains of mice infected intranasally with SPBN-TNF-{alpha}(+) showed significantly less virus spread than did mouse brains after SPBN-TNF-{alpha}(–) infection, and none of the SPBN-TNF-{alpha}(+)-infected mice succumbed to RV infection, whereas 80% of SPBN-TNF-{alpha}(–)-infected mice died. Reduced virus spread in SPBN-TNF-{alpha}(+)-infected mouse brains was paralleled by enhanced CNS inflammation, including T-cell infiltration and microglial activation. These data suggest that TNF-{alpha} exerts its protective activity in the brain directly through an as yet unknown antiviral mechanism and indirectly through the induction of inflammatory processes in the CNS.

* Corresponding author. Mailing address: Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University Marburg, Robert-Koch Str. 8, D-35037 Marburg, Germany. Phone: 49-6421-2866247. Fax: 49-6421-2868965. E-mail: weihe{at}staff.uni-marburg.de.

{dagger} Both authors contributed equally to the study.

Journal of Virology, December 2005, p. 15405-15416, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15405-15416.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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