Overexpression of tumor necrosis factor alpha by a recombinant rabies virus attenuates replication in neurons and prevents lethal infection in mice.
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.
Faber
Milosz
M
Department of Microbiology and Immunology, Center for Neurovirology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Bette
Michael
M
Preuss
Mirjam A R
MA
Pulmanausahakul
Rojjanaporn
R
Rehnelt
Jennifer
J
Schnell
Matthias J
MJ
Dietzschold
Bernhard
B
Weihe
Eberhard
E
D000818:Animals; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000821:virology; D011818:Rabies / Q000276:immunology / Q000517:prevention & control*; D011819:Rabies Vaccines / Q000008:administration & dosage* / Q000276:immunology; D011820:Rabies virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011995:Recombination, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects*
D011819:Rabies Vaccines; D014409:Tumor Necrosis Factor-alpha