Tumorigenic poxviruses up-regulate intracellular superoxide to inhibit apoptosis and promote cell proliferation.
Tumorigenic leporipoxviruses encode catalytically inactive homologs of cellular Cu-Zn superoxide dismutase (SOD1). The function of the orthologous myxoma virus M131R and Shope fibroma virus S131R gene products is uncertain, but they inhibit SOD1 activity by a process linked to binding its copper chaperone. Using a superoxide-sensitive dye (hydroethidine), we observed that virus infection increased intracellular superoxide levels in an M/S131R-dependent manner. To see whether this effect promotes infection, we deleted the Shope fibroma virus S131R gene and compared the clinical manifestations of wild-type and mutant virus infections in rabbits. S131RDelta virus produced significantly smaller fibroxanthosarcoma-like growths in vivo and, at a point where these growths were already receding, wild-type infections still showed extensive leukocyte infiltration, necrosis, and fibromatous cell proliferation. Coincidentally, whereas Jurkat cells are protected from mitochondria- and Fas-mediated apoptosis by wild-type myxoma virus in vitro, M131RDelta virus could not block Fas-initiated apoptosis as judged by DNA laddering, terminal deoxynucleotidyltransferase-mediated dUTP-fluorescein nick end labeling, and caspase 3 cleavage assays. These data suggest that tumorigenic poxviruses can modulate intracellular redox status to their advantage to stimulate infected cell growth and inhibit programmed cell death.
Teoh
Melissa L T
ML
Dept. of Medical Microbiology and Immunology, University of Alberta, 141 Medical Sciences Building, Edmonton, AB T6G 2H7, Canada.
Turner
Patricia V
PV
Evans
David H
DH
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D018152:Leporipoxvirus / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D011213:Poxviridae Infections / Q000821:virology*; D011817:Rabbits; D013482:Superoxide Dismutase / Q000378:metabolism / Q000502:physiology*; D000072105:Superoxide Dismutase-1; D014412:Tumor Virus Infections / Q000821:virology*; D015854:Up-Regulation; D037521:Virulence Factors; D015032:Zinc / Q000378:metabolism
D037521:Virulence Factors; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D015032:Zinc