Effect of administration of a recombinant adenovirus expressing the genes for IFN-gamma and interleukin-12 on acute murine toxoplasmosis.
The effect of recombinant murine interferon-gamma (rMuIFN-gamma) produced from an adenovirus construct on Toxoplasma gondii in tissue culture and on the outcome of a T. gondii infection in mice was determined. Supernatants from AdCMVMuIFN-gamma-infected mouse lung epithelial (MuLE) cells were evaluated for the ability to produce biologically active IFN-gamma by measuring the capacity of the supernatants to activate peritoneal macrophages for killing of T. gondii. The bioactivity of IFN-gamma in supernatants increased with increasing multiplicity of infection (moi). Replication was inhibited 43%, 67%, and 70% by supernatants from MuLE cells infected with AdCMVMuIFN-gamma moi 5, 10, and 50, respectively, (p < 0.01 compared with controls). Bioactivity of IFN-gamma also increased as the length of time after infection increased. T. gondii replication was inhibited 28% and 36%, respectively, by AdCMVMuIFN-gamma-infected MuLE cell supernatants recovered at 24 and 48 h (p < 0.01 compared with control). In vivo administration of AdCMVMuIFN-gamma exhibited 33% mortality by day 9 in mice acutely infected with T. gondii compared with 100% mortality in control mice (p = 0.045). Administration of AdCMVIL-12 reduced mortality to 40% compared with control mice. However, this reduction was not significant (p = 0.08). Overall survival was extended 2 days with AdCMVMuINF-gamma administration and 5 days with AdCMVIL-12. AdCMVMuIFN-gamma in vitro inhibits T. gondii, and in vivo AdCMVMuIFN-gamma and AdCMVIL-12 lead to increased survival in mice.
Mack
D G
DG
Department of Ophthalmology, University of Chicago, Chicago, IL 60637, USA. dmack@midway.uchicago.edu
Jaffe
H A
HA
D000208:Acute Disease; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004274:DNA, Recombinant / Q000008:administration & dosage; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D015316:Genetic Therapy; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D051379:Mice; D020545:Respiratory Mucosa / Q000276:immunology / Q000821:virology; D016019:Survival Analysis; D014122:Toxoplasma / Q000187:drug effects / Q000254:growth & development; D014124:Toxoplasmosis, Animal / Q000276:immunology / Q000628:therapy*; D014158:Transcription, Genetic
D017077:Culture Media, Conditioned; D004274:DNA, Recombinant; D004279:DNA, Viral; D018664:Interleukin-12; D007371:Interferon-gamma