A heritable defect in IL-12 signaling in B10.Q/J mice. II. Effect on acute resistance to Toxoplasma gondii and rescue by IL-18 treatment.
This study documents a defect in IL-12-dependent IFN-gamma responses in a substrain (B10.Q-H2-(q)/SgJ) of B10.Q mice that manifests as an acute susceptibility to infection by the intracellular protozoan pathogen, Toxoplasma gondii. Despite robust systemic production of IL-12, infected B10.Q/J animals fail to mount an early IFN-gamma response after parasite inoculation. Genetic experiments revealed that the host resistance and IFN-gamma production defects are determined by a single autosomal recessive locus distinct from the Stat4 gene. Nonetheless, a delayed IL-12-mediated IFN-gamma response emerges in later stages of acute infection but is unable to prevent host mortality. IL-18 administration restores, in an IL-12-dependent manner, the early IFN-gamma response and host resistance of B10.Q/J animals. These in vivo studies indicate that the partially impaired IL-12 responsiveness in B10.Q/J mice can result in defective host resistance and demonstrate a therapeutic function for IL-18 in reversing a genetically based immunodeficiency in IL-12-dependent IFN-gamma production.
Yap
G S
GS
Laboratories of. Parasitic Diseases and Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Ortmann
R
R
Shevach
E
E
Sher
A
A
D000208:Acute Disease; D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D020382:Interleukin-18 / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL / Q000235:genetics*; D018345:Mice, Knockout; D019655:Quantitative Trait, Heritable; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D015534:Trans-Activators / Q000235:genetics
D004268:DNA-Binding Proteins; D020382:Interleukin-18; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma