Interleukin-12 p40- and Fas ligand-dependent apoptotic pathways involving STAT-1 phosphorylation are triggered during infection with a virulent strain of Toxoplasma gondii.
Toxoplasma gondii is an opportunistic intracellular parasite. Infection with the high-virulence T. gondii strain RH induces inflammatory cytokine overproduction and uncontrolled apoptosis in lymphoid organs. Here, we show by fluorescent terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and binding of fluorescein isothiocyanate-conjugated VAD-FMK, an irreversible pan-caspase inhibitor, that parasite-triggered apoptosis occurs among CD4(+), CD8(+), B220(+), Gr-1(+), and NK1.1(+) splenic populations. Caspases 8 and 9 were activated during infection, implicating cell surface death receptors and mitochondria in apoptosis. Induction of apoptosis was absent among all cell populations in both interleukin-12 (IL-12) p40- and Fas ligand (FasL)-negative mice. STAT-1 phosphorylation correlated with onset of apoptosis during infection, but in the absence of IL-12 p40 and functional FasL, activation of this transcription factor failed to occur. The results demonstrate T. gondii-induced activation of multiple apoptotic pathways, dependent upon both IL-12 p40 and FasL, that may play a role in the lethal pathology of infection.
Gavrilescu
L Cristina
LC
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401, USA.
Denkers
Eric Y
EY
D000818:Animals; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053222:Fas Ligand Protein; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000502:physiology*; D053762:Interleukin-12 Subunit p40; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D021122:Protein Subunits / Q000502:physiology*; D050794:STAT1 Transcription Factor; D014123:Toxoplasmosis / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D053762:Interleukin-12 Subunit p40; D008562:Membrane Glycoproteins; D021122:Protein Subunits; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma