Gavrilescu L Cristina, Denkers Eric Y
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401, USA.
Infect Immun. 2003 May;71(5):2577-83. doi: 10.1128/IAI.71.5.2577-2583.2003.
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.
刚地弓形虫是一种机会性细胞内寄生虫。感染高毒力的刚地弓形虫RH株会诱导淋巴器官中炎性细胞因子过度产生和不受控制的细胞凋亡。在此，我们通过荧光末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记（TUNEL）分析以及异硫氰酸荧光素偶联的VAD-FMK（一种不可逆的泛半胱天冬酶抑制剂）的结合实验表明，寄生虫引发的细胞凋亡发生在CD4(+)、CD8(+)、B220(+)、Gr-1(+)和NK1.1(+)脾细胞群体中。在感染过程中，半胱天冬酶8和9被激活，这表明细胞表面死亡受体和线粒体参与了细胞凋亡。在白细胞介素-12（IL-12）p40和Fas配体（FasL）均阴性的小鼠的所有细胞群体中均未诱导细胞凋亡。STAT-1磷酸化与感染期间细胞凋亡的发生相关，但在缺乏IL-12 p40和功能性FasL的情况下，该转录因子未能被激活。结果表明，刚地弓形虫诱导的多种凋亡途径的激活依赖于IL-12 p40和FasL，这可能在感染的致死性病理过程中起作用。
