Toxoplasma gondii inhibits ultraviolet light-induced apoptosis through multiple interactions with the mitochondrion-dependent programmed cell death pathway

Abstract

SummaryCells infected with the protozoan parasite Toxoplasma gondii are resistant to diverse apoptotic stimuli. In this study, we perform a detailed analysis of the manipulation of the mitochondrial arm of the apoptotic cascade by the parasite. Apoptosis was induced using irradiation with ultraviolet light (UV), and the kinetics of caspase activation, cytochrome c release and activation of the upstream signalling pathways were examined. The evidence clearly points to T. gondii targeting multiple steps in the transmission [inhibition of c-Jun N-terminal kinase (JNK) activation in response to UV], triggering (inhibition of cytochrome c release by affecting the balance of pro-and antiapoptotic BCL-2 family members) and execution (inhibition of caspase 9 and caspase 3) phases of the apoptotic cascade. Interestingly, the multilevel pattern of inhibition that emerges suggests that the global inhibition of the mitochondrial arm of apoptosis is not likely to be contributed to by the small subset of mitochondria recruited to the T. gondii parasitophorous vacuole membrane.

Coxiella burnetii modulates Beclin 1 and Bcl-2, preventing host cell apoptosis to generate a persistent bacterial infection

“…For example, Chlamydia trachomatis and Toxoplasma gondii are known to possess anti-apoptotic activity. 40,41 Recently, it has been shown that a substrate (SidF) of the Dot/Icm T4SS is involved in preventing apoptosis in infected cells with Legionella pneumophila. Apparently, SidF would abolish the activities of two proapoptotic proteins members of the Bcl-2 family: BNIP3 and Bcl-rambo.…”

Host cell manipulation by the human pathogen Toxoplasma gondii

“…However, only a small subset of the host's mitochondria is associated with the PVM, an observation that is inconsistent with the global blockage of the mitochondrial pathway [97]. Also, products secreted by the parasite appear to be capable of limiting the activation of the executioner caspases 3 and 7, implying that rhoptry or dense proteins may be involved [98].…”

“…Activated caspase 9 cleaves caspase 3 leading to disassembly of the cell. T. gondii infected cells show only a small release of cytochrome c after induction of apoptosis via the mitochondrial pathway, thus dampening activation of caspases 9 in the apoptosome and subsequently precluding activation of caspase 3 ( Figure 2) [97,98]. However, it appears the parasite also independently targets caspases 3, since this enzyme remains in its inactive, zymogen form even in the presence of granzyme proteases that normally activate it upon delivery by cytotoxic T and natural killer cells [86].…”

“…Nonetheless, this weak release of cytochrome c persists in cells infected with T. gondii, suggesting additional parasite manipulation to restrain apoptosis. Indeed, infection by T. gondii induces the expression of anti-apoptotic members Bcl2, Bfl1, Bcl-Xl, Bcl-w, Mcl-1, and proteins involved in the degradation of the pro-apoptotic factors Bad and Bax (more on this below) [87,97,99]. Also, T. gondii infected HeLa cells with damaged DNA do not exhibit high levels of phosphorylated C-Jun N-terminal kinase (JNK), which is essential for the transmission of the apoptotic signal via the mitochondria arm [97].…”

“…Indeed, infection by T. gondii induces the expression of anti-apoptotic members Bcl2, Bfl1, Bcl-Xl, Bcl-w, Mcl-1, and proteins involved in the degradation of the pro-apoptotic factors Bad and Bax (more on this below) [87,97,99]. Also, T. gondii infected HeLa cells with damaged DNA do not exhibit high levels of phosphorylated C-Jun N-terminal kinase (JNK), which is essential for the transmission of the apoptotic signal via the mitochondria arm [97]. Thus Toxoplasma modulates the expression or activation of several key apoptosis regulators as a means of limiting apoptosis at multiple levels.…”