Fas/CD95-mediated apoptosis of type II cells is blocked by Toxoplasma gondii primarily via interference with the mitochondrial amplification loop.
The intracellular protozoan Toxoplasma gondii induces persistent infections in various hosts and is an important opportunistic pathogen of humans with immature or deficient immune responses. The ability to survive intracellularly largely depends on the blocking of different proapoptotic signaling cascades of its host cell. Fas/CD95 triggers an apoptotic cascade that is crucial for immunity and the outcome of infectious diseases. We have determined the mechanism by which T. gondii counteracts death receptor-mediated cell death in type II cells that transduce Fas/CD95 ligation via caspase 8-mediated activation of the mitochondrial amplification loop. The results showed that infection with T. gondii significantly reduced Fas/CD95-triggered apoptosis in HeLa cells by inhibiting the activities of initiator caspases 8 and 9 and effector caspase 3/7. Parasitic infection dose dependently diminished cleavage of caspase 8, the BH3-only protein Bid, and the downstream caspases 9 and 3. Importantly, interference with Fas/CD95-triggered caspase 8 and caspase 3/7 activities after parasitic infection was largely dependent on the presence of caspase 9. Within the mitochondrial amplification loop, T. gondii significantly inhibited the Fas/CD95-triggered release of cytochrome c into the host cell cytosol. These results indicate that T. gondii inhibits Fas/CD95-mediated apoptosis in type II cells primarily by decreasing the apoptogenic function of mitochondria.
Hippe
Diana
D
Institute for Medical Microbiology, Georg-August-University, Kreuzbergring 57, 37075 Göttingen, Germany.
Lytovchenko
Oleksandr
O
Schmitz
Ingo
I
Lüder
Carsten G K
CG
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D053470:Caspases, Effector / Q000378:metabolism; D053471:Caspases, Initiator / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D014122:Toxoplasma / Q000472:pathogenicity*; D019014:fas Receptor / Q000378:metabolism*
D061945:Caspase Inhibitors; D019014:fas Receptor; D045304:Cytochromes c; D053453:Caspase 9; D053470:Caspases, Effector; D053471:Caspases, Initiator