Inhibition of caspase activation and a requirement for NF-kappaB function in the Toxoplasma gondii-mediated blockade of host apoptosis.
Mammalian cells infected with the protozoan parasite Toxoplasma gondii are resistant to many apoptotic stimuli transmitted along both the mitochondrial and death receptor pathways. Apoptosis, and its inhibition in infected cells, was examined using multiple morphological, molecular and biochemical approaches. The data strongly indicate manipulation of the host apoptotic machinery at multiple levels, focusing on the inhibition of host caspases. Activation of the pro-apoptotic caspase family of proteases is a biochemical hallmark of apoptosis. Caspase activation occurs in a highly ordered cascade triggered by the initiator caspases 8 and 9, which activate the executioner caspase, caspase 3. Our findings indicate a profound blockade of caspase activation and activity as the molecular basis for the inhibition of apoptosis in T.-gondii-infected cells. Caspase inhibition was demonstrated using multiple intrinsic and synthetic substrates. Although the specific inhibitory molecule remains to be identified, data indicate an absolute requirement for the host transcription factor NF-kappaB and, by extension, genes regulated by it. We propose that T. gondii activates the host survival response, thereby increasing the overall resistance of infected cells to apoptotic stimuli.
Payne
T Matthew
TM
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose St, Lexington, KY 40536, USA.
Molestina
Robert E
RE
Sinai
Anthony P
AP
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D051379:Mice; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D014122:Toxoplasma / Q000378:metabolism*; D014123:Toxoplasmosis / Q000201:enzymology* / Q000473:pathology
D016328:NF-kappa B; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases