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First published online 9 September 2003
doi: 10.1242/jcs.00756

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Inhibition of caspase activation and a requirement for NF-B function in the Toxoplasma gondii-mediated blockade of host apoptosis

Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose St, Lexington, KY 40536, USA

^* Author for correspondence (e-mail: sinai{at}uky.edu)

Accepted 8 July 2003

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-B 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.

Key words: Toxoplasma gondii, Apoptosis, Caspase, NF-B

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