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First published online 9 September 2003
doi: 10.1242/jcs.00683

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Journal of Cell Science 116, 4359-4371 (2003)
doi: 10.1242/jcs.00683

Research Article

Activation of NF-{kappa}B by Toxoplasma gondii correlates with increased expression of antiapoptotic genes and localization of phosphorylated I{kappa}B to the parasitophorous vacuole membrane

Robert E. Molestina1, T. Matthew Payne1, Isabelle Coppens2 and Anthony P. Sinai1,*

1 Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY 40536, USA
2 Infectious Diseases Section, Yale University School of Medicine, New Haven, CT 06520, USA

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

Accepted 27 May 2003

Mammalian cells infected with Toxoplasma gondii are resistant to apoptosis induced by a variety of stimuli. We have demonstrated that the host transcription factor NF-{kappa}B plays a pivotal role in the T.-gondii-mediated blockade of apoptosis because inhibition is lost in cells lacking the p65 (RelA) subunit of NF-{kappa}B (p65–/–). In the present study, we examined the effects of T. gondii infection on NF-{kappa}B activation and the expression of genes involved in the apoptotic cascade. Infection of wild-type mouse embryonic fibroblasts (MEFs) with T.-gondii-induced nuclear translocation of the p50 and p65 subunits of NF-{kappa}B as examined by immunoblotting of nuclear extracts, immunofluorescence and electrophoretic mobility shift assays. A comparison of apoptotic gene expression profiles from wild-type and p65–/– MEFs revealed distinct patterns of induction in response to T. gondii infection. In particular, the differences seen in the Bcl-2 and IAP families are consistent with the antiapoptotic responses observed in the resistant wild-type cells compared with the sensitive p65–/– fibroblasts. Consistent with NF-{kappa}B activation, T. gondii infection promoted phosphorylation of the inhibitor I{kappa}B. Interestingly, phosphorylated I{kappa}B was concentrated on the parasitophorous vacuole membrane (PVM), suggesting a parasite-directed event. Results from this study suggest that activation of NF-{kappa}B plays an important role in stimulation of antiapoptotic gene expression by T. gondii. Furthermore, recruitment of phosphorylated I{kappa}B to the PVM implies the presence of intrinsic factor(s) in T. gondii that might be used to manipulate the NF-{kappa}B signaling pathway in the host to elicit a survival response during infection.

Key words: Toxoplasma gondii, Apoptosis, NF-{kappa}B, I{kappa}B, Bcl2, IAP


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