Inhibition of Apoptosis in Chlamydia-infected Cells: Blockade of Mitochondrial Cytochrome c Release and Caspase Activation

doi:10.1084/jem.187.4.487

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J. Exp. Med., Volume 187, Number 4, February 16, 1998 487-496

Inhibition of Apoptosis in Chlamydia-infected Cells: Blockade of Mitochondrial Cytochrome c Release and Caspase Activation

By Tao Fan,^* Hang Lu,^* He Hu,^* Lianfa Shi,^§ Grant A. McClarty,^* Dwight M. Nance, Arnold H. Greenberg,^§ and Guangming Zhong^*

From the ^* Department of Medical Microbiology, the Department of Pathology, and ^§ Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba R3E OW3 Canada

We report that chlamydiae, which are obligate intracellular bacterial pathogens, possess a novel antiapoptotic mechanism.Chlamydia-infected host cells are profoundly resistant to apoptosisinduced by a wide spectrum of proapoptotic stimuli including thekinase inhibitor staurosporine, the DNA-damaging agent etoposide,and several immunological apoptosis-inducing molecules such astumor necrosis factor- $alpha$ , Fas antibody, and granzyme B/perforin.The antiapoptotic activity was dependent on chlamydial but nothost protein synthesis. These observations suggest that chlamydiamay encode factors that interrupt many different host cell apoptoticpathways. We found that activation of the downstream caspase 3and cleavage of poly (ADP-ribose) polymerase were inhibited inchlamydia-infected cells. Mitochondrial cytochrome c release intothe cytosol induced by proapoptotic factors was also preventedby chlamydial infection. These observations suggest that chlamydialproteins may interrupt diverse apoptotic pathways by blockingmitochondrial cytochrome c release, a central step proposed toconvert the upstream private pathways into an effector apoptoticpathway for amplification of downstream caspases. Thus, we haveidentified a chlamydial antiapoptosis mechanism(s) that will helpdefine chlamydial pathogenesis and may also provide informationabout the central mechanisms regulating host cell apoptosis.

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