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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 apoptosis induced by a wide spectrum of proapoptotic stimuli including the kinase inhibitor staurosporine, the DNA-damaging agent etoposide, and several immunological apoptosis-inducing molecules such as tumor necrosis factor-, Fas antibody, and granzyme B/perforin. The antiapoptotic activity was dependent on chlamydial but not host protein synthesis. These observations suggest that chlamydia may encode factors that interrupt many different host cell apoptotic pathways. We found that activation of the downstream caspase 3 and cleavage of poly (ADP-ribose) polymerase were inhibited in chlamydia-infected cells. Mitochondrial cytochrome c release into the cytosol induced by proapoptotic factors was also prevented by chlamydial infection. These observations suggest that chlamydial proteins may interrupt diverse apoptotic pathways by blocking mitochondrial cytochrome c release, a central step proposed to convert the upstream private pathways into an effector apoptotic pathway for amplification of downstream caspases. Thus, we have identified a chlamydial antiapoptosis mechanism(s) that will help define chlamydial pathogenesis and may also provide information about the central mechanisms regulating host cell apoptosis.

This work was supported by the Medical Research Council (MRC) of Canada. G. Zhong is the recipient of an MRC scholarship.

Address correspondence to Guangming Zhong, Department of Medical Microbiology, University of Manitoba, 508-730 William Ave., Winnipeg, Manitoba, Canada R3E OW3. Phone: 204-789-3835; Fax: 204-789-3926; E-mail: gmzhong{at}cc.umanitoba.ca

¹ Abbreviations used in this paper: EB, chlamydial infectious elementary body; ECL, enhanced chemiluminescence; MOI, multiplicity of infection; PARP, poly(ADP-ribose) polymerase; PT, permeability transition; RB, chlamydial noninfectious reticulate body.

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