INHIBITION OF APOPTOSIS IN CHLAMYDIA-INFECTED CELLS - BLOCKADE OF MITOCHONDRIAL CYTOCHROME-C RELEASE AND CASPASE ACTIVATION

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 sp ectrum of proapoptotic stimuli including the kinase inhibitor staurosp orine, the DNA-damaging agent etoposide, and several immunological apo ptosis-inducing molecules such as tumor necrosis factor-alpha, Fas ant ibody, and granzyme B/perforin. The antiapoptotic activity was depende nt on chlamydial but not host protein synthesis. These observations su ggest that chlamydia may encode factors that interrupt many different host cell apoptotic pathways. We found that activation of the downstre am caspase 3 and cleavage of poly (ADP-ribose) polymerase were inhibit ed in chlamydia-infected cells. Mitochondrial cytochrome c release int o the cytosol induced by proapoptotic factors was also prevented by ch lamydial infection. These observations suggest that chlamydial protein s may interrupt diverse apoptotic pathways by blocking mitochondrial c ytochrome c release, a central step proposed to convert tile upstream private pathways into an effector apoptotic pathway for amplification of downstream caspases. Thus, we have identified a chlamydial antiapop tosis mechanism(s) that will help define chlamydial pathogenesis and m ay also provide information about the central mechanisms regulating ho st cell apoptosis.