A BACTERIAL INVASIN INDUCES MACROPHAGE APOPTOSIS BY BINDING DIRECTLY TO ICE

Shigella, the etiological agent of dysentery, kills macrophages by ind ucing apoptosis. Deletion mutants in the invasion plasmid antigen B (i paB) of Shigella flexneri are not cytotoxic. Here, we localized IpaB t o the cytoplasm of macrophages infected with S.flexneri. Purified IpaB induced apoptosis when microinjected into macrophages, indicating tha t IpaB is sufficient to induce apoptosis. Using a GST-IpaB fusion prot ein as a ligand in affinity purification, we isolated four IpaB bindin g proteins from macrophages which were identified as the precursor and the mature polypeptides of interleukin-1 beta converting enzyme (ICE) or a highly homologous protease. We found that IpaB binds directly to ICE and this enzyme is activated during S.flexneri infection. Further more, specific inhibitors of ICE prevented Shigella-induced apoptosis.