APOPTOSIS OF MOUSE DENDRITIC CELLS IS TRIGGERED BY LISTERIOLYSIN, THEMAJOR VIRULENCE DETERMINANT OF LISTERIA-MONOCYTOGENES

Infection of a murine-spleen dendritic cell line by Listeria monocytog enes was found to induce cell death through apoptosis. To characterize the bacterial product(s) involved in induction of apoptosis, dendriti c cells were infected with the L. monocytogenes EGD strain and several isogenic mutants deficient in the production of individual listerial virulence factors. The ability to induce cellular apoptosis was retain ed by all mutants tested, except the prfA and Delta hly mutants, both of which are unable to produce listeriolysin. Apoptosis was also induc ed by purified listeriolysin suggesting that this protein directly ind uces apoptosis. Purified recombinant listeriolysins rendered either we akly haemolytic by a C-484 to S mutation, or nonhaemolytic by a W-491 to A mutation exhibited little or no capacity to induce apoptosis, ind icating that both activities are associated within the same protein re gion. Treatment with purified lister iolysin or L. monocytogenes infec tion also triggers apoptosis in explanted bone-marrow dendritic cells. Thus invasion of dendritic cells by L. monocytogenes, which results i n cell death, may play an important role in the pathogenesis of lister ial infections by impairing immune responses, hindering bacterial clea rance and promoting spread of the infection.