Salmonella-induced caspase-2 activation in macrophages: A novel mechanism in pathogen-mediated apoptosis

The enterobacterial pathogen Salmonella induces phagocyte apoptosis in vitr o and in vivo. These bacteria use a specialized type III secretion system t o export a virulence factor, SipB, which directly activates the host's apop totic machinery by targeting caspase-1. Caspase-1 is not involved in most a poptotic processes but plays a major role in cytokine maturation. We show t hat caspase-1-deficient macrophages undergo apoptosis within 4-6 h of infec tion with invasive bacteria. This process requires SipB, implying that this protein can initiate the apoptotic machinery by regulating components dist inct from caspase-1. Invasive Salmonella typhimurium targets caspase-2 simu ltaneously with, but independently of, caspase-1. Besides caspase-2, the ca spase-1-independent pathway involves the activation of caspase-3, -6, and - 8 and the release of cytochrome c from mitochondria, none of a which occurs during caspase-1-dependent apoptosis. By using caspase-2 knockout macropha ges and chemical inhibition, we establish a role for caspase-2 in both casp ase-1-dependent and -independent apoptosis. Particularly, activation of cas pase-1 during fast Salmonella-induced apoptosis partially relies on caspase -2. The ability of Salmonella to induce caspase-1-independent macrophage ap optosis may play a role in situations in which activation of this protease is either prevented or uncoupled from the induction of apoptosis.