Induction of macrophage apoptosis by Salmonella thypimiurium: Mechanisms of activation and in vivo role of caspase-1

Salmonellosis is one of the emerging bacterial diseases, and the number of cases has been increasing steadily in the past few years. For Salmonella, as well as for many other facultative intracellular pathogens, the key to a successful infection lies in the outcome of their encounter with the host`s macrophages. Recently, the induction of apoptosis by Salmonella in macrophages has been documented in several laboratories, including our own. The apoptotic process induced by the pathogen is the fastest ever reported, and requires caspase-1, a protease implicated in the production and maturation of inflammatory cytokines. We intend to focus on three aspects of pathogen-mediated apoptosis: the mechanisms underlying caspase-1 activation in the eukaryotic cells; the identification of the apoptosis-inducing factor from Salmonella; and the role of caspase-1 in the establishment of the infection in vivo. The proposed experiments should help in learning fundamental aspects of host-pathogen interactions, and lead to a better understanding of the role of apoptosis induction and inflammation in an in vivo model of salmonellosis.