Salmonella enterica is a Gram-negative intracellular pathogen, which can cause typhoid fever and non-typhoidal salmonellosis. Every year ~22 million cases and ~200,000 deaths are reported for typhoid fever and ~93 million cases and ~155,000 deaths on non-typhoidal salmonellosis. The dendritic cell (DC) is at the heart of the host-pathogen interactions – a cascade of responses in DCs is crucial for the effective control of Salmonella infection (e.g. through activating antigen-specific T cells), but DCs are also targeted and exploited by a variety of Salmonella mechanisms for dissemination and immune evasion.
Our studies utilise murine bone marrow-derived DCs (BMDCs), which are sensitive to Salmonella-induced cell death within hours of infection. We found that several virulence factors, such as SPI-I and flagellin, were required for maximal death in BMDCs. Intriguingly, BMDCs that were not directly infected with Salmonella were killed upon infection of neighbouring cells in culture. This bystander cell death can be induced by co-culturing with filtered supernatant from infected BMDCs, suggesting a role for contact-independent mechanisms. Infected BMDCs released several cytokines, including IL-6, MCP-1 and TNF-a. However, blockade of intracellular protein transport and secretion of cytokines by monesin did not alter Salmonella-induced cell death in uninfected bystanders, suggesting that the bystander effect is not dependent on mediator released from the infected BMDCs. We also tested BMDCs from mice with gene knockouts in key pathways that are involved in DC immune responses against Salmonella, and observed significantly decreased death in ICE-/- BMDCs, suggesting that caspase-1-mediated pyroptosis could be responsible for direct as well as bystander BMDC death. Ongoing work aims to further elucidate the nature of this early death and long-term survival of DCs during Salmonella infection, which would contribute to treatments providing the host with protection against Salmonella.