Infectious diseases like typhoid fever, characterized by intracellular bacterial replication, remain a major problem of human health. Every year up to 20 million people worldwide are affected and around 150.000 individuals are killed by this life-threatening disease caused by Salmonella. The killing of infected cells through programmed cell death (i.e. pyroptosis, necroptosis, apoptosis) plays an important role in the host defence against intracellular pathogens. Cell suicide is thought to control pathogen replication by removing the replicative niche and re-exposing the pathogens to extracellular immune effector mechanisms. However, the relative importance of each of these pathways in infection control as well as their regulation and kinetics has not been fully elucidated.
To investigate this, we used two different strategies. We infected host cells with Salmonella mutants with different potential to induce distinct forms of cell death. This approach demonstrated how several bacterial factors such as flagellin or invasive protein A impact host cell death. Additionally, we infected mice and cells lacking individual or multiple cell death initiators to measure bacterial burdens and cell death kinetics. Surprisingly, the loss of pyroptosis, necroptosis or extrinsic apoptosis alone had only minor impacts on Salmonella control, demonstrating that host defence can employ several cell death pathways to limit intracellular infection. However, combined deficiency of these cell death pathways caused loss of bacterial control in mice and macrophages, indicating that killing of infected cells is required for the clearance of intracellular pathogens. Our current work focuses on the exploitation of this system by targeting cellular inhibitors of intrinsic apoptosis with BH3-mimetic compounds inducing host cell death of infected cells. All together, these findings not only uncover a highly coordinated and flexible backup system between several programmed cell death processes that protects the host from intracellular bacterial infections but additionally raises the possibility that BH3-mimetics can be used for Salmonella treatment.