Flexible Usage and Interconnectivity of Diverse Cell Death Pathways Protect against Intracellular Infection

• Published in: Immunity (Cambridge, Mass.) Vol. 53; no. 3; pp. 533 - 547.e7
• Main Authors: Doerflinger, Marcel, Deng, Yexuan, Whitney, Paul, Salvamoser, Ranja, Engel, Sven, Kueh, Andrew J., Tai, Lin, Bachem, Annabell, Gressier, Elise, Geoghegan, Niall D., Wilcox, Stephen, Rogers, Kelly L., Garnham, Alexandra L., Dengler, Michael A., Bader, Stefanie M., Ebert, Gregor, Pearson, Jaclyn S., De Nardo, Dominic, Wang, Nancy, Yang, Chenying, Pereira, Milton, Bryant, Clare E., Strugnell, Richard A., Vince, James E., Pellegrini, Marc, Strasser, Andreas, Bedoui, Sammy, Herold, Marco J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-09-2020; Elsevier Limited; Cell Press
• Subjects: Animals; Apoptosis; Apoptosis - immunology; Bacteria; Caspase 1 - deficiency; Caspase 1 - genetics; Caspase 12 - deficiency; Caspase 12 - genetics; Caspase 8 - genetics; caspase-1; caspase-11; Caspase-8; Caspases, Initiator - deficiency; Caspases, Initiator - genetics; Cell death; Crosstalk; Defects; Defense; Defense programs; effector caspases; Effectors; Fail safe systems; gasdermin D; Infections; Initiators; Intracellular; Investigations; Kinases; Macrophages; Macrophages - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mortality; Necroptosis; Necroptosis - immunology; Pathogens; Phosphorylation; Protein-serine/threonine kinase; Pyroptosis; Pyroptosis - immunology; Receptor-Interacting Protein Serine-Threonine Kinases - deficiency; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Salmonella; Salmonella - immunology; Salmonella Infections - immunology; Typhoid; pyroptosis; Salmonella; caspase-8; cell death; gasdermin D; apoptosis; caspase-11; effector caspases; caspase-1; necroptosis
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.07.004

Programmed cell death contributes to host defense against pathogens. To investigate the relative importance of pyroptosis, necroptosis, and apoptosis during Salmonella infection, we infected mice and macrophages deficient for diverse combinations of caspases-1, -11, -12, and -8 and receptor interacting serine/threonine kinase 3 (RIPK3). Loss of pyroptosis, caspase-8-driven apoptosis, or necroptosis had minor impact on Salmonella control. However, combined deficiency of these cell death pathways caused loss of bacterial control in mice and their macrophages, demonstrating that host defense can employ varying components of several cell death pathways to limit intracellular infections. This flexible use of distinct cell death pathways involved extensive cross-talk between initiators and effectors of pyroptosis and apoptosis, where initiator caspases-1 and -8 also functioned as executioners when all known effectors of cell death were absent. These findings uncover a highly coordinated and flexible cell death system with in-built fail-safe processes that protect the host from intracellular infections.
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•Mice lacking pyroptosis and apoptosis cannot control Salmonella infection•Macrophages lacking pyroptosis and apoptosis resist Salmonella-induced killing•Caspase-1 kills Salmonella-infected cells by activating GSDMD, BID, or other caspases•Caspase-1 and -8 act as cell death executioners when all cell death effectors are lost
The clearance of intracellular pathogens requires the killing of infected cells, but it remains unclear why host cells have so many different means of inducing programmed cell death. Doerflinger et al. demonstrate that interconnectivity between pyroptosis and apoptosis involving flexible deployment of caspases ensures control of Salmonella infection in mice.