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

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 interact...

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Published inImmunity (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
LanguageEnglish
Published United States Elsevier Inc 15.09.2020
Elsevier Limited
Cell Press
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Summary: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. [Display omitted] •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.
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These authors contributed equally
Present address: Menzies Health Institute Queensland, Griffith University, QLD, Australia
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2020.07.004