Department of Medicine, Division of Infectious Diseases and Immunology
Amino Acids, Peptides, and Proteins | Bacteria | Bacterial Infections and Mycoses | Cell Biology | Cellular and Molecular Physiology | Enzymes and Coenzymes | Immunity | Immunology of Infectious Disease
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.
Salmonella, apoptosis, caspase-1, caspase-11, caspase-8, cell death, effector caspases, gasdermin D, necroptosis, pyroptosis
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Copyright 2020. The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
DOI of Published Version
Doerflinger M, Deng Y, Whitney P, Salvamoser R, Engel S, Kueh AJ, Tai L, Bachem A, Gressier E, Geoghegan ND, Wilcox S, Rogers KL, Garnham AL, Dengler MA, Bader SM, Ebert G, Pearson JS, De Nardo D, Wang N, Yang C, Pereira M, Bryant CE, Strugnell RA, Vince JE, Pellegrini M, Strasser A, Bedoui S, Herold MJ. Flexible Usage and Interconnectivity of Diverse Cell Death Pathways Protect against Intracellular Infection. Immunity. 2020 Sep 15;53(3):533-547.e7. doi: 10.1016/j.immuni.2020.07.004. Epub 2020 Jul 30. PMID: 32735843; PMCID: PMC7500851. Link to article on publisher's site
Doerflinger M, Pereira M, Strasser A, Bedoui S, Herold MJ. (2020). Flexible Usage and Interconnectivity of Diverse Cell Death Pathways Protect against Intracellular Infection. Open Access Articles. https://doi.org/10.1016/j.immuni.2020.07.004. Retrieved from https://escholarship.umassmed.edu/oapubs/4359
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