Journal article

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

Marcel Doerflinger, Yexuan Deng, Paul Whitney, Ranja Salvamoser, Sven Engel, Andrew J Kueh, Lin Tai, Annabell Bachem, Elise Gressier, Niall D Geoghegan, Stephen Wilcox, Kelly L Rogers, Alexandra L Garnham, Michael A Dengler, Stefanie M Bader, Gregor Ebert, Jaclyn S Pearson, Dominic De Nardo, Nancy Wang, Chenying Yang Show all

IMMUNITY | CELL PRESS | Published : 2020

Abstract

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 fle..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by Leukemia and Lymphoma Society of America


Awarded by Cancer Council of Victoria


Awarded by Wellcome Trust


Awarded by German Research Council


Awarded by Australian Government Independent Research Institute Infrastructure Support Scheme


Funding Acknowledgements

We thank M. Patsis and G. Siciliano for expert animal care, B. Helbert and K. Mackwell for genotyping, S. Monard and his team for help with flow cytometry, V. Dixit and N. Kayagaki for insightful discussions, and all the members of the Herold, Strasser, and Bedoui laboratories. We thank Gordon Dougan (University of Cambridge) for the SL1344 GFP-expressing Salmonella strain. This work was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC) (project grants 1186575 and 1145728 to M.J.H., 1143105 to M.J.H. and A.S., 1159658 to M.J.H. and S.B., and 1016701 to A.S.; and fellowships 1020363 to A.S. and 1156095 to M.J.H.), the Leukemia and Lymphoma Society of America (LLS SCOR 700113 to A.S. and M.J.H.), the Cancer Council of Victoria (project grants 1147328 to M.J.H. and 1052309 to A.S., and a venture grant to M.J.H. and A.S.), the Australian Phenomics Network (to M.J.H. and A.J.K.), the Cass Foundation (to M.D.), the Wellcome Trust (investigator award 108045/Z/15/Z to C.E.B.), and the German Research Council (GRK2168 to S.E. and S.B.), as well as by operational infrastructure grants through the AustrYalian Government Independent Research Institute Infrastructure Support Scheme (361646 and 9000220) and the Victorian State Government Operational Infrastructure Support Program. The graphical abstract was created with the help of BioRender.com.