Journal article
Necroptotic signaling is primed in Mycobacterium tuberculosis-infected macrophages, but its pathophysiological consequence in disease is restricted
MD Stutz, S Ojaimi, C Allison, S Preston, P Arandjelovic, JM Hildebrand, JJ Sandow, AI Webb, J Silke, WS Alexander, M Pellegrini
Cell Death and Differentiation | NATURE PUBLISHING GROUP | Published : 2018
Abstract
Mixed lineage kinase domain-like (MLKL)-dependent necroptosis is thought to be implicated in the death of mycobacteria-infected macrophages, reportedly allowing escape and dissemination of the microorganism. Given the consequent interest in developing inhibitors of necroptosis to treat Mycobacterium tuberculosis (Mtb) infection, we used human pharmacologic and murine genetic models to definitively establish the pathophysiological role of necroptosis in Mtb infection. We observed that Mtb infection of macrophages remodeled the intracellular signaling landscape by upregulating MLKL, TNFR1, and ZBP1, whilst downregulating cIAP1, thereby establishing a strong pro-necroptotic milieu. However, blo..
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Awarded by National Health and Medical Research Council
Funding Acknowledgements
We thank James Vince, James Murphy and Najoua Lalaoui for discussions, Lachlan Whitehead and the Centre for Dynamic Imaging for assistance with image analysis, Benjamin Kile for supplying Ifnar1<SUP>-/-</SUP> mice, the Australian Red Cross Blood Service for supplying buffy packs and Liana Mackiewicz for technical support. This work was supported by National Health and Medical Research Council Australia (Grants 1006592, 1045549 and 1065626 to MP, 1039014 to SP, 1056282 to SO, 1016647 and 1058344 to WSA, and 1057905 and 1058190 to JS), The Sylvia & Charles Viertel Senior Medical Research Fellowship (M. P.), the Victorian State Government Operational Infrastructure Support and the Independent Research Institutes Infrastructure Support Scheme of the Australian Government National Health and Medical Research Council. The Walter and Eliza Hall Institute of Medical Research have a research license agreement with TetraLogic Pharmaceuticals (Malvern, PA, USA), the manufactures of the cIAP antagonist birinapant. MP and JS provided consultative advice to, and were on the scientific advisory board of, TetraLogic Pharmaceuticals.