Journal article

Macrophage and neutrophil death programs differentially confer resistance to tuberculosis

Michael Dominic Stutz, Cody Charles Allison, Samar Ojaimi, Simon Peter Preston, Marcel Doerflinger, Philip Arandjelovic, Lachlan Whitehead, Stefanie M Bader, Daniel Batey, Marie-Liesse Asselin-Labat, Marco J Herold, Andreas Strasser, Nicholas P West, Marc Pellegrini

IMMUNITY | CELL PRESS | Published : 2021

Abstract

Apoptosis can potently defend against intracellular pathogens by directly killing microbes and eliminating their replicative niche. However, the reported ability of Mycobacterium tuberculosis to restrict apoptotic pathways in macrophages in vitro has led to apoptosis being dismissed as a host-protective process in tuberculosis despite a lack of in vivo evidence. Here we define crucial in vivo functions of the death receptor-mediated and BCL-2-regulated apoptosis pathways in mediating protection against tuberculosis by eliminating distinct populations of infected macrophages and neutrophils and priming T cell responses. We further show that apoptotic pathways can be targeted therapeutically w..

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Grants

Awarded by National Health and Medical Research Council Australia


Funding Acknowledgements

This work was supported by National Health and Medical Research Council Australia (1147010 to M.P. and N.P.W., 101671 and 1020363 to A.S., GNT1182155 to M.-L.A.-L., 1056282 to S.O., and 1039014 to S.P.), The Sylvia and Charles Viertel Charitable Foundation Senior Medical Research Fellowship (to M.P. and M.-L.A.-L.), The Harry Secomb Trust (M.-L.A.-L.), and 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. We thank V. Dixit and N. Kayagaki (Genentech) for discussions and gasdermin-deficient mouse strains, J. Vince and K. Lawlor for Casp8<SUP>lox/lox</SUP>;Lyz2-Cre mice, B. Kile and S. Chappaz (Monash University) for Bax<SUP>lox/lox</SUP>;Lyz2-Cre;Bak<SUP>-/-</SUP> mice, C. Weeden for technical support, and L. Mackiewicz, M. Hobbs, and M. Dayton for animal care.