@article{402197063e014f2ab8c2935ef6bcd081,
title = "Macrophage and neutrophil death programs differentially confer resistance to tuberculosis",
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 with clinical-stage compounds that antagonize inhibitor of apoptosis (IAP) proteins to promote clearance of M. tuberculosis in mice. These findings reveal that any inhibition of apoptosis by M. tuberculosis is incomplete in vivo, advancing our understanding of host-protective responses to tuberculosis (TB) and revealing host pathways that may be targetable for treatment of disease.",
keywords = "IAP antagonist, Mycobacterium tuberculosis, apoptosis, caspase, cell death, macrophages, pyroptosis",
author = "Stutz, {Michael Dominic} and Allison, {Cody Charles} and Samar Ojaimi and Preston, {Simon Peter} and Marcel Doerflinger and Philip Arandjelovic and Lachlan Whitehead and Bader, {Stefanie M.} and Daniel Batey and Asselin-Labat, {Marie Liesse} and Herold, {Marco J.} and Andreas Strasser and West, {Nicholas P.} and Marc Pellegrini",
note = "Funding Information: 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 Casp8lox/lox;Lyz2-Cre mice, B. Kile and S. Chappaz (Monash University) for Baxlox/lox;Lyz2-Cre;Bak−/− mice, C. Weeden for technical support, and L. Mackiewicz, M. Hobbs, and M. Dayton for animal care. Conceptualization, M.D.S. C.C.A. S.O. S.P.P. M.J.H. A.S. and M.P.; investigation, M.D.S. C.C.A. S.O. S.P.P. M.D. P.A. S.M.B. and D.B.; formal analysis, M.D.S. C.C.A. S.O. M.D. and L.W.; resources, A.S. and M.-L.A.-L.; software, L.W.; writing, M.D.S. and M.P.; funding acquisition, M.P. N.P.W. A.S. and M.-L.A.-L.; supervision, M.P. N.P.W. A.S. M.J.H. and M.-L.A.-L. The Walter and Eliza Hall Institute holds a patent on the method of use of IAP inhibitors for the treatment of intracellular infections (WO2014205516), which lists M.P. as an inventor. Funding Information: 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 lox/lox ;Lyz2-Cre mice, B. Kile and S. Chappaz (Monash University) for Bax lox/lox ;Lyz2-Cre;Bak −/− mice, C. Weeden for technical support, and L. Mackiewicz, M. Hobbs, and M. Dayton for animal care. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = aug,
day = "10",
doi = "10.1016/j.immuni.2021.06.009",
language = "English (US)",
volume = "54",
pages = "1758--1771.e7",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "8",
}