Macrophage and neutrophil death programs differentially confer resistance to tuberculosis
- Author(s)
- Stutz, MD; Allison, CC; Ojaimi, S; Preston, SP; Doerflinger, M; Arandjelovic, P; Whitehead, L; Bader, SM; Batey, D; Asselin-Labat, ML; Herold, MJ; Strasser, A; West, NP; Pellegrini, M;
- Journal Title
- Immunity
- Publication Type
- epub ahead of print
- 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.
- Publisher
- Cell Press
- Keywords
- IAP antagonist; Mycobacterium tuberculosis; apoptosis; caspase; cell death; macrophages; pyroptosis; method of use of IAP inhibitors for the treatment of intracellular infections
- Research Division(s)
- Infectious Diseases And Immune Defence; Advanced Technology And Biology; Blood Cells And Blood Cancer; Personalised Oncology
- PubMed ID
- 34256013
- Publisher's Version
- https://doi.org/10.1016/j.immuni.2021.06.009
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-07-20 11:18:15
Last Modified: 2021-07-20 02:20:43