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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1758-1771.e7
JournalImmunity
Volume54
Issue number8
DOIs
StatePublished - Aug 10 2021
Externally publishedYes

Keywords

  • IAP antagonist
  • Mycobacterium tuberculosis
  • apoptosis
  • caspase
  • cell death
  • macrophages
  • pyroptosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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