A Caspase-Independent Pathway Mediates Macrophage Cell Death in Response to Mycobacterium tuberculosis Infection
Open accessAbstract
Macrophages can undergo apoptosis after infection with Mycobacterium tuberculosis. This macrophage response deprives the bacillus of its niche cell and supports the host response through better antigen presentation. The intracellular pathways of apoptosis that elaborate this macrophage response are not well understood. To address this issue, we investigated the contribution of various apoptosis pathways to M. tuberculosis-induced macrophage cell death. We found that macrophages die in a caspase-independent manner after infection with M. tuberculosis(at multiplicities of infection ranging from 1 to 20). There was evidence for the involvement of both the mitochondria (cleavage of Bid) and the lysosomes (cathepsin-mediated DNA fragmentation) in this cell death pathway. Dying macrophages displayed several features typical of apoptosis, including DNA fragmentation, nuclear condensation, and exposure of phosphatidylserine on the plasma membrane. However, nuclear fragmentation was not observed, which suggests that M. tuberculosis-induced cell death differs in some respects from classical apoptosis. This novel mechanism of cell death was blocked by serine protease inhibitors. A better understanding of this protective macrophage response may direct new vaccine and treatment options.
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High burden infection with or high intracellular growth rates of virulent M. tuberculosis strains trigger a caspase-independent type of cell death, probably caused by metabolic exhaustion.
“High burden infection with or high intracellular growth rates of virulent M. tuberculosis strains also trigger a caspase-independent type of cell death, probably caused by metabolic exhaustion (126).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [126]
Certain virulent M. tuberculosis strains trigger necrosis by inner mitochondrial membrane rupture.
“Certain virulent M. tuberculosis strains trigger necrosis by inner mitochondrial membrane rupture (124–127).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [126]
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- Authors
- O'Sullivan, M. P., O'Leary, S., Kelly, D. M., & Keane, J.
- Affiliations
- Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, and St. James's Hospital, Dublin, Ireland
- Trinity College Dublin (IE)
- Corresponding author
- Keane, Joseph
- ORCID
- Keane, Joseph
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2007-04
- Volume
- 75
- Issue
- 4
- Pages
- 1984-1993
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC1865710
- OpenAlex
- W2111397679
- Cited by
- 74
- References
- 51
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2022: 1 · 2021: 5 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 6 · 2013: 4 · 2012: 7
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Infection and Immunity (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- Mycobacterium tuberculosis, macrophage cell death, caspase-independent cell death, apoptosis, mitochondria, lysosomes, Bid cleavage, cathepsins, DNA fragmentation, serine protease, tuberculosis infection, host defense
- MeSH terms
- Bacillus, Cathepsins, Cell Line, Cell Survival, Cells, Cultured, Humans, Lysosomes, Macrophages, Mitochondria, Mycobacterium tuberculosis, Phosphatidylserines, Sulfones, Serine Proteinase Inhibitors, Apoptosis, Caspases, BH3 Interacting Domain Death Agonist Protein, DNA Fragmentation
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