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Identification of Virulence Markers of Mycobacterium abscessus for Intracellular Replication in Phagocytes
Published on: September 27, 2018
Mycobacterium tuberculosis replicates within necrotic human macrophages
Thomas R Lerner1, Sophie Borel1, Daniel J Greenwood1
1Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London NW1 1AT, England, UK.
Abstract:
Mycobacterium tuberculosis modulation of macrophage cell death is a well-documented phenomenon, but its role during bacterial replication is less characterized. In this study, we investigate the impact of plasma membrane (PM) integrity on bacterial replication in different functional populations of human primary macrophages. We discovered that IFN-γ enhanced bacterial replication in macrophage colony-stimulating factor-differentiated macrophages more than in granulocyte-macrophage colony-stimulating factor-differentiated macrophages. We show that permissiveness in the different populations of macrophages to bacterial growth is the result of a differential ability to preserve PM integrity. By combining live-cell imaging, correlative light electron microscopy, and single-cell analysis, we found that after infection, a population of macrophages became necrotic, providing a niche for M. tuberculosis replication before escaping into the extracellular milieu. Thus, in addition to bacterial dissemination, necrotic cells provide first a niche for bacterial replication. Our results are relevant to understanding the environment of M. tuberculosis replication in the host.
Insights
Mycobacterium tuberculosis uses necrotic macrophages as a replication niche. Preserving plasma membrane integrity is key to controlling bacterial growth within different macrophage populations, impacting tuberculosis pathogenesis.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Mycobacterium tuberculosis (M. tuberculosis) extensively modulates macrophage cell death pathways.
- The specific role of macrophage cell death in M. tuberculosis replication remains less understood.
Purpose of the Study:
- To investigate how plasma membrane (PM) integrity influences M. tuberculosis replication within distinct human primary macrophage populations.
- To elucidate the mechanisms by which M. tuberculosis exploits macrophage populations for replication.
Main Methods:
- Live-cell imaging
- Correlative light electron microscopy (CLEM)
- Single-cell analysis
- Differentiation of human primary macrophages using M-CSF and GM-CSF
Main Results:
- IFN-γ significantly enhanced M. tuberculosis replication in M-CSF-differentiated macrophages compared to GM-CSF-differentiated macrophages.
- Macrophage permissiveness to M. tuberculosis growth correlates with their ability to maintain plasma membrane integrity.
- Necrotic macrophages serve as an initial niche for M. tuberculosis replication before extracellular dissemination.
Conclusions:
- Plasma membrane integrity is a critical factor determining macrophage permissiveness to M. tuberculosis.
- M. tuberculosis utilizes necrotic macrophages as a replication niche, contributing to bacterial dissemination.
- Understanding these host-pathogen interactions is vital for tuberculosis research.
