Mycobacterium tuberculosis replicates within necrotic human macrophages

• DOI: 10.1083/jcb.201603040
• Publication Date: 2017-02-28T15:12:34Z
• Authors: Thomas R. Lerner; Sophie Borel; Daniel J. Greenwood; Urska Repnik; Matthew R.G. Russell; Susanne Herbst; Martin L. Jones; Lucy M. Collinson; Gareth Griffiths; Maximiliano G. Gu...
• Keywords: DNA Replication; 0303 health sciences; Cell Death; Macrophage Colony-Stimulating Factor; Macrophages; Granulocyte-Macrophage Colony-Stimulating Factor; Cell Differentiation; Mycobacterium tuberculosis; 3. Good health; Interferon-gamma; Necrosis; 03 medical and health sciences; Leukocytes, Mononuclear; Humans; Single-Cell Analysis; Research Articles; Cells, Cultured

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.