Interferon-γ Regulates the Death of<i>M. tuberculosis-Infected</i>Macrophages

Lee, Jinhee; Kornfeld, Hardy

doi:10.4137/jcd.s2822

Cited by 45 publications

(40 citation statements)

References 37 publications

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“…Our conclusion that macrophage necrosis is induced by a high intracellular burden of H37Rv is consistent with several previous studies [4], [6], [30], [31], [32]. We speculate that although it may be possible to influence specific features of Mtb-induced cell death using inhibitors, as others have done [4], [6], [50], [51], cell death is an inevitable outcome in our infection model at MOI 10.…”

Section: Discussionsupporting

confidence: 93%

Human Macrophages Infected with a High Burden of ESAT-6-Expressing M. tuberculosis Undergo Caspase-1- and Cathepsin B-Independent Necrosis

et al. 2011

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Mycobacterium tuberculosis (Mtb) infects lung macrophages, which instead of killing the pathogen can be manipulated by the bacilli, creating an environment suitable for intracellular replication and spread to adjacent cells. The role of host cell death during Mtb infection is debated because the bacilli have been shown to be both anti-apoptotic, keeping the host cell alive to avoid the antimicrobial effects of apoptosis, and pro-necrotic, killing the host macrophage to allow infection of neighboring cells. Since mycobacteria activate the NLRP3 inflammasome in macrophages, we investigated whether Mtb could induce one of the recently described inflammasome-linked cell death modes pyroptosis and pyronecrosis. These are mediated through caspase-1 and cathepsin-B, respectively. Human monocyte-derived macrophages were infected with virulent (H37Rv) Mtb at a multiplicity of infection (MOI) of 1 or 10. The higher MOI resulted in strongly enhanced release of IL-1β, while a low MOI gave no IL-1β response. The infected macrophages were collected and cell viability in terms of the integrity of DNA, mitochondria and the plasma membrane was determined. We found that infection with H37Rv at MOI 10, but not MOI 1, over two days led to extensive DNA fragmentation, loss of mitochondrial membrane potential, loss of plasma membrane integrity, and HMGB1 release. Although we observed plasma membrane permeabilization and IL-1β release from infected cells, the cell death induced by Mtb was not dependent on caspase-1 or cathepsin B. It was, however, dependent on mycobacterial expression of ESAT-6. We conclude that as virulent Mtb reaches a threshold number of bacilli inside the human macrophage, ESAT-6-dependent necrosis occurs, activating caspase-1 in the process.

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Section: Discussionsupporting

confidence: 93%

Human Macrophages Infected with a High Burden of ESAT-6-Expressing M. tuberculosis Undergo Caspase-1- and Cathepsin B-Independent Necrosis

et al. 2011

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“…Among factors contributing to these dynamics, we note that the survival of macrophages challenged with M. tuberculosis at MOI=1 in vitro is prolonged by IFN-γ activation, which prevents bacilli from growing to a burst size load [13]. We reported that IFN-γ exerts an opposite effect and accelerates necrosis of macrophages with a high intracellular bacillary load (MOI=25) [14]. This could explain the elimination of MPs containing >10 AFB at 24 weeks after infection with H37Ra which has limited or no replicative capacity at that late phase of TB disease and therefore does not continuously drive host cells to high AFB loads.…”

Section: Discussionmentioning

confidence: 99%

Bacillary replication and macrophage necrosis are determinants of neutrophil recruitment in tuberculosis

Repasy

Martínez

Lee

et al. 2015

Microbes and Infection

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We previously determined that burst size necrosis is the chief mode of mononuclear cell death in the lungs of mice with tuberculosis. The present study explored the link between infection-induced necrosis of mononuclear phagocytes and neutrophil accumulation in the lungs of mice challenged with one of four Mycobacterium tuberculosis strains of increasing virulence (RvΔphoPR mutant, H37Ra, H37Rv and Erdman). At all time points studied, Erdman produced the highest bacterial load and the highest proportion and number of M. tuberculosis-infected neutrophils. These parameters, and the proportion of TUNEL-positive cells, tracked with virulence across all strains tested. Differences in neutrophil infection were not reflected by levels of chemoattractant cytokines in bronchoalveolar lavage fluid, while interferon-γ (reported to suppress neutrophil trafficking to the lung in tuberculosis) was highest in Erdman-infected mice. Treating Erdman-infected mice with ethambutol decreased the proportion of mononuclear phagocytes with high bacterial burden and the ratio of infected neutrophils to infected mononuclear cells in a dose-dependent manner. We propose that faster replicating M. tuberculosis strains cause more necrosis which in turn promotes neutrophil recruitment. Neutrophils infected with M. tuberculosis constitute a biomarker for poorly controlled bacterial replication, infection-induced mononuclear cell death, and increased severity of immune pathology in tuberculosis.

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“…Hence, the reduction in IFNγ signaling may profoundly impair the ability of the host to check the replication of invading intracellular bacteria. IFNγ signaling can also rescue macrophages infected with low doses of Mtb from cell death [146], and stimulates hematopoiesis to repopulate depleted lymphocytes and neutrophils in infected tissues [147]. Thus, suppression of IFNγ signaling by type I IFNs could account for an increased presence of dying cells in tissues of infected mice.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of type I and II interferons on myeloid cells and resistance to intracellular bacterial infections

2012

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The type I and II interferons (IFNs) play important roles in regulating immune responses during viral and bacterial infections and in the context of autoimmune and neoplastic diseases. These two IFN types bind to distinct cell surface receptors that are expressed by nearly all cells to trigger signal transduction events and elicit diverse cellular responses. In some cases, type I and II IFNs trigger similar cellular responses while in other cases the IFNs have unique or antagonistic effects on host cells. Negative regulators of IFN signaling also modulate cellular responses to the IFNs and play important roles in maintaining immunological homeostasis. In this review article, we provide an overview of how IFNs stimulate cellular responses. We discuss the disparate effects of type I and II IFNs on host resistance to certain intracellular bacterial infections and provide an overview of models that have been proposed to account for these disparate effects. Mechanisms of antagonistic cross talk between type I and II IFNs are also introduced.

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Interferon-γ Regulates the Death ofM. tuberculosis-InfectedMacrophages

Cited by 45 publications

References 37 publications

Human Macrophages Infected with a High Burden of ESAT-6-Expressing M. tuberculosis Undergo Caspase-1- and Cathepsin B-Independent Necrosis

Human Macrophages Infected with a High Burden of ESAT-6-Expressing M. tuberculosis Undergo Caspase-1- and Cathepsin B-Independent Necrosis

Bacillary replication and macrophage necrosis are determinants of neutrophil recruitment in tuberculosis

Differential effects of type I and II interferons on myeloid cells and resistance to intracellular bacterial infections

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