ATP-Mediated Killing of<i>Mycobacterium bovis</i>Bacille Calmette-Guérin Within Human Macrophages Is Calcium Dependent and Associated with the Acidification of Mycobacteria-Containing Phagosomes

Stober, Carmel B.; Lammas, David A.; Li, Cheuk M.; Kumararatne, D. S.; Lightman, Stafford L.; McArdle, Craig A.

doi:10.4049/jimmunol.166.10.6276

Cited by 74 publications

(73 citation statements)

References 56 publications

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“…Note added in proof. During revision of this manuscript, Lammas and colleagues (8) reported, in contrast to their earlier findings, that ATP-induced killing of BCG is Ca 2ϩ dependent and is associated with phagosomal acidification (46).…”

Section: Discussionmentioning

confidence: 48%

ATP Stimulates Human Macrophages to Kill Intracellular Virulent Mycobacterium tuberculosis Via Calcium-Dependent Phagosome-Lysosome Fusion

Kusner

Barton²

2001

The Journal of Immunology

140

114

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Advances in therapy for tuberculosis will require greater understanding of the molecular mechanisms of pathogenesis and the human immune response in this disease. Exposure of Mycobacterium tuberculosis-infected human macrophages to extracellular ATP (ATPe) results in bacterial killing, but the molecular mechanisms remain incompletely characterized. In this study, we demonstrate that ATPe-induced bactericidal activity toward virulent M. tuberculosis requires an increase in cytosolic Ca2+ in infected macrophages. Based on our previous work with primary infection of human macrophages, we hypothesized that the Ca2+ dependence of ATP-induced killing of intracellular M. tuberculosis was linked to promotion of phagosome-lysosome fusion. Using confocal laser-scanning microscopy, we demonstrate that ATPe induces fusion of the M. tuberculosis-containing phagosome with lysosomes, defined by accumulation of three lysosomal proteins and an acidophilic dye. Stimulation of phagosome-lysosome fusion by ATPe exhibited distinct requirements for both Ca2+ and phospholipase D and was highly correlated with killing of intracellular bacilli. Thus, key signal transduction pathways are conserved between two distinct models of human macrophage antituberculous activity: primary infection of naive macrophages and physiologic stimulation of macrophages stably infected with M. tuberculosis.

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Section: Discussionmentioning

confidence: 48%

ATP Stimulates Human Macrophages to Kill Intracellular Virulent Mycobacterium tuberculosis Via Calcium-Dependent Phagosome-Lysosome Fusion

Kusner

Barton²

2001

The Journal of Immunology

140

114

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“…Taken together, these findings indicate the possible involvement of an additional purinergic receptor that may contribute to the loss of bacterial viability seen in ATP-treated cells. We have provisionally characterized this additional purine receptor as P2Y 11 (35).…”

Section: Discussionmentioning

confidence: 99%

ATP-Mediated Killing of Intracellular Mycobacteria by Macrophages Is a P2X7-Dependent Process Inducing Bacterial Death by Phagosome-Lysosome Fusion

Fairbairn

Stober

Kumararatne

et al. 2001

The Journal of Immunology

Self Cite

218

181

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Mycobacterium tuberculosis survives within host macrophages by actively inhibiting phagosome fusion with lysosomes. Treatment of infected macrophages with ATP induces both cell apoptosis and rapid killing of intracellular mycobacteria. The following studies were undertaken to characterize the effector pathway(s) involved. Macrophages were obtained from p47phox and inducible NO synthase gene-disrupted mice (which are unable to produce reactive oxygen and nitrogen radicals, respectively) and P2X7 gene-disrupted mice. RAW murine macrophages transfected with either the natural resistance-associated macrophage protein gene 1 (Nramp1)-resistant or Nramp1-susceptible gene were also used. The cells were infected with bacille Calmette-Guérin (BCG), and intracellular mycobacterial trafficking was analyzed using confocal and electron microscopy. P2X7 receptor activation was essential for effective ATP-induced mycobacterial killing, as its bactericidal activity was radically diminished in P2X7−/− macrophages. ATP-mediated killing of BCG within p47phox−/−, inducible NO synthase−/−, and Nramps cells was unaffected, demonstrating that none of these mechanisms have a role in the ATP/P2X7 effector pathway. Following ATP stimulation, BCG-containing phagosomes rapidly coalesce and fuse with lysosomes. Blocking of macrophage phospholipase D activity with butan-1-ol blocked BCG killing, but not macrophage death. ATP stimulates phagosome-lysosome fusion with concomitant mycobacterial death via P2X7 receptor activation. Macrophage death and mycobacterial killing induced by the ATP/P2X7 signaling pathway can be uncoupled, and diverge proximal to phospholipase D activation.

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“…Peritoneal macrophages typically express mRNA for P2Y1, P2Y2, P2Y6 and possibly P2Y4 as well as P2X1, P2X4 and P2X7 receptors (120)(121)(122). P2X7 activation is associated with Interleukin-1 secretion and killing of Mycobacteria, Chlamydia and fungi in monocyte-macrophages (52,(123)(124)(125)(126)(127)(128). Polymorphisms of P2X7 have been associated with decreased killing of Mycobacteria (129)(130)(131).…”

Section: 551purinergic Receptorsmentioning

confidence: 99%

“…P2X4 and P2X7 receptors (120-122). P2X7 activation is associated with Interleukin-1 secretion and killing of Mycobacteria, Chlamydia and fungi in monocyte-macrophages (52,(123)(124)(125)(126)(127)(128) …”

mentioning

confidence: 99%

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Beldi

Enjyoji²,

Wu³

et al. 2008

Front Biosci

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Extracellular nucleotides (e.g. ATP, UTP, ADP) are released by activated endothelium, leukocytes and platelets within the injured vasculature and bind specific cell-surface type-2 purinergic (P2) receptors. This process drives vascular inflammation and thrombosis within grafted organs. Importantly, there are also vascular ectonucleotidases i.e. ectoenzymes that hydrolyze extracellular nucleotides in the blood to generate nucleosides (viz. adenosine). Endothelial cell NTPDase1/ CD39 has been shown to critically modulate levels of circulating nucleotides. This process tends to limit the activation of platelet and leukocyte expressed P2 receptors and also generates adenosine to reverse inflammatory events. This vascular protective CD39 activity is rapidly inhibited by oxidative reactions, such as is observed with liver ischemia reperfusion injury. In this review, we chiefly address the impact of these signaling cascades following liver transplantation. Interestingly, the hepatic vasculature, hepatocytes and all non-parenchymal cell types express several components co-ordinating the purinergic signaling response. With hepatic and vascular dysfunction, we note heightened P2-expression and alterations in ectonucleotidase expression and function that may predispose to progression of disease. In addition to documented impacts upon the vasculature during engraftment, extracellular nucleotides also have direct influences upon liver function and bile flow (both under physiological and pathological states). We have recently shown that alterations in purinergic signaling mediated by altered CD39 expression have major impacts NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2010 June 25. Published in final edited form as:Front Biosci. ; 13: 2588-2603. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses. Future clinical applications in transplantation might involve new therapeutic modalities using soluble recombinant forms of CD39, altering expression of this ectonucleotidase by drugs and/or using small molecules to inhibit deleterious P2-mediated signaling while augmenting beneficial adenosine-mediated effects within the transplanted liver. KeywordsTransplantation; Liver; Purinergic Receptors; Bile; CD39; ecto-ATPase; Endothelium; Immunology; Metabolism; NTPDase; Platelet; Vasculature; Review INTRODUCTIONPurinergic signaling comprises release of extracellular nucleotides, stimulation of purinergic receptors and the modulation of nucleotide levels by ectoenzymes. Over the past decade, many advances have been made in the study of purinergic receptors and the regulation of extracellular nucleotide concentrations (1). It is now generally accepted that extracellular nucleotides (e.g. ATP, UTP, ADP), and the derivative nucleosides (e.g. adenosine from ATP), are released in a regulated manner by cells to provide the primary components for purinergic responses (2). Specific nucleo...

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ATP-Mediated Killing ofMycobacterium bovisBacille Calmette-Guérin Within Human Macrophages Is Calcium Dependent and Associated with the Acidification of Mycobacteria-Containing Phagosomes

Cited by 74 publications

References 56 publications

ATP Stimulates Human Macrophages to Kill Intracellular Virulent Mycobacterium tuberculosis Via Calcium-Dependent Phagosome-Lysosome Fusion

ATP Stimulates Human Macrophages to Kill Intracellular Virulent Mycobacterium tuberculosis Via Calcium-Dependent Phagosome-Lysosome Fusion

ATP-Mediated Killing of Intracellular Mycobacteria by Macrophages Is a P2X7-Dependent Process Inducing Bacterial Death by Phagosome-Lysosome Fusion

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

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