Inhibition of Ca2+ Signaling by <i>Mycobacterium tuberculosis</i>Is Associated with Reduced Phagosome–Lysosome Fusion and Increased Survival within Human Macrophages

Malik, Zulfiqar Ali; Denning, Gerene M.; Kusner, David J.

doi:10.1084/jem.191.2.287

Cited by 281 publications

(301 citation statements)

References 64 publications

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“…Unless otherwise stated, materials were from previously published sources (14,16,(31)(32)(33)(34). Polyclonal Abs to PLD1 or PLD2 were raised by immunizing rabbits with specific peptides for each protein (four for PLD1, two for PLD2), as previously described (28).…”

Section: Methodsmentioning

confidence: 99%

“…PBMC were isolated and cultured in Teflon wells for 5 days in RPMI 1640 (pH 7.4) with 20% fresh autologous serum as previously described (14,31). Macrophages were purified by adherence to 6-well plastic tissue culture plates or glass chamber slides for 2 h at 37°C in 5% CO 2 .…”

Section: Preparation Of Macrophagesmentioning

confidence: 99%

“…Monolayers were washed three times and then incubated in RPMI 1640 with 2.5% autologous serum, without antibiotics, for use in experiments. Effects of experimental manipulations on macrophage viability were assessed by exclusion of trypan blue, and monolayer density was determined by nuclei counting with naphthol blue-black stain (14,31). Purity and viability of macrophage were Ͼ95% by Wright staining and trypan blue exclusion, respectively.…”

Section: Preparation Of Macrophagesmentioning

confidence: 99%

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Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Barton¹,

Bourgoin²,

Kusner

2004

The Journal of Immunology

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Phagocytosis is a fundamental feature of the innate immune system, required for antimicrobial defense, resolution of inflammation, and tissue remodeling. Furthermore, phagocytosis is coupled to a diverse range of cytotoxic effector mechanisms, including the respiratory burst, secretion of inflammatory mediators and Ag presentation. Phospholipase D (PLD) has been linked to the regulation of phagocytosis and subsequent effector responses, but the identity of the PLD isoform(s) involved and the molecular mechanisms of activation are unknown. We used primary human macrophages and human THP-1 promonocytes to characterize the role of PLD in phagocytosis. Macrophages, THP-1 cells, and other human myelomonocytic cells expressed both PLD1 and PLD2 proteins. Phagocytosis of complement-opsonized zymosan was associated with stimulation of the activity of both PLD1 and PLD2, as demonstrated by a novel immunoprecipitation-in vitro PLD assay. Transfection of dominant-negative PLD1 or PLD2 each inhibited the extent of phagocytosis (by 55–65%), and their combined effects were additive (reduction of 91%). PLD1 and PLD2 exhibited distinct localizations in resting macrophages and those undergoing phagocytosis, and only PLD1 localized to the phagosome membrane. The COS-7 monkey fibroblast cell line, which has been used as a heterologous system for the analysis of receptor-mediated phagocytosis, expressed PLD2 but not PLD1. These data support a model in which macrophage phagocytosis is coordinately regulated by both PLD1 and PLD2, with isoform-specific localization. Human myelomonocytic cell lines accurately model PLD-dependent signal transduction events required for phagocytosis, but the heterologous COS cell system does not.

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Section: Methodsmentioning

confidence: 99%

Section: Preparation Of Macrophagesmentioning

confidence: 99%

Section: Preparation Of Macrophagesmentioning

confidence: 99%

See 1 more Smart Citation

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Barton¹,

Bourgoin²,

Kusner

2004

The Journal of Immunology

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“…M. tuberculosis may be taken up via mannose receptors that fail to trigger killing events. It also inhibits complement-receptor-mediated Ca 2z signalling, which may contribute to the failure of killing mechanisms [141]. Mycobacteria can inhibit acidification of the phagosome [142] and modify intracellular trafficking of vacuoles, so they behave like part of the endosomal recycling compartment, rather than as toxic phagolysosomes [143].…”

Section: Macrophage Function and M Tuberculosismentioning

confidence: 99%

M. tuberculosis: immunology and vaccination

2001

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Tuberculosis is increasing. Current treatment regimens require at least 6 months, because latent or stationary phase organisms are difficult to kill. Such regimens do not achieve full compliance, and "directly observed therapy short course" (DOTS) is having less impact than expected. This worrying situation is aggravated by coinfection with human immunodeficiency virus (HIV), and by the increase in drug-resistant strains.We need new insights that lead to more rapid therapies and immunotherapies, and more reliable vaccines.Recent insights have come from: understanding of the relationship between Mycobacterium tuberculosis and macrophages; the multiple T cell types that recognise mycobacterial peptides, lipids and glycolipids; the critical role of interferon-c (IFNc) and interleukin-12 (IL-12) in human mycobacterial infection revealed by genetically defective children; quantitation of the presence and importance of Th2 lymphocyte activation in human tuberculosis; the role of local conversion of inactive cortisone to active cortisol in the lesions; the recognition that some effective prophylactic vaccines also work as immumotherapeutics whereas others do not. In the longer term the recent sequencing of the M. tuberculosis genome will lead to further advances.In the short term, effective immunotherapy remains the most accessible breakthrough in the management of tuberculosis. The types of practical advance that will result from sequencing the genome are discussed speculatively, but cannot yet be predicted with certainty.

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“…Castaño D, Rojas M que indican que desde los eventos más tempranos de la infección con Mycobacterium tuberculosis hay alteraciones en el tránsito vesicular que pueden ser definitivas en el curso de la infección (1,2). En la primera parte de esta revisión, se resumen algunos aspectos generales del tránsito vesicular para el mejor entendimiento de la segunda parte, en la que se revisan los hallazgos experimentales sobre la modulación de las proteínas Rab durante la infección micobacteriana.…”

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Alteraciones en el reclutamiento y activación de proteínas Rab durante la infección micobacteriana

Castaño

Rojas

2010

biomedica

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En el fagosoma, Mycobacterium spp. altera la activación y reclutamiento de diferentes proteínas "del gen Ras de cerebro de rata", comúnmente conocidas como Rab. En este manuscrito se revisa una serie de reportes que han demostrado que los fagosomas que contienen micobacterias tienen una expresión mayor y sostenida de Rab5, Rab11, Rab14 y Rab22a, y menor o ninguna expresión de Rab7, Rab9 y Rab6. Esto se correlaciona con aumento de la fusión de estos fagosomas con endosomas tempranos y de reciclaje, lo que les permite mantener ciertas características de compartimentos tempranos, permite que las bacterias obtengan acceso a nutrientes y previene la activación de mecanismos contra la micobacteria. La expresión de mutantes constitutivamente activos de las Rab de endosomas tempranos impide la maduración de fagosomas que contienen esferas de látex o micobacterias inactivadas por calor. Mientras que su silenciamiento, mediante ARN de interferencia o mediante dominantes negativos, induce la maduración de fagosomas micobacterianos. Los mecanismos exactos por los que las micobacterias alteran la dinámica de expresión de estas GTPasas, afectando la maduración fagolisosómica, no se han establecido. El problema podría explicarse por defectos en el reclutamiento de las proteínas que interactúan con Rab, como la cinasa-3 del fosfatidilinositol y el antígeno endosómico temprano 1. La identificación de los mecanismos empleados por Mycobacterium spp. para interrumpir el ciclo de activación de las Rab, será esencial para comprender la fisiopatología de la infección micobacteriana y útil como posibles blancos farmacológicos.Palabras clave: tuberculosis, Mycobacterium tuberculosis, proteínas de unión a GTP rab, proteínas SNARE, fagosomas, endosomas. Alterations in recruitment and activation of Rab proteins during mycobacterial infectionAt the phagosome level, Mycobacterium spp. alters activation and recruitment of several "Ras gene from rat brain" proteins, commonly known as Rab. Mycobacterial phagosomes have a greater and sustained expression of Rab5, Rab11, Rab14 and Rab22a, and lowered or no expression of Rab7, Rab9 and Rab6. This correlates with increased fusion of the phagosomes with early and recycling endosomes acquiring some features of early phogosomes, allowing the bacteria to gain access to nutrients and preventing the activation of anti-mycobacterial mechanisms. The expression of constitutively active mutants of Rab from the early stage endosomes prevents the maturation of phagosomes containing latex beads or heat-inactivated mycobacteria. Silencing of these mutants by interference RNA or dominant negative forms induces the maturation of mycobacterial phagosomes. The mechanisms have not been established by which mycobacteria alter the expression of these GTPases and thereby shift the phagolysosomal maturation. The problem can be explained by alterations in the recruitment of proteins that interact with Rab, such as phosphoinositide 3-kinases and early endosomal antigen 1. Identifying the mechanisms used by Mycobacterium sp...

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Inhibition of Ca2+ Signaling by Mycobacterium tuberculosisIs Associated with Reduced Phagosome–Lysosome Fusion and Increased Survival within Human Macrophages

Cited by 281 publications

References 64 publications

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

M. tuberculosis: immunology and vaccination

Alteraciones en el reclutamiento y activación de proteínas Rab durante la infección micobacteriana

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