Differential Induction of Apoptosis and Necrosis in Monocytes from Patients with Tuberculosis and Healthy Control Subjects

Gil, Diana P. Gómez; León, Laura G.; Correa, Lucía I.; Maya, José R.; París, Sara C.; García, Luis F.; Rojas, Mauricio

doi:10.1086/386369

Cited by 51 publications

(43 citation statements)

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“…In the presence of elevated levels of IL-4 (seen in TB patients), this balance is further shifted towards necrotic cell death, which by releasing the bacteria contributes to the progress of the infection, local inflammation and pathology. It is interesting to note that as we would predict, macrophages from TB patients -but not PPD positive donors -are more prone to necrosis rather than apoptosis when exposed to activating stimuli and that TNF-a appears to play a role in this [57]. This is an attractive hypothesis as it explains a number of apparently contradictory results and offers alternate (or possibly complementary) explanations for the effect of both IL-4 and Etanercept on control of TB.…”

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confidence: 76%

“…These experiments allow us to refine the hypothesis a little further: while apoptosis is promoted in active TB (presumably by the host, attempting to clear infected cells) M. tuberculosis is able to survive by specifically inhibiting the sensitivity of monocytic cells to apoptotic cell death -while activated T cells may be removed by activation-induced cell death. Necrotic cell death is augmented by inhibition of proCaspase 8 activation (for example, by elevated expression of FLIP L ), which sensitizes the cells to TNF-a-induced cell deathbut by necrosis rather than apoptosis [57,71,72]. In the presence of elevated levels of IL-4 (seen in TB patients), this balance is further shifted towards necrotic cell death, which by releasing the bacteria contributes to the progress of the infection, local inflammation and pathology.…”

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Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

et al. 2009

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Mycobacterium tuberculosis remains one of the world's deadliest pathogens in part because of its ability to persist in the face of an active immune response. It has been suggested that apoptosis of infected macrophages is one way in which the host deals with intracellular pathogens and that M. tuberculosis can inhibit this process. To assess the relevance of this process for human disease, we compared the expression of multiple genes involved in the activation of the extrinsic (''death receptor initiated'') pathway of apoptosis in 29 tuberculosis patients, 70 tuberculosis contacts and 27 community controls from Ethiopia. We found that there is a strong upregulation of genes for factors that promote apoptosis in PBMC from individuals with active disease, including TNF-a and its receptors, Fas and FasL and proCaspase 8. The anti-apoptotic factor FLIP, however, was also upregulated. A possible explanation for this dichotomy was given by fractionation of PBMC using CD14, which suggests that macrophage/monocytes may regulate several key molecules differently from non-monocytic cells (especially TNF-a and its receptors, a finding confirmed by protein ELISA) potentially reducing the sensitivity to apoptotic death of monocyte/macrophages -the primary host cell for M. tuberculosis. This may represent an important survival strategy for the pathogen. IntroductionDespite vaccination and drug treatment campaigns, tuberculosis (TB) causes an estimated 8-9 million new cases and mortality of 2-3 million deaths annually [1]. The TB epidemic is largely confined to developing countries, and is particularly serious in Sub-Saharan Africa [2], where it is fanned by the HIV epidemic. Despite the high mortality, most infected people do not immediately develop active disease, but become latently infected -though they may later reactivate their disease, if they become immunocompromised [3]. It is thought that perhaps as much as a third of the world's population is latently infected, [4] Eur. J. Immunol. 2010. 40: 291-301 DOI 10.1002 Clinical immunology 291 complicating control efforts by providing a reservoir from which new cases continually arise. Understanding immunity to Mycobacterium tuberculosis, so that more effective vaccines can be developed, is thus an international priority. The response to infection with M. tuberculosis is characterized by a strong inflammatory cell-mediated immune response, with elevated expression of both and . These two cytokines are essential for controlling mycobacterial infections [11][12][13] but in most cases, M. tuberculosis survives to establish a latent infection -which can rapidly reactivate if TNF-a production is blocked [14]. The precise mechanisms involved in this process are still only poorly known. We and others have previously shown that a bias towards IL-4 expression is associated with elevated risk of disease [15] while a bias towards the IL-4 antagonist IL-4d2, or towards IFN-g, is associated with reduced pathology, a better prognosis after infection, recovery after treatment and with ...

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Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

et al. 2009

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“…It is widely known that in alveolar macrophages, apoptosis is a common defence mechanism against M. tuberculosis infection via a TNF-a-mediated pathway (Placido et al, 1997). Monocytes from patients with active TB when compared to those from healthy donors are not only likely to secrete more IL-10 than TNF-a in response to stimulation with PPD, but they are also more likely to undergo necrosis than apoptosis (Gil et al, 2004). Utilizing the slowly progressive primary tuberculosis (SPTB) mouse model, Abebe et al (2006) have demonstrated a 20-fold increase in the expression levels of IL-10 in the lungs of mice with progressive tuberculosis as compared to mice with latent tuberculosis.…”

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confidence: 99%

“…These cytokines are known to play a significant role in the pro-and antiinflammatory components respectively of the immune response to M. tuberculosis infection (Flynn et al, 1995;Gong et al, 1996). Mycobacterial proteins/lipids released from the phagosome of M. tuberculosis-infected macrophages have also been shown to modulate levels of cytokine secretion during infection, to the advantage of the pathogen (Gil et al, 2004;Placido et al, 1997;Rivera-Marrero et al, 2004).…”

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confidence: 99%

Expression, production and release of the Eis protein by Mycobacterium tuberculosis during infection of macrophages and its effect on cytokine secretion

et al. 2007

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The eis gene of Mycobacterium tuberculosis has been shown to play a role in the survival of the avirulent Mycobacterium smegmatis within the macrophage. In vitro and in vivo analysis of Deis deletion mutants and complemented strains showed no effect on survival of M. tuberculosis in U-937 macrophages or in a mouse aerosol infection model, respectively. Further studies were done in an attempt to determine the role of eis in M. tuberculosis intracellular survival and to define a phenotypic difference between wild-type and the Deis deletion mutant. Bioinformatic analysis indicated that Eis is an acetyltransferase of the GCN5-related family of N-acetyltransferases. Immunofluorescence microscopy and Western blot analysis studies demonstrated that Eis is released into the cytoplasm of M. tuberculosis-infected U-937 macrophages. Eis was also found in the extravesicular fraction and culture supernatant of M. tuberculosis-infected macrophages. The effect of Eis on human macrophage cytokine secretion was also examined. Eis modulated the secretion of IL-10 and TNF-a by primary human monocytes in response both to infection with M. tuberculosis and to stimulation with recombinant Eis protein. These results suggest that Eis is a mycobacterial effector that is released into the host cell to modulate inflammatory responses, possibly via transcriptional or post-translational means.

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“…Durante la infección in vitro de monocitos de pacientes con tuberculosis, se observan células necróticas y apoptóticas, mientras que en los monocitos de los individuos sanos, se encuentran esencialmente células apoptóticas (41). Se ha determinado que la apoptosis contribuye al control del crecimiento de M. tuberculosis y la necrosis favorece tanto su supervivencia como su diseminación (42).…”

Section: Alteraciones De La Expresión Y Activación De Las Rab Duranteunclassified

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

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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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Differential Induction of Apoptosis and Necrosis in Monocytes from Patients with Tuberculosis and Healthy Control Subjects

Abstract: Results suggest that apoptosis of monocytes exposed to mycobacteria may partly explain the protective immune response found in PPD-positive control subjects, whereas necrosis may be determinant of the bacterial dissemination and tissue damage that occur in patients with active TB.

Cited by 51 publications

References 44 publications

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

Expression, production and release of the Eis protein by Mycobacterium tuberculosis during infection of macrophages and its effect on cytokine secretion

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

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