Activation of apoptosis, but not necrosis, during Mycobacterium tuberculosis infection correlated with decreased bacterial growth: Role of TNF-α, IL-10, caspases and phospholipase A2

Arcila, Mary Luz; Sánchez, María Dulfary; Ortiz, Blair; Barrera, Luis F.; García, Luis F.; Rojas, Mauricio

doi:10.1016/j.cellimm.2007.11.006

Cited by 62 publications

(47 citation statements)

References 35 publications

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“…There have been reports of mycobacterial infection inducing either apoptosis (35,47,48) or necrosis (20,49,50). The discrepancy could be caused by the use of different bacterial viru- lence strains, cell types, types of infection, or host genetic susceptibility factors (51) or by the type of assay.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterial Secretion Systems ESX-1 and ESX-5 Play Distinct Roles in Host Cell Death and Inflammasome Activation

Abdallah

Bestebroer

Savage

et al. 2011

The Journal of Immunology

129

113

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During infection of humans and animals, pathogenic mycobacteria manipulate the host cell causing severe diseases such as tuberculosis and leprosy. To understand the basis of mycobacterial pathogenicity, it is crucial to identify the molecular virulence mechanisms. In this study, we address the contribution of ESX-1 and ESX-5—two homologous type VII secretion systems of mycobacteria that secrete distinct sets of immune modulators—during the macrophage infection cycle. Using wild-type, ESX-1– and ESX-5–deficient mycobacterial strains, we demonstrate that these secretion systems differentially affect subcellular localization and macrophage cell responses. We show that in contrast to ESX-1, the effector proteins secreted by ESX-5 are not required for the translocation of Mycobacterium tuberculosis or Mycobacterium marinum to the cytosol of host cells. However, the M. marinum ESX-5 mutant does not induce inflammasome activation and IL-1β activation. The ESX-5 system also induces a caspase-independent cell death after translocation has taken place. Importantly, by means of inhibitory agents and small interfering RNA experiments, we reveal that cathepsin B is involved in both the induction of cell death and inflammasome activation upon infection with wild-type mycobacteria. These results reveal distinct roles for two different type VII secretion systems during infection and shed light on how virulent mycobacteria manipulate the host cell in various ways to replicate and spread.

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Section: Discussionmentioning

confidence: 99%

Mycobacterial Secretion Systems ESX-1 and ESX-5 Play Distinct Roles in Host Cell Death and Inflammasome Activation

Abdallah

Bestebroer

Savage

et al. 2011

The Journal of Immunology

129

113

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“…A. actinomycetemcomitans strains 652 and JP2 were cultured under microaerophilic conditions at 37°C in brain heart infusion (Difco) medium supplemented with 40 mg of NaHCO 3 per liter. Due to the similarities between Legionella pneumophila-induced and Mycobacterium tuberculosis-induced apoptosis in cultured U937 cells and primary human monocyte-derived macrophages (4,30), U937 cells were chosen for these studies. The Jurkat T-lymphocyte cell line and the U937 human monocytic cell line were grown in RPMI 1640 medium (Mediatech Cellgro, Herndon, VA) supplemented with 10% bovine growth serum (HyClone, Logan, UT) and 5% penicillin/streptomycin (Sigma, St. Louis, MO) in 5% CO 2 at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitansCytolethal Distending Toxin Induces Apoptosis in Nonproliferating Macrophages by a Phosphatase-Independent Mechanism

2009

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Aggregatibacter actinomycetemcomitans strains that express cytolethal distending toxin (Cdt) are associated with localized aggressive periodontitis. However, the in vivo targets of Cdt in the human oral cavity have not been firmly established. Here, we demonstrate that A. actinomycetemcomitans Cdt kills proliferating and nonproliferating U937 monocytic cells at a comparable specific activity, approximately 1.5-fold lower than that against the Cdt-hypersensitive Jurkat T-cell line. Cdt functioned both as a DNase and a phosphatidylinositol 3-phosphate (PIP 3 ) phosphatase, and these activities were distinguished by site-specific mutagenesis of the active site residues of CdtB. Using these mutants, we determined that the DNase activity of CdtB is required for cell cycle arrest and caspase-dependent induction of apoptosis in proliferating U937 cells. In contrast, Cdt holotoxin induced apoptosis by a mechanism independent of caspase-and apoptosis-inducing factor in nonproliferating U937 cells. Furthermore, apoptosis of nonproliferating U937 cells was unaffected by the Cdt mutant possessing reduced phosphatase activity or by the addition of a specific PIP 3 phosphatase inhibitor, suggesting that the induction of apoptosis is independent of phosphatase activity. These results indicate that Cdt intoxication of proliferating and nonproliferating U937 cells occurs by distinct mechanisms and suggest that macrophages may also be potential in vivo targets of Cdt.

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“…From the 7 genes (CD209B, CILP, SHISA3, TIMD4, PLA2G2D, CPNE4, and MMP3) associated with lethality, the metalloproteinase gene MMP3 was not differentially expressed in response to the VP24 mutant but was almost 50-fold upregulated in response to the double mutant. Among the other genes, CD209B, also known as SIGNR1, encodes a C-type lectin that has been implicated in the humoral immune response to influenza virus infection (25), PLA2G2D encodes phospholipase A2 group IID that has been associated with apoptosis and chemotaxis (1,9), and CPNE4 encodes copine IV, a calciumdependent membrane-binding protein that may regulate events at the interface of cell membrane and cytoplasm (49). Our results suggest that the differential expression of these genes, especially that of the metalloproteinases, which recently have been linked to diverse pathological conditions such as inflammatory disorders and cancer (42,45), is important for severe Ebola virus pathogenicity.…”

Section: Vol 85 2011 Functional Genomics Analysis Of Ebola Virus Inmentioning

confidence: 99%

Functional Genomics Reveals the Induction of Inflammatory Response and Metalloproteinase Gene Expression during Lethal Ebola Virus Infection

Cillóniz

Ebihara

Ni³

et al. 2011

J Virol

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Ebola virus is the etiologic agent of a lethal hemorrhagic fever in humans and nonhuman primates with mortality rates of up to 90%. Previous studies with Zaire Ebola virus (ZEBOV), mouse-adapted virus (MA-ZEBOV), and mutant viruses (ZEBOV-NP ma , ZEBOV-VP24 ma , and ZEBOV-NP/VP24 ma ) allowed us to identify the mutations in viral protein 24 (VP24) and nucleoprotein (NP) responsible for acquisition of high virulence in mice. To elucidate specific molecular signatures associated with lethality, we compared global gene expression profiles in spleen samples from mice infected with these viruses and performed an extensive functional analysis. Our analysis showed that the lethal viruses (MA-ZEBOV and ZEBOV-NP/VP24 ma ) elicited a strong expression of genes 72 h after infection. In addition, we found that although the host transcriptional response to ZEBOV-VP24 ma was nearly the same as that to ZEBOV-NP/VP24 ma , the contribution of a mutation in the NP gene was required for a lethal phenotype. Further analysis indicated that one of the most relevant biological functions differentially regulated by the lethal viruses was the inflammatory response, as was the induction of specific metalloproteinases, which were present in our newly identify functional network that was associated with Ebola virus lethality. Our results suggest that this dysregulated proinflammatory response increased the severity of disease. Consequently, the newly discovered molecular signature could be used as the starting point for the development of new drugs and therapeutics. To our knowledge, this is the first study that clearly defines unique molecular signatures associated with Ebola virus lethality.

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Activation of apoptosis, but not necrosis, during Mycobacterium tuberculosis infection correlated with decreased bacterial growth: Role of TNF-α, IL-10, caspases and phospholipase A2

Cited by 62 publications

References 35 publications

Mycobacterial Secretion Systems ESX-1 and ESX-5 Play Distinct Roles in Host Cell Death and Inflammasome Activation

Mycobacterial Secretion Systems ESX-1 and ESX-5 Play Distinct Roles in Host Cell Death and Inflammasome Activation

Aggregatibacter actinomycetemcomitansCytolethal Distending Toxin Induces Apoptosis in Nonproliferating Macrophages by a Phosphatase-Independent Mechanism

Functional Genomics Reveals the Induction of Inflammatory Response and Metalloproteinase Gene Expression during Lethal Ebola Virus Infection

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