Survival of Virulent <i>Mycobacterium tuberculosis</i> Involves Preventing Apoptosis Induced by Bcl‐2 Upregulation and Release Resulting from Necrosis in J774 Macrophages

Zhang, Jianling; Jiang, Ru; Takayama, Hisao; Tanaka, Yoshinori

doi:10.1111/j.1348-0421.2005.tb03673.x

Cited by 75 publications

(66 citation statements)

References 27 publications

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“…This hypothesis is compatible with the in vitro data already published showing inhibition of apoptosis in infected macrophages by virulent M. tuberculosis (but not avirulent mycobacteria) [27,28,55,[59][60][61][62][63]. It is also consistent with multiple reports suggesting that upregulation of Fas/FasL in vivo is specifically associated with T-cell death in TB [38,[64][65][66][67].…”

Section: Discussionsupporting

confidence: 81%

“…Fortunately, there are two findings that may explain the apparent paradox. It has been suggested that M. tuberculosis can subvert the apoptotic cascade by modulating expression of markers downstream of primary signaling [54,55]. We therefore analyzed expression of a number of apoptosismodulating genes downstream of these markers and in selected cases, also at expression of these genes in CD14…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…Meanwhile, it has been well discussed that infection with virulent M. tuberculosis induces necrosis rather than apoptosis (4-7). Zhang et al (6) reported that a virulent M. tuberculosis strain has the ability to upregulate Bcl-2 expression, which could attenuate the proapoptotic function of Bim. To establish a new clinical anti-M. tuberculosis treatment based on our findings, further examinations are needed that clarify the role of the proapoptotic response observed in this study during virulent M. tuberculosis infection.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mechanism Underlying the Basic Defensive Response of Macrophages against Mycobacterium Infection

Iyoda

Takada

Fukatsu

et al. 2014

The Journal of Immunology

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Following inhalation of Mycobacterium tuberculosis, including bacillus Calmette–Guérin (BCG), pathogens enter and grow inside macrophages by taking advantage of their phagocytic mechanisms. Macrophages often fail to eliminate intracellular M. tuberculosis, leading to the induction of host macrophage death. Despite accumulating evidence, the molecular mechanisms underlying M. tuberculosis infection–induced cell death remain controversial. In this study, we show the involvement of two distinct pathways triggered by TLR2 and β2 integrin in BCG infection–induced macrophage apoptosis. First, BCG infection induced activation of ERK1/2, which in turn caused phosphorylation/activation of the proapoptotic protein Bim in mouse macrophage-like Raw 264.7 cells. BCG-infected Raw cells treated with U0126, an MEK/ERK inhibitor, led to the suppression of Bim phosphorylation alongside a remarkable increase in the number of viable macrophages. Small interfering RNA–mediated knockdown of Bim rescued the macrophages from the apoptotic cell death induced by BCG infection. Stimulation with Pam3CSK, a TLR2 agonist, induced macrophage apoptosis with a concomitant increase in the phosphorylation/activation of MEK/ERK and Bim. These observations indicate the important role of the TLR2/MEK/ERK/Bim pathway in BCG infection–induced macrophage apoptosis. Second, we used the β2 integrin agonists C3bi and fibronectin to show that the β2 integrin–derived signal was involved in BCG infection–induced apoptosis, independent of MEK/ERK activation. Interestingly, latex beads coated with Pam3CSK and C3bi were able to induce apoptosis in macrophages to the same extent and specificity as that induced by BCG. Taken together, two distinct pattern-recognition membrane receptors, TLR2 and β2 integrin, acted as triggers in BCG infection–induced macrophage apoptosis, in which MEK/ERK activation played a crucial role following the engagement of TLR2.

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“…The importance of apoptosis and its manipulation by M.tb becomes increasingly evident [80,81]. Moreover, H37Rv, but not H37Ra, inhibits apoptosis in vitro [82] and causes exacerbated necrosis in Mf in vitro [83]. Apoptosis sensitizer gene BTG1, synergistically enhanced by LPS and IFN-g, has been implicated in activation-induced apoptosis [84].…”

Section: Immunosuppressionmentioning

confidence: 99%

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

Beisiegel¹,

Mollenkopf²,

Hahnke³

et al. 2009

Eur J Immunol

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Progression and outcome of tuberculosis is governed by extensive crosstalk between pathogen and host. Analyses of global changes in gene expression during immune response to infection with Mycobacterium tuberculosis (M.tb) can help identify molecular markers of disease state and progression. Global distribution of M.tb strains with different degrees of virulence and drug resistance, especially for the immunocompromised host, make closer analyses of host responses more pressing than ever. Here, we describe global transcriptional responses of inducible nitric oxide synthase-deficient (iNOS -/-) and WT mice infected with two related M.tb strains of markedly different virulence, namely the M.tb laboratory strains H37Rv and H37Ra. Both hosts exhibited highly similar resistance to infection with H37Ra. In contrast, iNOS -/-mice rapidly succumbed to H37Rv, whereas WT mice developed chronic course of disease. By differential analyses, virulence-specific changes in global host gene expression were analyzed to identify molecular markers characteristic for chronic versus acute infection. We identified several markers unique for different stages of disease progression and not previously associated with virulencespecific host responses in tuberculosis.

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Survival of Virulent Mycobacterium tuberculosis Involves Preventing Apoptosis Induced by Bcl‐2 Upregulation and Release Resulting from Necrosis in J774 Macrophages

Cited by 75 publications

References 27 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

A Novel Mechanism Underlying the Basic Defensive Response of Macrophages against Mycobacterium Infection

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

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